Bioavailability and metabolism of isosorbide dinitrate from a transdermal spray. The plasma pharmacokinetics of isosorbide dinitrate (ISDN), isosorbide-2-nitrate (IS-2-N) and isosorbide-5-nitrate (IS-5-N) were investigated in 12 healthy volunteers after a single cutaneous administration of 60 mg ISDN (CAS 87-33-2) in the form of a solution sprayed onto the skin (TD Spray Iso Mack), in comparison with an intravenous infusion of 5 mg ISDN. After the intravenous dose, the apparent steady state volume of ISDN distribution came to 179.9 l, total body clearance was 3.14 l min-1, and terminal half-life was 79 min, on average. The transdermal absorption resulted in an average peak plasma concentration of 6.9 ng ISDN ml-1 at 5 h after the administration. ISDN concentrations between 1 and 5 ng ml-1 were maintained over at least 15 h. On average, 16.5% of the topically applied ISDN reached the systemic circulation. Total variations in Cmax (CV = 47.9%) and AUC (CV = 36.0%) of transdermal ISDN were similar to those usually observed after oral ISDN.


Pharmacological studies of the new antiinflammatory agent 3-formylamino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-o ne. 1st communication: antiinflammatory, analgesic and other related properties. The antiinflammatory, analgesic and antipyretic activities of 3-formylamino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-on e (T-614, CAS 123663-49-0) were investigated in various animal models and compared with those of nimesulide, indomethacin and ibuprofen. The antiinflammatory potency of T-614 on carrageenin-induced paw edema, paper disk granuloma and established adjuvant arthritis was greater than that of ibuprofen, but slightly lower than those of nimesulide and indomethacin. In acute inflammatory models, unlike indomethacin, T-614 suppressed the edemas provoked by dextran and bromelain in rats, but its inhibitory action on ultraviolet erythema in guinea-pigs was weak. Although the analgesic activity of T-614 was hardly demonstrated in writhing tests in mice, its potency against the inflammatory pain such as Randall-Selitto test, adjuvant-induced hyperalgesia and antigen-induced arthritic pain in rats was superior to that of ibuprofen. Moreover, it had a potent analgesic effect on urate-induced synovitis in dogs. T-614 exerted a prompt and strong antipyretic effect in both yeast-induced febrile rats and lipopolysaccharide-induced febrile rabbits. T-614 had virtually no gastrointestinal ulcerogenic action and did not affect water and sodium excretion in rats. T-614 is a novel antiinflammatory compound with different pharmacological properties from that of the reference drugs.


Pharmacokinetic study of tolmetin in the rat. The pharmacokinetics of tolmetin (CAS 26171-23-3) was studied in male Wistar rats after intravenous and oral administration of 32.95 mg/kg. After intravenous administration of the drug, it was shown that the most probable model was the two-compartment-open model with Michaelis-Menten elimination. After oral administration, the drug was absorbed rapidly (K01 = 0.1304 min-1). The bioavailability was 96.94% and the drug was mostly excreted as 1-methyl-5-(4-carboxybenzoyl)-1H-pyrrole-2-acetic acid, while the excretion of the unchanged drug was 6.12%.


Anti-inflammatory, analgesic, and antipyretic effects and gastrointestinal toxicity of the new anti-inflammatory drug N-(3-[3-(piperidinylmethyl)phenoxy]propyl)-carbamoylmethylthio ]ethyl 1-(p-chlorobenzoyl) 5-methoxy-2-methyl-3-indolylacetate. The anti-inflammatory, analgesic, and antipyretic effects and gastrointestinal toxicity of N-(3-[3-(piperidinylmethyl) phenoxy] propyl)- carbamoylmethylthio] ethyl 1-(p-chlorobenzoyl) 5-methoxy-2-methyl-3-indolylacetate (CP-331, CAS 127966-70-5), a new anti-inflammatory drug, were evaluated using indomethacin as a control. CP-331 exerted anti-inflammatory, analgesic and antipyretic effects on the models of carrageenin-induced paw edema, increased vascular permeability, ultraviolet light-induced erythema, granuloma proliferation, adjuvant arthritis, inflammatory pain, and yeast-induced fever. However, these effects were observed at a molar level similar to or higher than that of indomethacin. In addition, CP-331 influenced more markedly than indomethacin the delayed type hypersensitivity to sheep red blood cells. On the other hand, CP-331 did not damage the gastric mucosa even at a high dose of 1,000 mg/kg and also induced slighter damage to the intestinal mucosa than indomethacin. Thus, CP-331 exerted anti-inflammatory, analgesic, and antipyretic effects but without showing gastric toxicity, which is a common side effect of anti-inflammatory drugs. These results suggest the clinical applicability of this drug in the long-term therapy of inflammatory diseases such as rheumatoid arthritis.


Effects of salbutamol and bitolterol mesilate on pO2 levels in asthmatic patients and healthy volunteers. The hypoxic effects of salbutamol 200 micrograms (CAS 18559-94-9) and bitolterol mesilate 740 micrograms (Biterol, CAS 30392-41-7), both administered by pressurized aerosol, were assessed by transcutaneous pO2 monitoring in 18 asthmatic subjects and in 12 normal volunteers. Unlike the latter, the asthmatics showed a highly significant difference in ptcO2 time course after the two drugs. After bitolterol mesylate the decrease in ptcO2 was much more gradual and the maximal decrease showed a 10-min time lag vs. salbutamol, which may partly explain the well known chronotropic effect of bitolterol. The clinical importance of the beta 2-induced hypoxemia may be related more to the dynamics of the ptcO2 decrease than to its absolute magnitude, which is usually fairly moderate.


Induction of glutathione S-transferase activity by curcumin in mice. Curcumin, a natural constituent of Curcuma longa (turmeric, CAS 458-37-7), has been studied for its induction of glutathione S-transferase activity in mice. At a dose of 250 mg/kg orally for 15 days, the enzyme activity in liver was increased by 1.8 fold. Its effect on other tissues like stomach, small intestine, lungs, kidney was not significant. Curcumin also depleted sulfhydryl levels in tissues, especially in stomach where 45% depletion was observed.


Crystalline lactulose in the therapy of hepatic cirrhosis. Evaluation of clinical and immunological parameters. Preliminary results. Crystalline lactulose (Laevolac Cristalli, CAS 4618-18-2), a pure form of the disaccharide widely employed in the therapy of complications of liver cirrhosis, was administered, after a pharmacological wash-out of 10 days and following a randomized design, to 10 cirrhotic patients for 30 days at the dosage of 60 g/d, while another 10 subjects with similar characteristics received no treatment. Besides the parameters usually monitored for the evaluation of liver function and state of hepatic encephalopathy, immunological patterns such as lymphocyte subpopulations CD3, CD4, CD8, CD16(NK), CD25 and antibacterial activity against Ty2 strain of Salmonella typhi were evaluated. At the end of the study (day 30) a significant decrease of blood ammonia was observed, as expected, only in the group treated with lactulose with respect to the control group, as well as a significant increase of CD16 and antibacterial activity (1/3); an enhanced level of CD25, although not significant, was also noticed in the treated group with respect to the control group. These findings seem to show an effect of activation on cell-mediated immune system depressed during liver cirrhosis, produced by lactulose. Further studies are needed to confirm these data and to clarify the possible mechanisms involved.


Missing neutral DNase activity in lymphocytes and phytohemagglutinin-stimulated lymphocytes after high dose methotrexate therapy. After high dose methotrexate (CAS 59-05-2) therapy of children with non-metastatic osteosarcoma the neutral DNase activity is missing in lymphocytes and in phytohemagglutinin (PHA)-stimulated lymphocytes. The neutral DNase activity reappeared in lymphocytes 14 days and in PHA-stimulated lymphocytes 10 days after the end of therapy. The DNA polymerase activity is low when neutral DNase is missing and increases when neutral DNase activity reappeared. The neutral DNase activity in lymphocytes and in PHA-stimulated lymphocytes is probably identical with DNase I. Drug induced changes in DNA conformation can enhance DNase I cleavage rate. It is assumed, that high dose methotrexate alters DNA conformation and therefore binds DNase I; after this, free DNase I is no more detectable.


Efficacy and safety of cefotiam hexetil in the treatment of ear, nose and throat infections. In 60 patients suffering from acute ear, nose and throat infections the efficacy and safety of cefotiam hexetil (SCE-2174, CAS 61622-34-2) which is a pro-drug of cefotiam was studied. The clinical success rate (improvement/cure) achieved with a daily administration of 600 mg was 90%. In 63% of the cases being evaluable for bacteriological response an eradication of the causative pathogens at the end of the treatment period was found. The majority of the patients tolerated well the compound. Side effects which were possibly, likely or definitely related to the treatment were observed in 12 patients. In 7 of these patients the treatment had to be stopped due to side effects which is equivalent to an intolerance rate of 12%. The data obtained in the present study indicate that cefotiam hexetil is a potent drug for the treatment of acute and acute on top of chronic infections of the upper aerodigestive tract.


Enhancement of the penetration of dithranol and increase of effect of dithranol on the skin by liposomes. An assessment was made in healthy skin of dithranol erythema caused by a 10-min occlusive application of 0.5% dithranol (CAS 1143-38-0) in liposomal gel (Natipide II) with and without the addition of 3% salicylic acid, and of 0.5% dithranol in vaseline and in a removable standard ointment base, both with 3% salicylic acid. Both liposomal preparations led to a significant potentiation of the dithranol erythema. The results indicate a strong promotion of the penetration of dithranol by the liposomal gel.


Platelet-activating factor antagonists in experimental shock. Platelet-activating factor (PAF) at 10 micrograms/kg i.v. induced profound hyperkalemia, changes of hematological parameters, patterns of ECG, and acid-base balance in rats. In separate experiments infusions of PAF at 30 ng/kg/min or injection of endotoxin from E. coli (15 mg/kg i.v.) induced a marked drop in blood pressure. All these changes were antagonized by pretreatment or post-treatment (in case of hypotension) by the selective hetrazepinoic PAF antagonists apafant (WEB 2086, CAS 105219-56-5; 0.1-5 mg/kg i.v.), bepafant (WEB 2170, CAS 114776-28-2; 0.05-1.0 mg/kg i.v.), or STY 2108 (0.01-0.1 mg/kg), respectively. The results support the view that PAF can mimic features of endotoxin shock and that the hetrazepines (like apafant, bepafant) are useful tools to clarify the role of PAF in such conditions.


Synthesis of laminarin sulfates with anticoagulant activity. Laminarin sulfates were synthesized without significant degradation of the genuine laminarin chain using SO3/pyridine complex as a sulfation reagent. 6 derivatives with a degree of sulfation (d.s.) ranging from 0.30 to 2.26 could be obtained. According to methylation analysis the C-6-OH-groups of the glucose molecules were preferentially substituted, followed by the OH-groups at C-2 and C-4. The derivatives Lam S1 (d.s. = 0.30) and Lam S2 (d.s. = 0.64) showed no activity in the blood coagulation tests. With increasing d.s. the anticoagulant activity increased until an optimum d.s. of 1.49. Anticoagulant laminarin sulfates showed significant activity in the activated partial thromboplastin time (APTT) test but were less active in the anti-Factor Xa as well as anti-Factor IIa assay. Therefore, the anticoagulant activity of the synthesized laminarin sulfates is due to the interaction at an early stage of the coagulation cascade and neither to a direct inhibition of Factor Xa and IIa nor to an indirect effect mediated by antithrombin III.


[The effect of co-dergocrine mesylate on erythrocyte deformability of hyperosmolar blood in vitro]. Addition of low doses of co-dergocrine mesilate (CAS 8067-24-1), a drug containing a mixture of hydrated ergot alkaloids to hyperosmolar blood in vitro leads to a dose-dependent increase in erythrocyte filterability through a 8 mu filter system. The concentrations of co-dergocrine mesilate used in the present experiments ranged from 0.04675-6.0 mg/100 ml blood. Blood samples were incubated for 90 min at 37 degrees C, measuring temperature was 37 degrees C. It could be shown that the drug-induced increase in erythrocyte filterability was not dependent on the presence of leucocytes. At higher osmolarity values, when the erythrocytes were more rigid, higher concentrations of codergocrine mesilate were needed in order to obtain a comparable improvement in red cell deformability.


Effect of drug therapy on the relapse of peptic ulcers. 1st communication: the effect of acute therapy. The following study was conducted in order to investigate the effect of drug therapy on the relapse of peptic ulcers. Acute therapy with pirenzepine (Gastrozepin, CAS 28797-61-7) (100 mg/d) or cimetidine (CAS 51481-61-9) (800 mg/d) was given to 402 patients with peptic ulcers using the envelope method. Subsequently, 1-year maintenance therapy with pirenzepine (75 mg/d) or placebo was carried out in a double-blind study in 251 patients who had been cured within 3 months. During the study period, an endoscopic examination was repeated regularly to study the relapse of ulcers. When the results were stratified and analyzed by Cutler-Ederer's life table method to see changes in relapse over time, it was noted that the acute therapy for active ulcers did have an influence on the course of relapse after the ulcer lesions had been cured. Pirenzepine, a M1 antagonist, was superior to cimetidine, a H2 antagonist, in the prevention of relapse of ulcers after they had been cured. The results suggest that the prevention of relapse of peptic ulcers should be started at the stage of acute therapy for active ulcers and that care should be taken in selecting drugs. The results also suggest that the natural history of peptic ulcers with respect to their relapse can be modified to a certain extent by drug therapy although the period for such cannot be specified.


Effect of drug therapy on the relapse of peptic ulcers. 2nd communication: the effect of maintenance therapy. One-year maintenance therapy with pirenzepine (Gastrozepin, CAS 28797-61-7) (75 mg/d) or placebo was performed in a double-blind fashion in 251 patients to investigate the relapse by means of endoscopic examinations repeated every 3 months. Enrolled were the patients who had been cured within 3 months by acute therapy with either pirenzepine or cimetidine randomly given by the envelope method. When the results were analyzed by Cutler-Ederer's life table method to monitor manifestation of relapse, the maintenance therapy with pirenzepine did not show any significant difference from placebo in all the patients enrolled. However, stratified analysis according to various combinations of background factors revealed that there was significant difference in 1-year cumulative non-relapse rates between the pirenzepine maintenance therapy group and the placebo group, suggesting prophylactic effect of the maintenance therapy with pirenzepine on relapse. An increase of daily dose more than 75 mg in maintenance therapy may be expected to display the prophylactic effect of pirenzepine on ulcer relapse in a definite manner.


[Bioequivalence and bioavailability after single administration of effervescent ranitidine tablets]. An open two-way cross-over study in 12 healthy male volunteers was performed in order to determine the relative bioavailability of a 150 mg ranitidine (Zantic, CAS 66357-35-5) effervescent tablet sweetened with saccharine in comparison to the 150 mg standard ranitidine dispersible tablet (Trinkette). On two occasions separated by a wash-out period of 1 week volunteers received a single oral dose of both formulations. On each administration day blood samples were collected at predetermined time points in order to investigate the pharmacokinetic parameters. Single oral doses of ranitidine were very well tolerated by healthy male volunteers. The non-parametric 95% confidence intervals for AUC and Cmax were 87 to 116% and 84 to 107%, respectively. The relative bioavailability of the ranitidine effervescent tablet was 99% compared to the dispersible tablet. The mean of the Cmax ratio was 95%. The ranitidine effervescent tablet could thus be claimed to be bioequivalent to the dispersible tablet.


3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitor simvastatin and the human lens. Clinical results of a 3-year follow-up. Simavastatin (MK-733, Zocor, CAS 79902-63-9), a new 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, was administered for a period of at least 3 years to 21 patients suffering from primary hypercholesterolemia. Significant decreases were noted for plasma cholesterol (30%), low density lipoprotein cholesterol (40%), whereas an increase in plasma high density lipoprotein cholesterol (11%) was observed. The drug therapy was well tolerated and clinical examinations revealed no adverse effects. No development of cataracts or other ocular side effects have been observed during this 3-year follow-up period.


Interaction of spironolactone with mercury. A possible molecular mechanism. The protective activity of spironolactone (CAS 52-01-7) against mercuric acetate intoxication and the action of a spironolactone-mercuric acetate complex were studied on female Sprague-Dawley rats. Spironolactone was given 30 min after the toxic agent. It was found that spironolactone reversed the toxic effects of mercury, the mercury-spironolactone complex was much less toxic than mercuric acetate and its toxicity disappeared with the administration of spironolactone. A molecular mechanism for the protective action of spironolactone against mercury intoxication is proposed. The presence of both the steroidal skeleton and the thioacetyl group in the same molecule is necessary for the protection against mercury intoxication.


Nimesulide in the treatment of advanced cancer pain. Double-blind comparison with naproxen. In a clinical double-blind study, the analgesic efficacy and the side-effects of nimesulide (Aulin, CAS 51803-78-2) and naproxen administered to 68 patients affected by advanced cancer pain were compared. Patients were treated with non-steroidal anti-inflammatory drugs according to the first step of the pharmacological analgesic scale of the WHO. The dose administered was 200 mg b.i.d. (every 12 h) for nimesulide and 500 mg b.i.d. (every 12 h) for naproxen. From this study the analgesic effect and the tolerability of the two drugs appeared to be similar. Both drugs resulted to be effective with a low incidence of adverse events that may be related to their use.


Effects of novel retinoids on growth and differentiation of a rhabdomyosarcoma cell line. The influence of all-trans-retinoic acid-beta-D-glucopyranosylester, all-trans-retinoic acid-beta-D-galactopyranosylester, methyl-(1-O-retinoyl-beta-D-glucopyranoside)uronate and all trans-retinyl-beta-D-glucuronide were investigated on the celle line BA-HAN-1C. This clonal cell line was derived from a dimethylbenzanthracene induced rhabdomyosarcoma in the rat. The tumor cells were incubated for 5 days with medium which was supplemented with various concentrations of the different compounds. The action of the retinoids were measured by comparing the cellular growth and the creatine kinase activity (as differentiation marker) with an supplemented cell line. The retinoids which are based on all-trans-retinoic acid (all-trans-retinoic acid-beta-D-glucopyranosylester, all-trans-retinoic acid-beta-D-galactopyranosylester, methyl-(1-O-retinoyl-beta-D-glucopyranoide)uronate and their chemical precursors) showed similar biological effects as all-trans-retinoic acid and could be used in higher concentrations than retinoic acid without the appearance of toxic effects. The all-trans-retinyl-beta-D-glucuronide derivatives did not show any influence on the cell growth and their creatinine kinase activity. With respect to the effects of the compounds two hypothesis about their function were possible: They act as a whole molecule, or: they are bound to a receptor where the really effective substance, all-trans-retinoic acid is released from the molecule by hydrolytic cleavage as required. Investigations with the carbohydrates D-glucose, D-galactose and D-uronic acid disproved the second theorie because these substances enormously support the growth of the tumor cells. The effectively of the free all-trans-retinoic acid would have been diminished by these components. However, this effect did not appear if hydrolysis is considered.


Fibrinogen and antithrombin III blood levels fluctuations during isoniazid or isoniazid plus rifampicin administration. Nineteen randomized patients, treated with isoniazid (INH, CAS 54-85-3) for tuberculosis chemoprophylaxis or isoniazid plus rifampicin (RMP, CAS 13292-46-1) combination for tuberculosis therapy, were studied in order to explore the effects of these drugs on fibrinogen and antithrombin III blood levels. Other hepatic biology indices were also measured (aminotransferases, alkaline phosphatase, prothrombin time etc). The results suggested a relationship between INH or INH + RMP administration and fibrinogen as well as antithrombin III blood levels. The data indicate a protective effect of the RMP synchronous administration (by enzyme induction mechanisms) in the preservation of fibrinogen blood levels.


Synthesis of some hydroxamic acid derivatives of benzimidazole and their antibacterial and antifungal activities. A number of 1H-benzimidazole-2-propanoic acid derivatives have been synthesized by Phillips method, and their antibacterial and antifungal activities have been tested. The chemical structures of the synthesized compounds were elucidated by spectroscopic (IR, NMR, mass) and elementary analysis. Investigation of antimicrobial activity of the compounds was done by agar dilution technique using bacteria (Staphylococcus aureus ATCC 25923, Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853, Mycobacterium smegmatis ATCC 607) and yeast-like fungi (Candida albicans, Candida tropicalis, Candida pseudotropicalis, Candida kruzei, Candida globrata). Among the compounds tested N-hydroxy-3-(1H-benzimidazol-2-yl)-propionamide (Compound 6) showed considerable activity against both Candida albicans and Candida tropicalis.


Subcellular distribution and antifungal effects of fluconazole in human phagocytic cells. Demonstration of the antifungal agent in neutrophil polymorphonuclear leucocytes and monocytes by autoradiography and electron micrography. Electron microscopic autoradiography was used to demonstrate the presence of [3H] fluconazole (CAS 86386-73-4) in neutrophils and monocytes isolated from volunteers. Quantitative analysis of the autoradiographs showed significant accumulation of fluconazole in both phagocytic cells. The distribution of fluconazole was equal in the different intracellular compartments such as cytoplasm and nucleus. Fluconazole (20 micrograms/ml) induced ultrastructural changes in Candida albicans cells which had been phagocytized by neutrophils or monocytes (macrophages) in vitro. Particularly, changes in the plasma membrane and in the cytoplasmic structure of the intraphagocytic yeast cells were observed electron microscopically.


Comparative assessment of the cytotoxic effects of different xenobiotics in three hepatoma cell lines. MH1C1, HTC and HEPA 1c1c7 hepatoma cell lines were selected in this study as the bioindicators of the cytotoxicity induced by six chemicals: butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), cycloheximide (CHE), cyclophosphamide (CPA), potassium dichromate (Cr VI) and 2,4-dinitrophenol (DNP). The concentrations used were in the range from 10(-6) mol/l to 10(-2) mol/l, and the exposure time was 24 h. Two end-points were measured to evaluate cytotoxicity: the detachment of dead cells from the monolayer (CS), as evaluated by detection of the total macromolecules present in the cell monolayers solubilized in alkali and the loss of colony-forming efficiency (CF). The dose-response curves were different from one compound to another, but generally similar with the two assays, the colony formation being the most sensitive test. Some technical problems like the toxicity of the solvents at the highest concentrations, the different sizes of colonies, the unspecific cellular detachment due to overgrowth during the experimental time, can be overcome by accurate standardization of the protocols used for each cell line. The sensitivity of the three cell lines was very similar, with some differences in the case of compounds exerting intermediate toxic effects, like CHE and DNP. The most toxic compound was Cr (VI), the least toxic one was CPA. The low cytotoxic effects displayed by CPA could be due to a lack of bioactivation and/or an increase of the inactivating enzymes, which are typical of hepatoma cell lines.


Effect of acetylsalicylic acid, ascorbate and ibuprofen on the macrophage system. The influence of ascorbic acid (CAS 50-81-7), acetylsalicylic acid (CAS 50-78-2) and ibuprofen (CAS 15687-27-1) on macrophages of C57BL/6 mice was investigated in vitro. It has been shown that ascorbic acid or acetylsalicylic acid alone did not stimulate or inhibit the production of interleukin-6, whereas a combination of both substances caused a significant stimulation. The viral replication in L929 fibroblasts was not affected by ascorbate and/or acetylsalicylic acid. In addition, the tumor-necrosis factor (TNF) synthesis of peritoneal macrophages was neither stimulated nor inhibited by both substances, alone or in combination. The oxygen radical production, however, was definitely inhibited by ascorbic acid, the effect of acetylsalicylic acid was far less marked, but at the high concentrations the inhibition was clearly discernible. Ibuprofen, a propionic acid derivate, was able to reduce the replication of vesicular stomatitis virus in L929 fibroblast cells. At the highest concentration of ibuprofen, 100 micrograms/ml, 34% of the fibroblast were able to survive. This protective effect declined as the ibuprofen concentration decreased. Ibuprofen could not stimulate peritoneal macrophages to secrete TNF, whereas the oxygen radical production was significantly reduced. In addition, ibuprofen activated mouse macrophages to produce interleukin-6 in a dose dependent way. The results of the in vitro experiments presented clearly show that ascorbic acid, acetylsalicylic acid in ibuprofen influenced the unspecific immune system.


Coumarin congeners as antidepressants.

Coumarin congeners as antidepressants. 3-Carboethyl coumarin (I) was converted to coumarin 3-acid hydrazide (II). This on reaction with appropriate aldehyde yielded 3-arylidino amino coumarin (III). Compound III on diazotisation and reaction with ferric chloride yielded the corresponding formazans viz. 3-substituted phenyl azoarylidino, amido coumarins (IVa1-a10) and oxadiazoles viz. 2-aryl-5-(3-coumarinyl)-1,3,4-oxadiazoles (Va1-a3), respectively. Simultaneously 3-carboethyl coumarin on hydrolysis gave 3-carboxy coumarin (VI) which on reaction with aryl amine in methylene chloride yielded 3-(N-aryl)amido coumarin (VIIa1-a3). The compounds were screened for their antidepressant activity against a tricyclic antidepressant (imipramine). Compounds IVa4, IVa5 and IVa9 exhibited activity better than imipramine with no toxicity (ALD50 greater than 1000 mg/kg) but IVa5 showed some side effects.


Inotropic and chronotropic effect of glycerol formal on the isolated rabbit heart. Glycerol formal (CAS 5464-28-8), an organic solvent used to vehicle drugs to target cells, has been shown to possess its own toxicopharmacological properties. The present work was undertaken to study its direct effect on the isolated rabbit heart. At 2.3 and 4.6 mmol/l (bolus) glycerol formal exerted a positive inotropic effect. Upon a perfusion of 4.5 mmol/l/h, the left ventricular pressure and the coronary flow were increased, while at 11 mmol/l/h these two parameters showed a tendency to decrease. Glycerol formal upon a perfusion at 11 mmol/l/h decreased mildly the positive inotropic effect of noradrenaline, and strongly that produced by acetylcholine at a nicotinic dose, while it accentuated the bradycardia induced by acetylcholine at a muscarinic dose. On the contrary it potentiated the stimulant effect of nicotine. The positive inotropic effects of tyramine, dimethylphenylpiperazinium and potassium chloride were decreased showing an inhibition of noradrenaline liberation induced by glycerol formal at the doses used. The action of glycerol formal on agents inducing a positive inotropic effect, except nicotine, and its cardiodepressant effect are probably partly due to its action on the Ca2+ ion.


The status of PAI-1 as a risk factor for arterial and thrombotic disease: a review. Plasminogen activator inhibitor-1 (PAI-1) is a rapid inhibitor of tissue plasminogen (tPA) in vivo. Evidence suggests that the level of plasma PAI-1 activity is responsible for the regulation of the whole fibrinolytic process through this tPA/PAI-1 interaction. Levels of PAI-1 have therefore emerged as a candidate for a thrombotic risk factor. Recent epidemiological data supports the view that high plasma levels of PAI-1 may be important in the pathogenesis of arterial and thrombotic disease. These data are reviewed and their significance discussed. PAI-1 expression has been shown to be regulated by many different factors in vitro and the relevance of these data to in vivo physiology is addressed. The current knowledge of the biochemistry, expression and genetics of PAI-1 is also presented and the significance of this to disease pathogenesis is discussed.


Lipolysis of triglyceride-rich lipoproteins activates coagulant factor XII: a study in familial lipoprotein-lipase deficiency. A high factor VII coagulant activity (VIIc), a marker of increased risk of coronary heart disease, is frequently found in types IIb and IV hyperlipidaemia, but its cause is not fully understood. Factor VII can be activated by factor XIIa, generated from factor XII upon activation of the contact system of coagulation. Ten patients with familial lipoprotein-lipase (LPL) deficiency and 10 healthy control subjects were therefore compared to explore the hypothesis that high concentrations of unesterified fatty acids (UFA), released from triglyceride-rich lipoproteins by LPL, are a source of factor XII activation and hence the increased VIIc that is observed post-prandially and in non-LPL-deficient hypertriglyceridaemic states. Mean plasma cholesterol and triglyceride concentrations were, respectively, 1.5- and 19-fold higher in the patients than controls, due to increases in very-low-density lipoproteins and chylomicrons. The concentration and composition of plasma UFA were similar in both groups. In conformity with the hypothesis, VIIc was not increased in the LPL-deficient group, despite their massive hypertriglyceridaemia. Furthermore, when the patients' plasma was treated with LPL, factor XII was activated promptly and substantially, whereas no similar effect was observed in the controls. These results suggest that high concentrations of circulating triglyceride-rich lipoproteins will increase VIIc in the presence of LPL.


Experimental induction of atherosclerosis associated with femoral arteriovenous fistulae in rabbits on a stock diet. Chronic femoral arteriovenous fistulae were surgically produced in stock-fed rabbits. The aortic bifurcation and branching sites of the ilio-femoral arteries from each side were examined histologically by the serial section technique in rabbits killed at varying times from 121 to 800 days postoperatively. Similar preparations were examined from old multiparous breeding does and rabbits with a control femoral arteriotomy. Tears of the internal elastic lamina were prominent in the abdominal aorta and homolateral ilio-femoral arteries of those with fistulae but were only occasional and sporadic in contralateral arteries and control animals. Intimal proliferation at branching sites proximal to the fistula exhibited varying degrees of enlargement, extension and progression to overt atherosclerosis with lipid accumulation, fibrin deposition and calcification. Such changes were minimal proximally in contralateral vessels of a few rabbits and non-existent in control material. These results (i) constitute the first experimental induction of the progression of intimal proliferation to overt atherosclerosis at branching sites in stock-fed animals and (ii) substantiate the importance of haemodynamics in atherogenesis.


Effect of sucrose diet on expression of apolipoprotein genes A-I, C-III and A-IV in rat liver. A sucrose-rich diet stimulates hepatic lipogenesis and induces net production of very low density lipoproteins in the liver. To study changes of hepatic apolipoprotein gene expression in response to such a diet, we measured the mRNA abundance of apolipoproteins A-I, C-III and A-IV in livers of rats fed a sucrose-rich diet or a control diet for 3 weeks. In livers of sucrose-fed rats, the abundance of cellular and nuclear apo A-IV mRNA increased to 185% +/- 21% and 142% +/- 22% of control values (P less than 0.01), respectively. In sucrose-fed rats, the transcriptional activity of the apo A-IV gene, measured in a cell-free transcription system using isolated liver nuclei, increased to 144% +/- 23% of control (P less than 0.05). In contrast, this diet neither affected the abundance of cellular and nuclear apo A-I and apo C-III mRNA nor the transcriptional activity of these genes in liver. These results are consistent with specialization of the regulatory elements of the genes coding for apolipoproteins A-I, C-III and A-IV. Alternatively, enhanced transcription of the apo A-IV gene may preclude increased synthesis of apo A-I and/or apo C-III mRNA due to the close linkage of the three genes in the rat genome.


Apolipoprotein A-I and apolipoprotein B containing lipoprotein particles in coronary patients treated with extracorporal low density lipoprotein precipitation (HELP). Evidence for chemical and biological heterogeneity of human plasma lipoprotein density classes has been steadily accumulating over the last 15 years. Furthermore, several recent reports have indicated potential clinical significance of certain lipoprotein subspecies as either atherogenic or antiatherogenic. It is generally accepted that lipid lowering treatments can retard or even reverse development of atherosclerotic lesions. However, very little is known about effects of various lipid lowering treatments on specific lipoprotein particles. The purpose of this study was to explore the effects of heparin induced extracorporal low density lipoprotein precipitation (HELP) on various subspecies of plasma lipoprotein particles defined primarily by their apolipoprotein composition. Using particle specific enzyme immunoassays, the immediate changes in lipoprotein particle profiles were analyzed after a single HELP treatment in 12 patients with angiographically documented coronary artery disease. In a separate group of 6 patients, particles were repeatedly measured over a period of 96 h following a HELP treatment. Single HELP treatment caused an immediate and highly significant decrease (67%) in the concentration of simple lipoprotein particles containing apolipoprotein B (apo B) as a sole apolipoprotein (LP-B). Various subspecies of complex particles containing apo B and other apolipoproteins (Lp-B-complex) were also decreased although to a lesser degree (44-53%). HELP treatment caused an insignificant, 3% decrease of lipoprotein particles containing apo A-I but no apo A-II (Lp-A-I) and a 6% decrease in the concentration of particles containing both apo A-I and apo A-II (Lp-A-I:A-II). During the 96-h period following HELP treatment various apo B containing particles recovered at different rates in different patients.(ABSTRACT TRUNCATED AT 400 WORDS)


Hypercholesterolaemia alters arterial and blood factors related to atherosclerosis in hypertension. To evaluate the influence of hypercholesterolaemia on arterial and blood factors related to cardiovascular disease in hypertension, 20 normocholesterolaemic and 31 hypercholesterolaemic hypertensive patients underwent determinations of whole blood filterability (WBF), plasma fibrinogen concentration (PF) and aortic pulse wave velocity (PWV). Both of the groups had similar age, body mass index, cumulative smoking dose and blood pressure. Hypercholesterolaemics had lower WBF (P less than 0.02), higher PF (P less than 0.02) and higher PWV (P less than 0.01) than normocholesterolaemics. In the whole population WBF correlated with age (P less than 0.005), mean blood pressure (P less than 0.01), total cholesterol (P less than 0.05) and plasma fibrinogen (P less than 0.01). However, in a multivariate analysis where age and pressure were controlled as variables, only the association between WBF and PF remained significant (P less than 0.001). Thus, the higher fibrinogen affects whole blood filterability in hypercholesterolaemic hypertensive patients. In the whole population PWV correlated positively with HDL cholesterol (P less than 0.01) and age (P less than 0.001) and the association with HDL cholesterol remained significant in a multivariate analysis (P less than 0.001) where age was controlled. The effect of ageing on arterial rigidity seems to be similar in both hypertensive groups as deduced from the identical regression slopes relating pulse wave velocity to age. So in hypertension with high cholesterol, arterial rigidity was increased without changes in arterial stiffening with age.


Short-term interruption of training affects both fasting and post-prandial lipoproteins. Exercise training alters plasma lipoprotein profiles in a manner compatible with decreased coronary artery disease risk. The aim of this study was to ascertain whether interruption of training (detraining) was associated with potentially undesirable changes in the metabolism of post-prandial lipoproteins and plasma levels of Lp(a). Eight normolipidemic, male runners who ran 30-40 miles/week were studied in the trained state and after 14-22 days of detraining. Two of the subjects were studied in the reverse order to control for any confounding effects of exercise sequence. Detraining resulted in (1) a 12% (P = 0.002) reduction in the subjects' aerobic capacity, (2) a 7.7% (P = 0.007) reduction in fasting concentrations of high density lipoprotein cholesterol (HDL-C), (3) a 21% (P = 0.01) reduction in post-heparin lipoprotein lipase activity. Lp(a) concentrations did not change significantly (mean increase 15%, P = 0.076). Fasting plasma concentrations of total cholesterol (TC), triglycerides (TG) and low density lipoprotein-cholesterol (LDL-C) did not change in the detrained state. There was little fluctuation over 24 h in plasma concentrations of TC, LDL-C and HDL-C in either the trained or detrained states. TG concentrations fluctuated over the 24 h in accord with food intake, but there were no exercise-related changes. Exercise had a dramatic effect on chylomicron and chylomicron remnant metabolism as measured by retinyl palmitate measurements. The mean areas under the concentration vs. time curves (AUC) for chylomicron-retinyl esters increased by 41% (P = 0.013) and for chylomicron remnant-retinyl ester by 37% (P = 0.058) following detraining.(ABSTRACT TRUNCATED AT 250 WORDS)


Long-term treatment of neonatal aortic smooth muscle cells with beta VLDL induces cholesterol accumulation. A model for smooth muscle derived foam cells was developed by treating smooth muscle cells isolated from the aortae of neonatal rabbits with beta VLDL for up to 1 month. Hyperlipidemic beta VLDL isolated from cholesterol fed rabbits induced proliferation of the cells that were maintained in lipid deficient serum. In addition, the lipoprotein fraction stimulated [14C]oleic acid incorporation into [14C]cholesteryl ester, even in cultures that had been chronically exposed to the lipoprotein. The accumulation of cholesterol was evaluated and small amounts of cholesteryl ester were demonstrated in cultures treated for 3 days with beta VLDL. However, continued exposure to the lipoprotein resulted in larger elevations in total cholesterol, approximately 65% of which was in the esterified form in cultures treated with 100 micrograms beta VLDL/ml for 24 days. When cholesterol levels were examined as a function of time, it was determined that both total cholesterol and cholesteryl ester levels increased. Approximately 2-3 weeks after lipoprotein was introduced to the culture, maximum levels were attained. Triglyceride levels were also measured and found to increase more than two-fold in cultures that had been incubated in the presence of beta VLDL for 24 days, when compared to cultures incubated in its absence. Examination of the cultures by electron microscopy revealed intracytoplasmic lipid droplets in beta VLDL treated cells. These results suggest that beta VLDL treatment of neonatal aortic smooth muscle cells provides an ideal model in which to study the lipid laden smooth muscle cells that characterize the atherosclerotic plaque.


Activation of leukocytes with complement C5a is associated with prostanoid-dependent constriction of large arteries in atherosclerotic monkeys in vivo. Activated leukocytes release a variety of substances which have been shown in vitro to modulate vascular tone. The chemotactic peptide complement C5a is a physiological activator of leukocytes. We injected human recombinant complement C5a (10 and 100 micrograms) into the blood-perfused hind limb of normal and atherosclerotic cynomolgus monkeys and examined vascular responses. In both normal and atherosclerotic monkeys, the high dose of C5a produced about 65% decrease in leukocyte cell count in venous blood drainage from the hind limb. Injection of C5a produced a pronounced increase in resistance of large arteries (segment from iliac artery to dorsal pedal artery) in atherosclerotic, but not in normal monkeys. The constrictor effect of C5a in atherosclerotic monkeys was abolished by the thromboxane A2 receptor antagonist SQ 29,548 (2 mg/kg i.v.). The platelet-activating factor antagonist WEB 2086 (5 mg/kg, i.v.) did not alter vascular responses to C5a. We conclude that activation of leukocytes produces constriction of large arteries in atherosclerotic, but not normal, monkeys in vivo. This response may be mediated in part by release of thromboxane A2.


Lipoprotein risk factors in vegetarian women of Indian descent are unrelated to dietary intake. Dietary intakes, anthropometric indices and plasma lipoprotein and alpha-tocopherol concentrations were measured in premenopausal vegetarian women of Indian descent (n = 22) and in white women of European descent consuming either mixed (n = 22) or vegetarian diets (n = 18). The Indian women were shorter in height than the white women and had a higher proportion of body fat. Energy intakes were lower in the Indian women, both in absolute terms and per kg body weight. The proportion of energy derived from saturated fatty acids was lower and that from polyunsaturated fatty acids was greater in both Indian and white vegetarians compared with the subjects on mixed diets. Intakes of dietary fibre and vitamins C and E were higher in the white vegetarians compared with the other groups. Plasma concentrations of total and LDL cholesterol and apolipoprotein B and the ratio of apolipoprotein B/apolipoprotein AI were lower and HDL and HDL2 cholesterol, alpha-tocopherol concentrations and the ratio of alpha-tocopherol/cholesterol were greater in the white vegetarian group than in the other groups. Total plasma cholesterol was associated with measures of truncal obesity, especially subscapular skinfold thickness and the percentage energy derived from saturated fatty acids. Plasma concentrations of apo(a) were higher and those of HDL and HDL2 cholesterol and sex hormone binding globulin (SHBG) were lower in the Indian vegetarian women compared with both groups of white women. No relationship could be found between apo(a), HDL and HDL2 cholesterol concentration and nutrient intake but HDL and HDL2 were negatively associated with the proportion of body fat and apo(a) weakly with subscapular skinfold thickness.(ABSTRACT TRUNCATED AT 250 WORDS)


Effective reduction of plasma LDL levels by LDL apheresis in familial defective apolipoprotein B-100. The clinical response to long-term reduction of the plasma LDL cholesterol concentration was studied in a man with severe coronary artery disease associated with familial defective apolipoprotein B-100 (FDB). Plasma exchange repeated at 2-week intervals, combined with lipid-lowering drugs, led to remission of angina and improved exercise test performance. A similar clinical response was achieved after LDL apheresis with dextran sulphate columns repeated once every 2 weeks in combination with drug treatment. The reduction in plasma LDL cholesterol level brought about by LDL apheresis was at least as marked in the FDB patient as in 5 patients with familial hypercholesterolaemia. We conclude that FDB patients with coronary artery disease may derive clinical benefit from prolonged reduction of their plasma cholesterol levels and that LDL containing apo B-100 in which arginine at position 3500 is replaced by glutamine is removed from plasma by dextran sulphate columns as efficiently as is normal LDL.


Disruption of endothelial barrier function by lipolytic remnants of triglyceride-rich lipoproteins. Remnants, resulting from the lipolysis of triglyceride-rich lipoproteins, injured cultured endothelial cells and resulted in decreased barrier function of the vascular endothelium. Endothelial cells were cultured on micropore filters. Albumin transfer across endothelial cell monolayers was measured after a 24-h exposure to media enriched with control or in vitro-lipolyzed samples of various hypertriglyceridemic (HTG) sera and its isolated lipoprotein (VLDL, LDL and HDL) and serum free protein (d greater than 1.21 g/ml) fractions. Compared with control cultures, neither control HTG serum nor its isolated lipoprotein and serum-free protein fractions had any effect on albumin transfer. In contrast, lipolyzed HTG (L-HTG) serum and all of its isolated lipoprotein fractions (L-VLDL, L-IDL, L-LDL and L-HDL) caused a marked decrease in endothelial barrier function, evidenced by a significant increase in albumin transfer across endothelial monolayers. The L-IDL and L-HDL fractions were more effective in increasing albumin transfer than the L-VLDL and L-LDL fractions. The extent of the L-IDL and L-HDL mediated increases in albumin transfer was concentration dependent. An exposure of 12 h was required for L-HDL to increase albumin transfer. The L-HDL mediated increase in albumin transfer was reversible only after a 12-h exposure at low concentrations. The free protein fraction from L-HTG serum had no significant effect on the barrier function of endothelial cells. The presence of normolipidemic HDL in culture medium prevented disruption of the endothelial barrier induced by L-IDL but not by L-HDL. The decrease in endothelial barrier function induced by lipolyzed samples of HTG serum or lipoproteins appeared to be correlated with the level of free fatty acids contained in lipolytic remnants. Enrichment of LDL, and in particular HDL, with fatty acid significantly increased albumin transfer. Compared with lipolyzed samples, sera/lipoproteins oxidized in vitro by Cu2+ ions had little effect on endothelial barrier function, which did not correlate with their respective thiobarbituric acid-reacting substance (TBARS) values. TBARS remained within normal range after L-HDL incubation with endothelial cells for up to 48 h. At most concentrations tested, exposure to lipolyzed but not oxidized lipoproteins resulted in morphological perturbations of cell monolayers. These data suggest that lipolytic remnants of triglyceride-rich lipoproteins may play an important role in the development of atherosclerosis by decreasing the barrier function of the vascular endothelium. The remnant-induced injury of the arterial wall may permit the entry of cholesterol-rich lipolytic remnants as well as LDL into the arterial wall.


Studies on apolipoprotein(a) phenotypes. Part 1. Phenotype frequencies in a healthy Japanese population. The frequency distribution for serum lipoprotein(a) (Lp(a)) concentrations in healthy Japanese was highly skewed, with a mean +/- S.D. of 14.6 +/- 13.6 mg/dl and a median of 11.0 mg/dl. The present study provides the first evidence on the frequencies of Lp(a) phenotypes and alleles in healthy Japanese subjects. There was a strong inverse relationship between the apparent molecular weights of apo(a) isoforms and plasma Lp(a) concentrations, as reported previously. However, because of the considerable overlap between the Lp(a) concentrations of the different phenotypes, it was impossible to predict Lp(a) concentration from Lp(a) phenotypes, or vice versa. The present results suggest that the distribution of Lp(a) concentrations, mean and median values and Lp(a) phenotype and allele frequencies in healthy Japanese are not significantly different from the results for Europeans, whereas they are significantly different from other Asian populations, i.e. Chinese, Indians and Malaysians.


The effect of concurrent administration of isradipine on the development of fatty streaks in the cholesterol-fed rabbit: a morphometric study. Calcium antagonists attenuate the development of aortic lesions in cholesterol-fed rabbits. This study was undertaken to examine the influence of isradipine (dose: 0.3 mg/kg per day orally) on the histological components of these lesions in New Zealand White rabbits (age: 12 weeks, weight: 2-2.5 kg). Five groups of animals were fed standard chow with the following supplements for 3 weeks: Group 1, no supplements; Group 2, 40 g cholesterol; Group 3, 60 g cholesterol; Group 4, 40 g cholesterol + isradipine; Group 5, 60 g cholesterol + isradipine. After 3 weeks, the animals were killed and the aorta prepared for morphometry. The volume of intima/cm aorta was estimated and the volume fraction (Vv) of the intima occupied by components of the lesions was estimated by point counting. By integrating these two measurements the volume/unit length (mm3/cm) of the following components of the aorta were estimated: intima, non-cellular components, endothelial cells, myointimal cells, lipid accumulating myointimal cells and foam cells. Cholesterol feeding for 3 weeks was associated with significant increases in the volume of non-cellular components of the intima, endothelial cells, myointimal cells, lipid accumulating myointimal cells and foam cells. Administration of isradipine significantly reduced all these parameters. It is concluded that isradipine attenuates cellular hyperplasia and accumulation of non-cellular components of lesions in cholesterol fed rabbits.


Serum selenium concentration and risk of ischaemic heart disease in a prospective cohort study of 3000 males. Whether an association, causative or not, exists between the level of serum selenium and the risk of ischaemic heart disease (IHD) remains unsettled. We investigated the issue in a cohort of 3387 males aged 53-74 years (mean 63). Based on information about health status, life-style and socioeconomic factors given in a prefilled comprehensive questionnaire, the men were interviewed and the information validated. Following the interview, they underwent a clinical examination and had a venous blood sample drawn for the determination of a number of biochemical characteristics. Three hundred and forty-six men were excluded due to prevalent cardiovascular disease, including stroke. During the next three years (1986-1989) 107 men (approximately 3%) suffered an IHD event; 25 events were fatal. Compared to others, men with serum selenium levels less than or equal to 1 mumol/l, approximately the lowest tertile, had a 70% increased risk of IHD, relative risk (RR) with 95% confidence limits was 1.70 (1.14-2.53). After multivariate adjustment for cholesterol, social class, smoking and age, RR was 1.55 (1.00-2.39). Serum selenium level was significantly (P less than 0.05), but not strongly, correlated with a number of IHD risk factors: serum cotinine, tobacco smoking, social class, alcohol consumption, total cholesterol, hypertension, age and physical inactivity. Body mass index, HDL-cholesterol and triglycerides were not significantly associated with serum selenium. We conclude that middle-aged and elderly Danish men with serum selenium less than or equal to 1 mumol/l had a significantly increased risk of ischaemic heart disease. This association was not explained by the interrelationship of serum selenium and major cardiovascular risk factors.


Inheritability of atherosclerosis and the role of lipoproteins as risk factors in the development of atherosclerosis in WHHL rabbits: risk factors related to coronary atherosclerosis are different from those related to aortic atherosclerosis. Inheritability of atherosclerosis and the influences of serum lipids on atherosclerosis were examined by following its progression in selectively bred WHHL rabbits. Our studies indicate (1) coronary atherosclerosis is clearly inherited from parents by offspring whereas inheritability of aortic atherosclerosis is uncertain; (2) coronary stenosis is positively correlated to serum cholesterol level, although the correlation coefficient is markedly low: in contrast, no relationship between serum lipid levels and aortic atherosclerosis was observed; (3) cholesterol-rich VLDL showed atherogenicity in aorta, but not in coronary arteries; (4) an unknown lipoprotein detected by 3.6% polyacrylamide gel electrophoresis was related to coronary atherosclerosis, although no relationship between the unknown lipoprotein and aortic atherosclerosis was observed. These findings suggest that there are two types of genetic factors involved in atherosclerosis, one of which is unique to coronary atherosclerosis whereas the other is related to only aortic atherosclerosis.


Comparative hypolipidemic effects of lovastatin and simvastatin in patients with heterozygous familial hypercholesterolemia. We have compared the effects of lovastatin and simvastatin on plasma lipoproteins, fibrinogen and urinary mevalonic acid excretion in twenty-three patients with heterozygous familial hypercholesterolemia. After a baseline period patients were randomly assigned to receive lovastatin or simvastatin at doses of 10, 20 and 40 mg twice daily, for a period of 2 months each, and then, after a 4-week wash-out period, all patients received the alternate drug for a similar period of therapy. Both drugs were well-tolerated and no patients were withdrawn due to side effects. Lipid values returned to baseline after discontinuation of therapy and no carry-over effect was observed. Treatment with lovastatin resulted in decreases in LDL cholesterol concentrations from 274 mg/dl at baseline to 211, 192 and 178 mg/dl, respectively, on doses of 20, 40 and 80 mg/day. Treatment with simvastatin reduced concentrations of LDL cholesterol to 194, 168 and 156 mg/dl, respectively, on doses of 20, 40 and 80 mg/day. Concentrations of HDL cholesterol increased on both drugs, but no dose response relationship was apparent. Both drugs reduced the 24-h urinary excretion of mevalonic acid, an intermediate in cholesterol biosynthesis, but the magnitude of decrease was similar with lovastatin and simvastatin. Small, but statistically non-significant decreases in fibrinogen occurred with both drugs. Patients who showed the greatest hypolipidemic effect during treatment with lovastatin also showed an excellent therapeutic response to simvastatin and vice versa. We conclude that, on a milligram per milligram basis, simvastatin is twice as potent as lovastatin in the treatment of familial hypercholesterolemia and that with both drugs, reductions in LDL cholesterol concentrations are accompanied by decreases in the urinary excretion of mevalonic acid.


Impaired left ventricular relaxation and hyperinsulinemia in patients with primary hypercholesterolemia. Fifteen non-obese patients with familial hypercholesterolemia and fifteen normocholesterolemic subjects matched for age, body mass index, waist/hip ratio, arterial blood pressure and sedentary life style underwent blood sampling for determination of fasting plasma glucose, insulin, total-, LDL-, HDL-cholesterol, triglycerides, free fatty acids, apolipoprotein A1 and B. In both groups of subjects we determined erythrocyte membrane microviscosity and performed an echocardiographic study. We demonstrated that hypercholesterolemic patients had a significant increase in fasting plasma total cholesterol (8.9 +/- 0.5 vs. 5.5 +/- 0.3 mmol/l, P less than 0.001), insulin (79 +/- 4 vs. 58 +/- 4 pmol/l, P less than 0.05) and apolipoprotein B (2.2 +/- 0.5 vs. 1.3 +/- 0.5 g/l P less than 0.01). In the echocardiographic study we found a significant impairment in left ventricular relaxation (isovolumic relaxation time (IRT) 106 +/- 6 vs. 73 +/- 7 ms, P less than 0.01). Erythrocyte membrane microviscosity (0.253 +/- 0.004 vs. 0.225 +/- 0.003, P less than 0.05) was also increased in hypercholesterolemic patients. Finally we found that erythrocyte membrane microviscosity correlated with fasting plasma insulin levels (r = -0.46, P less than 0.03) and IRT (r = -0.52, P less than 0.01).


Collagen types I and III, collagen content, GAGs and mechanical strength of human atherosclerotic plaque caps: span-wise variations. Measurements of total collagen, of the ratio of collagen types III/(I+III) and of sulphated glycosaminoglycans (GAGs) were compared with mechanical strength for individual ulcerated and non-ulcerated human aortic plaque caps and with intima adjacent to the plaques. The distributions of the collagen type ratio were similar for both ulcerated and non-ulcerated plaque caps but different from that of the adjacent intima. The proportions of different collagen types were not related to fracture stress and are thus unlikely to affect the potential to ulcerate. The distributions of the sulphated GAGs showed lower amounts for the plaque caps compared with the nearby intima, with the centres of ulcerated plaque caps having the lowest values. Total collagen had higher values in the peripheries of plaque caps compared with the nearby intima, but was distinctly lower in the centres of ulcerated plaque caps. Plaque caps appeared to require a higher collagen content than adjacent intima to support a given level of mechanical strength, suggesting that while collagen production had occurred in the plaque caps it was not as efficiently organized to resist fracture as a similar amount of collagen in the adjacent intima. Ulcerated plaque caps are notable for much larger transverse (centre vs. periphery) gradients of connective tissue constituents than for non-ulcerated plaque caps. The development of these transverse gradients may be a critical aspect in determining the propensity of a plaque to ulcerate.


Studies on apolipoprotein(a) phenotypes. Part 2. Phenotype frequencies and Lp(a) concentrations in different phenotypes in patients with angiographically defined coronary artery diseases. In the present paper, we have evaluated serum Lp(a) concentrations, the frequencies of Lp(a) phenotypes and alleles and the association between the Lp(a) phenotypes and serum Lp(a) levels in 470 patients with angiographically defined coronary artery disease (CAD). Serum Lp(a) concentrations were significantly increased in proportion to the number of diseased vessels in the CAD patients. The frequencies of Lp(a) phenotypes in the CAD patients were significantly different from those in healthy subjects. In particular, the frequency of double-band phenotypes was higher in the CAD group. The frequencies of Lp(a) alleles in the CAD patients, however, were not significantly different from those in the healthy subjects. There was a strong inverse relationship between the apparent molecular weights of apo(a) isoforms and serum Lp(a) concentrations. Lp(a) levels in the CAD patients were higher than those in the healthy subjects with the same phenotype. The present results suggest that it is important to consider some posttranslational or environmental modifications and other factors, in addition to the genetic factor, when assessing contributions to plasma Lp(a) levels.


Influence of the level of dietary ethanol in mice with murine AIDS on resistance to Streptococcus pneumoniae. Chronic ethanol consumption impairs cellular immune functions. This may explain the increased occurrence of various opportunistic infections in heavy ethanol users. Immunological alterations associated with Acquired Immune Deficiency Syndrome (AIDS) also permit more opportunistic infections. In this study, we used a murine model of retrovirus infection induced by LP-BM5 murine leukemia virus. The combined effects of ethanol use and early retroviral infection (prior to the development of AIDS) on resistance to Streptococcus pneumoniae were investigated. Consumption of ethanol by non-retrovirus-infected mice resulted in decreased resistance to S. pneumoniae. However, retrovirus-infected mice fed a diet containing high concentrations of ethanol (6 and 7% v/v) exhibited a greater resistance to S. pneumoniae infection than retrovirus-infected mice fed diets with lower concentrations (5%) or no ethanol. The total number of white blood cells also decreased as serum ethanol levels increased. There were also fewer lymphocytes and more neutrophils and monocytes in retrovirus-infected mice fed ethanol. Diet consumption decreased as the concentration of ethanol increased in the diet. Consumption was dependent upon the dark-light cycle. The highest diet consumption was observed during the first 4 hr of the dark period. The level of ethanol in serum was influenced by the amount of the diet consumed and its ethanol concentration. Both retrovirus infection and ethanol consumption effected survival after S. pneumoniae infection.


Alcohol consumption and biological markers for alcoholism in idiopathic dilated cardiomyopathy: a case-controlled study. The aim of this study was to compare alcohol consumption and biological markers for alcoholism in a population of 23 men (57 +/- 8 years) admitted to hospital with idiopathic dilated cardiomyopathy (DCM), and a control group of 46 men (54 +/- 8 years) with coronary artery disease, matched for age. The DCM group had a higher daily alcohol consumption (82 g/day vs. 30 g/day, P < 0.0002). This difference was greater for the consumption of wine (63 g/day in the DCM group vs. 24 g/day in the control group, P < 0.002). Duration of regular daily alcohol consumption was longer in DCM patients (34 years vs. 22 years, P < 0.01) as well as duration of heavy alcohol consumption (> 60 g/day) (25 years vs. 10 years, P < 0.001). Among the biological markers, only the serum levels of immunoglobulin A were significantly increased in the DCM group (3.7 g/l vs. 2.7 g/l, P < 0.03). In this French population, alcohol is strongly linked to DCM. Biological markers appear to be poor predictors of alcohol intoxication in this so-called 'idiopathic' myocardial disease.


The antioxidant status of patients with either alcohol-induced liver damage or myopathy. The antioxidant status of alcoholic patients was assessed by direct measurement of the plasma antioxidants alpha-tocopherol and beta-carotene and of selenium as a marker of glutathione peroxidase. Overall, the alcoholic group showed significant decreases in the mean plasma values of beta-carotene, zinc and selenium when compared to the control subjects. When the patients were subdivided according to their liver histology, beta-carotene showed a progressive decrease in plasma concentration with increasing liver damage, whereas alpha-tocopherol levels were only depleted in the patients with cirrhosis. There were significant decreases in the plasma concentrations of both alpha-tocopherol and selenium in all patients with alcoholic skeletal muscle myopathy, whereas patients with normal muscle biopsies showed adequate antioxidant status. Such results support a role for free radical-mediated damage in end organ injury, particularly myopathy, in alcohol misusers.


Influence of acetaldehyde on the vasopressor effect of serotonin in pithed rats. In pithed rats, the intravenous (i.v.) administration of serotonin (3, 10, 30, 100, 300 and 1000 micrograms/kg) produced a dose-dependent increase in blood pressure. The pressor response to serotonin was reduced by acute acetaldehyde administration in a dose of 30 mg/kg i.v. and by 5-HT2 antagonist ketanserin (0.03 mg/kg i.v.). However, the lowest doses of acetaldehyde (10 and 20 mg/kg) were ineffective. In in vitro studies we also demonstrated that acetaldehyde (0.43 mM/l) and ketanserin (0.1 microM/l) inhibited the serotonin-induced vasoconstriction of isolated rat tail artery. In both experimental models the combination of acetaldehyde with ketanserin decreased the action of serotonin to the same extent as did ketanserin alone. In pithed rats pretreated with a high dose of ketanserin (3 mg/kg i.v.) serotonin produced hypotension by stimulation of 5-HT1 receptors. This effect was not enhanced by acetaldehyde (30 mg/kg) injection. Our data suggested that the action of acetaldehyde on the effects of serotonin in pithed rats was non-specific and independent of its interaction with serotonergic 5-HT1 and 5-HT2 receptors in blood vessels.


Attenuation of the behavioural effects of ethanol in mice by des-enkephalin-gamma-endorphin (ORG 5878). This study shows inhibition of the increase in locomotor activity induced by ethanol (2 g/kg i.p.) in mice by a low dose (0.1 mg/kg i.p.) of the non-opioid beta-endorphin fragment ORG 5878 (des-enkephalin-gamma-endorphin). ORG 5878 (0.1 mg/kg i.p.) also significantly antagonised the large increase in electroshock seizure threshold produced by ethanol (1.5 g/kg i.p.). In contrast, the hypothermia induced by ethanol (2 g/kg i.p.) was not altered by ORG 5878 (0.1 mg/kg i.p.). The effects of ORG 5878 showed an abnormal dose-response relationship, in that a high dose (1 mg/kg i.p.) did not significantly suppress any of the behavioural effects of ethanol examined although there was some indication that it attenuated the stimulant action of ethanol. ORG 5878 (0.1, 1 mg/kg i.p.) did not have any intrinsic effects on locomotion, seizure threshold or body temperature in mice. These results are the first demonstration that ORG 5878 may act as an ethanol antagonist in some paradigms.


Atropine as an inhibitor of voluntary ethanol intake in male rats. A single ethanol injection (2.0 g/kg, i.p.) administered to male rats will reduce voluntary ethanol intake (water vs. ethanol 10%) if tested for 24 hr, 6 days after the injection. Maximal inhibition, when compared to saline-injected controls (S), is seen after ethanol injections (E) once a week for 5-6 weeks. At this maximal inhibition atropine (A) or saline (S) was injected i.p. prior to the voluntary 24 hr intake of ethanol. In experiment 1, the doses 1 and 2 mg/kg were used, and in experiment 2, 4 and 8 mg/kg. Each experiment consisted of groups AE, SE, AS and SS, according to the above descriptions. In group AS, atropine reduced 24 hr voluntary ethanol intake with a maximal effect following the 4 mg/kg dose. In group AE, atropine did not increase the inhibitory effect induced by the ethanol injections. Total fluid intake was not influenced. After the treatment period a continuous choice (water vs. 10% ethanol) was offered for 8 (exp. 1) or 11 (exp. 2) weeks. During these evaluation periods the ethanol intake in group SE was always significantly smaller than the corresponding intake in group SS. In the atropine-injected groups (AE and AS) a similar significant difference in voluntary ethanol intake was observed at the beginning but not at the end of the evaluation periods. At the end of exp. 2 a significantly larger number of muscarinic binding sites was obtained in the cortex but not in the striatum of group SE when compared with groups AS and SS. In group AS a negative correlation was found in the striatum between the ethanol intake recorded after the atropine injection in week 5 and 6 and muscarinic binding sites. Atropine, probably by acting on muscarinic binding sites, seemed to have a specific inhibitory effect on voluntary 24 hr ethanol intake, which was similar to the effect induced by the ethanol injections.


Alcohol elimination and the regulation of alcohol consumption in AA and ANA rats. Previous studies have usually found that animals with either higher alcohol elimination rates or ADH (alcohol dehydrogenase, EC1.I.I.I) activities have higher voluntary intakes of alcohol than ones with lower elimination rates. This relationship has now been studied in the AA and ANA rat lines genetically developed, respectively, for high and low alcohol consumption. Female AA and ANA rats had their alcohol elimination rate measured before being given a free choice between 10% (v/v) alcohol and water for 3 weeks. The elimination rate was then measured again and liver ADH activity was determined. The alcohol elimination rate was significantly higher in AA than ANA rats before drinking and was increased by alcohol drinking in AA but not ANA rats. ADH activity was similar in both lines and unrelated to either alcohol drinking or elimination rates, suggesting that the enzyme activity is not a rate-limiting factor in the alcohol metabolism of these two lines. The present results support the conclusion that alcohol elimination and alcohol consumption are partially determined by genetics. Furthermore, although alcohol elimination itself probably does not have direct control over drinking, some factor related to the alcohol elimination rate appears to be among the mechanisms influencing the level of alcohol drinking.


Measurement of carbohydrate-deficient transferrin by isoelectric focusing/western blotting and by micro anion-exchange chromatography/radioimmunoassay: comparison of diagnostic accuracy. At present, the most reliable marker of recent and heavy alcohol intake is carbohydrate-deficient transferrin (CDT). While most CDT quantitation methods (including immunofixation and micro anion-exchange chromatography [MAEC] combined with radioimmunoassay [RIA]) either lack the precision required for diagnostic usage or are not commercially available, we recently described an isoelectric focusing/Western blotting (IEF/WB) procedure that provides sensitive and specific assessment of serum CDT content. However, a modified MAEC/RIA kit, supposedly more reliable than the original, is also being advanced as suitable for widespread clinical application. Therefore, we compared this modified MAEC/RIA procedure to the IEF/WB method of CDT quantitation in the following 108 subjects; 53 alcoholics undergoing detoxification without clinical or histological evidence of liver disease, 24 recently drinking alcoholics with biopsy-proven liver disease, eight alcoholics abstinent for more than 30 days with biopsy-proven liver disease, seven non-drinking patients with non-alcoholic liver disease, and 16 healthy controls. Although CDT measurements by the two methods were correlated (r = 0.60, P < 0.01), serum CDT values obtained with IEF/WB were nearly five-fold higher than those obtained with MAEC/RIA (e.g. 140.0 +/- 58 versus 28.5 +/- 16 mg/l among the active drinkers). Of the two methods, IEF/WB exhibited significantly greater sensitivity than MAEC/RIA for detecting recent, heavy drinking (75% versus 61%, P < 0.05) and generated no false positives whereas MAEC/RIA gave falsely elevated CDT levels in 37% of the abstinent alcoholics.(ABSTRACT TRUNCATED AT 250 WORDS)


Korsakoff minus Wernicke syndrome.

Korsakoff minus Wernicke syndrome. It is commonly believed that Korsakoff's amnesic state in alcoholics is characteristically the sequel to Wernicke's disease. However, in a study of 44 Korsakoff patients it was found that 33 had developed serious memory impairment without having had alarming neurological symptoms. This insidious nature of the onset of the disease indicates that all alcohol-dependent patients should be treated with vitamin B.


Drinking patterns among medical in-patients with reference to MAST categories: a comparative study. The aim of the study was to describe the drinking patterns and alcohol consumption of patients screened by the Michigan Alcoholism Screening Test (MAST) in a sample of medical patients from a general hospital of a French-speaking, wine-drinking country. Data were recorded using a structured interview administered to 103 consecutively admitted 20-75-year-old MAST-positive patients and 103 age-matched and sex-matched MAST-negative controls admitted to the same ward. Relevant differences between MAST-positive and MAST-negative patients included the frequent report of recent and total abstinence in MAST-positive patients (23% versus 4% in controls), their tendency to drink alone, and less often during mealtimes, at home, or with family or friends than MAST-negative patients. Alcohol consumption was significantly higher in MAST-positive patients of both sexes with 250 and 270 g per week being the optimal discriminative cut-off level of consumption for men and women, respectively (kappa coefficient, 0.70 and 0.81, respectively). Regular drinking was the predominant drinking status of both MAST-positive and MAST-negative patients. This study suggests that a screening test such as the MAST, developed in an English-speaking country may be useful in a French-speaking, wine-drinking country. The test identified patients with drinking patterns that are culturally abnormal, yet in certain respects similar to those of alcoholic patients from other drinking cultures. These findings therefore emphasize the worldwide relevance of the concept of the alcohol dependence syndrome in addition to the transcultural usefulness of alcoholism screening tests.


Amniotic fluid index: correlation with amniotic fluid volume. We calculated the amniotic fluid indexes (AFIs) of 310 women on 459 occasions. Normative data were analyzed and compared with data in several high-risk groups. In the normal gestations there was a progressive increase in AFI with advancing gestation until 32 weeks, after which there was a decline. The mean AFIs in abnormal gestations varied with the clinical diagnoses. These values were compared to those obtained by assessing amniotic fluid volume (AFV), that is a pocket more than 2 cm. There were 51 patients with abnormal AFVs. Forty-two had decreased fluid, six also had decreased AFIs; nine had increased AFVs and five (all with diabetes) also had increased AFIs. Thus, AFIs in normal pregnancies showed an orderly pattern of change with gestational age, and there was no accurate correlation between AFI and AFV. Thus, using AFV alone may lead to false interpretations of amniotic fluid status.


Control of inspiratory timing in newborn infants. In order to determine if inspiratory time in preterm infants was influenced by lung volume, two studies were carried out. In the first investigation, carbon dioxide was used to stimulate tidal volume to a level three to six times normal. The anticipated decrease in inspiratory time at increased tidal volumes was not found. These preterm infants behaved in a similar fashion to vagotomized animals studied in the same way by Clark and von Euler. In the second investigation, Hering-Breuer activity was measured in relation to lung volume changes occurring with growth, measured in a body plethysmograph. Although thoracic gas volume correlated well with age and weight, inspiratory slowing with airway occlusion was found to be independent of both age and lung volume. These investigations suggest that neurologic factors have a significant influence on the inspiratory time in newborn human infants.


Comparison of fetal lung maturation in preterm singleton and twin pregnancies. Preterm labor or premature rupture of membranes is one of the major complications of twin pregnancies and contributes to the increased maternal and perinatal morbidity and mortality. Forty-seven twin pregnancies and a comparable group of singleton pregnancies constitute the study population. These patients' pregnancies were complicated only by preterm labor. The lecithin to sphingomyelin ratio is used as an index of fetal lung maturation. Analysis of the data reveals that fetal lung maturation is biochemically comparable between twin and singleton pregnancies and among twins for a given gestational age in this clinical setting.


Urinary arginine vasopressin excretion and hyponatremia in the sick neonates. We attempted to clarify the renal physiologic response to arginine vasopressin (AVP) in the 12 sick neonates: three with respiratory distress syndrome (RDS), three with meconium aspiration syndrome, two with transient tachypnea of the newborn, two with neonatal asphyxia, and two low birthweight infants during the first 2 days of life. Plasma atrial natriuretic factor (ANF), urinary AVP, osmolality, free water clearance and creatinine clearance (Ccr) were measured at 8 to 16 hours of life (stage 1) and 24 to 32 hours of life (stage 2). Urinary AVP was expressed as the ratio of AVP to Ccr (urine AVP/Ccr). These subjects were divided into two groups: group A represented five infants with a urine AVP/Ccr ratio of 2000 or higher and group B, seven infants with a ratio of less than 2000 at stage 1. Hyponatremia occurred in two infants of group A at stage 2. Number of infants on mechanical ventilation was four in group A and one in group B. There were no significant differences in gestational age, birthweight, Apgar scores at 1 and 5 minutes, blood gas pH and mean arterial blood pressure between groups A and B. A good correlation was observed between logarithm of urine AVP/Ccr ratio and urinary osmolality (p < 0.01). A negative correlation was observed between logarithm of urine AVP/Ccr ratio and free water clearance (p < 0.01). Body weight of infants of group A at stage 2 was greater than at stage 1 (p < 0.05). Higher plasma ANF concentrations were observed in infants of group A at stage 2 when compared with those at stage 1 (p < 0.1).(ABSTRACT TRUNCATED AT 250 WORDS)


Perinatal bacteremia due to group F streptococci. Perinatal septicemia due to Lancefield groups A, B, C, and G, but not the group F, streptococci have been documented. A case of perinatal bacteremia and septicemia due to group F streptococci is described.


Prenatal ultrasonic prediction of autopsy-proven pulmonary hypoplasia. The sensitivity, specificity, and positive and negative predictive values for ultrasound estimation of fetal chest circumference in relation to autopsy-proven pulmonary hypoplasia are described in 58 singleton pregnancies at risk (39 with associated preterm premature rupture of the membranes at 30 weeks' gestation or less and of 12 or more days' duration, and 19 with associated anomalies). The ultrasonographic diagnosis of pulmonary hypoplasia was based on values at or below the lower limit of the 95% confidence intervals (for predicting a future observation) for normal pregnancies for each of the following tests; chest circumference in relation to gestational age and to femur length, for the chest circumference to abdominal circumference ratio and for a combination of the three measurements. At necropsy, the diagnosis of pulmonary hypoplasia was based on lung weight to birthweight ratio or radial alveolar counts. Pulmonary hypoplasia was diagnosed in 16 cases at autopsy. The clinicians and the pathologist were blinded to the ultrasonographic measurements. All tests performed well with a sensitivity of 0.55 to 0.80, specificity of 0.90 to 1.00, positive predictive value of 0.80 to 1.00, negative predictive value of 0.87 to 0.91, and an overall accuracy of 0.87 to 0.91. We conclude that ultrasound measurement of fetal chest circumference is of value with regard to the management of pregnancies at risk for lethal pulmonary hypoplasia.


Transvaginal sonography at 5 to 14 weeks' gestation: fetal stomach, abnormal cord insertion, and yolk sac. Transvaginal ultrasound evaluation of the fetal digestive system was performed on 1000 fetuses at 5 to 14 weeks' gestation. The normal physiologic process of the midgut herniation into the cord as well as the embryonal connection between the yolk sac and fetus were detected. Peristalsis of the stomach was noted as early as 14 weeks' gestation. Because gastric emptying is probably improper at this age, gastric pseudomasses were visualized in some cases.


Significance of atypical cervical cytology in pregnancy. To ascertain the significance of squamous atypia encountered during routine Papanicolaou smear screening in pregnancy, we reviewed our experience with 76 pregnant women seen during a 4-year period. All were evaluated with repeat cytology and colposcopy during pregnancy and again postpartum. Colposcopic examination during pregnancy revealed a normal transformation zone without evidence of intraepithelial neoplasia in 46 women. In six of these women, repeat cytology was interpreted as cervical intraepithelial neoplasia (CIN) grade 1. In 30 women, an abnormal transformation zone was identified--14 with a negative repeat cytology. In five women, the transformation zone was interpreted as compatible with CIN 2 or CIN 3. Colposcopically directed biopsies were performed in 31 women, in all but two postpartum. Of the 76 women, human papilloma virus or CIN was identified on biopsy in 16 women (21%). We propose that an isolated report of atypical squamous cells on cervical cytology obtained at the initial prenatal visit does not warrant colposcopic evaluation during pregnancy, unless a repeat cytology suggests CIN. Repeat cytology and evaluation to exclude infections and inflammatory lesions is appropriate. However, if a subsequent cytology is abnormal, postpartum colposcopy and colposcopically directed biopsies seem appropriate, since the prevalence of HPV or CIN was 21%.


Fetoplacental and uteroplacental Doppler blood flow velocity analysis in premature rupture of membranes. The value of Doppler velocimetry in predicting fetal distress or perinatal infection was investigated in 60 patients with premature rupture of the membranes (PROM) between 25 and 38 weeks of gestation. Studies were performed in the umbilical and uterine arteries after admission to the hospital and repeated every 24 to 76 hours until delivery. Results of the last study, performed less than 24 hours before delivery and comparison between longitudinal studies in the same patient, failed to disclose statistical differences between patients who did or did not develop the perinatal complications under study. We conclude that Doppler velocimetry is not a sensitive enough means of predicting fetal distress or infection in PROM.


Prediction of pregnancy outcome by combined analysis of the fetal electrocardiogram and systolic time intervals. A microcomputer-based system has been developed that continuously analyzes the fetal electrocardiogram (ECG) and Doppler cardiogram during labor by noninvasive means. Three systolic time intervals (preejection period [PEP], ventricular ejection time [VET], and isovolumetric contraction time), and four ECG parameters (P-R interval, QRS wave duration, T/QRS amplitude ratio, and S-T slope) are simultaneously measured and displayed. Normal values were derived from 126 uncomplicated pregnancies at term. A second group of 89 cases showing fetal heart rate patterns suggestive of fetal distress were subsequently studied: 64 had a good outcome (umbilical artery pH 7.20 or higher and a 5-minute Apgar score 7 or greater) and 25 were asphyxiated. Results were retrospectively analyzed. All asphyxiated fetuses had preejection period, PEP to VET ratio and T to QRS ratio values of more than 1 SD above the mean for the normal population. The PEP to VET ratio, which is an indicator of myocardial function independent of heart rate, proved to be the most sensitive predictor of fetal asphyxia. We conclude that analysis of systolic time intervals and ECG parameters of the fetal heart during labor improves the diagnostic accuracy of fetal heart rate monitoring.


Severe preeclampsia in preterm pregnancy between 26 and 32 weeks' gestation. Obstetric management of severe preeclampsia between 26 and 32 weeks' gestation presents a significant management dilemma. We examined the antenatal courses and perinatal outcomes of 67 such affected pregnancies and compared them with a group of 134 patients, matched for gestational age, who delivered after preterm rupture of membranes or preterm labor. Although the severe preeclamptic group had more patients with chronic hypertension and renal disease, 67% had no prior medical problems. The obstetric and other medical characteristics of both groups were similar. Neonatal outcomes in the severe preeclampsia group differed from those in the control group: they had lower mean birthweight, 5-minute Apgar score and umbilical arterial pH were lower, and their rates of respiratory distress syndrome and perinatal death were higher. Temporization for more than 72 hours was not possible in 60 of 67 preeclamptic pregnancies due to rapid deterioration of the mother (56 cases) or fetus (4 cases). The rate of poor neonatal outcomes in severe preeclampsia exceeded that expected with preterm delivery alone and may reflect preexisting fetal compromise, served better by early intervention and delivery.


Significance of positive cervical cultures for Chlamydia trachomatis in patients with preterm premature rupture of membranes. We tested the hypothesis that in patients with preterm premature rupture of membranes the presence of Chlamydia trachomatis in the cervix shortens the latent period (time from rupture of membranes to delivery) and increases the incidence of chorioamnionitis and early endometritis. A total of 178 conservatively managed patients with PROM between 22 and 35 weeks' gestation had cervical cultures for chlamydia, group B Streptococcus (GBS) and Neisseria gonorrhoeae performed at the time of rupture. Patients with GBS and gonorrhea were treated at the time the culture results were available and excluded from analysis. The remaining patients were divided into group 1: 26 patients (14.6%) positive for only chlamydia (and not treated until discharge from the hospital); group 2: 120 patients (67.4%) negative for all three organisms. The two groups did not differ in cesarean rate, duration of conservative management, hospital stay, or birthweight. Furthermore, the rates of chorioamnionitis (30.8% group 1; 38.3% group 2) or early endometritis (11.5% group 1; 20.8% group 2) were similar. We conclude that in patients with preterm premature rupture of membranes, the presence of chlamydia in the cervix appears to neither decrease the latent period nor increase the incidence of chorioamnionitis and early endometritis.


Ultrasonographic assessment of fetal and neonatal spleen. To assess the growth and function of the fetal spleen, ultrasonographic examinations were performed on 229 normal fetuses, ranging from 20 to 41 weeks, menstrual age. Curvilinear relationships were found between the menstrual age and splenic length (R2 = 92.7%), circumference (R2 = 93.9%), and area (R2 = 95.2%). A normal range of splenic length, circumference, and area measurements for estimating the growth of the fetal spleen during normal pregnancy was generated. Splenic parameter values just after delivery were significantly lower than those measured within 7 days before delivery, and returned to former sizes 24 hours later, in both vaginal delivery and cesarean section groups. Splenic parameter values in the vaginal delivery group were also significantly lower than those in the cesarean section group, just after delivery. Moreover, neonatal splenic length showed negative correlations with lactate dehydrogenase (p < 0.001) and glutamic oxaloacetic transaminase (p < 0.05) in the umbilical venous blood, respectively. These results provide a foundation for the evaluation of fetal splenic growth and function during pregnancy and the early neonatal period.


Characteristics associated with successful weaning in ventilator-dependent preterm infants. Eighteen ventilator-dependent preterm infants with hyaline membrane disease were studied for 24 hours before and after an attempt at extubation. All were treated with theophylline prior to weaning and achieved average levels of 8.9 +/- 1.7 micrograms/ml (49 +/- 9 mumol/liter) in 13 successfully weaned infants and 8.4 +/- 1.1 micrograms/ml (47 +/- 6 mumol/liter) in 5 infants not extubated, p > 0.05. Infants successfully weaned were significantly (p < 0.01) older, more mature (29 +/- 1 versus 26 +/- 2 weeks' gestational age) and heavier (1107 +/- 236 versus 1016 +/- 256 gm) than infants not successfully extubated. Infants successfully weaned differed only in developing a greater maximal inspiratory force (33.8 +/- 12.3 versus 23.3 +/- 15.0 cm H2O) and higher compliance (1.1 +/- 0.3 versus 0.7 +/- 0.3) during the preweaning treatment period. These results indicate that maturity and size play a significant role in the ability to wean a preterm infant from the ventilator successfully, that maximal inspiratory force and compliance are higher in preterm infants who can be successfully extubated, and that methylxanthines do not uniformly improve pulmonary function in all potentially extubatable preterm infants.


Preeclampsia effect on platelet count.

Preeclampsia effect on platelet count. Thrombocytopenia is well recognized when preeclampsia is complicated by the hemolysis, elevated liver tests, low platelet count (HELLP) syndrome. We studied the effect of preeclampsia on the platelets of women whose platelet count and liver function were within normal range. We prospectively evaluated 67 preeclamptic women, gestational age 30 to 42 weeks, with disease of variable severity. The platelet counts of these patients, obtained within 24 hours preceding delivery, were significantly lower than the platelet counts of 71 control subjects. The platelet counts did not differ significantly between patients with mild and severe preeclampsia. Our findings suggest the existence of subclinical thrombocytopenia in preeclamptic women whose platelet values are within normal range.


Reduction in the middle cerebral artery pulsatility index after decompression of polyhydramnios in twin gestation. Amniotic fluid decompression was performed for symptomatic polyhydramnios complicating four sets of discordant twin gestations. Doppler ultrasound waveforms of the middle cerebral artery were determined before and after the procedure in seven of the eight fetuses. After amniocentesis, the pulsatility index of the middle cerebral artery (PIMCA) was reduced in all fetuses (p < 0.01). When one considers only the larger twin in each set, the magnitude of the change in PIMCA was relatively consistent among the different sets (-0.60 +/- 0.14; p < 0.01; range, -0.45 to -0.79). The smaller twins showed a much more variable response (-0.82 +/- 0.70; range, -0.05 to -1.75). The pulsatility index of the umbilical artery (PIUA) showed no consistent trend in the five subjects in which it was determined. In principle, the cerebrovascular dilation indicated by the PIMCA measurements may in part be due to acute increases in maternal and fetal carbon dioxide tensions following relief of maternal restrictive lung dysfunction. More importantly, the acute fall in amniotic fluid pressure--the external pressure to which the fetoplacental unit is exposed--leads to pooling of blood in fetal and placental veins, and thereby reduces the effective blood volume of the fetoplacental unit. This effective hypovolemia, functionally analogous to that produced by fetal hemorrhage, elicits changes in regional vascular resistances that favor cerebrovascular perfusion. The impact of acute amniotic fluid decompression on the fetal circulation reflected in the marked changes in PIMCA suggests a role for monitoring to avoid large acute changes in pressure during therapeutic amniocentesis.


An easy and accurate method of estimating newborn birthweight for resuscitation. Emergency administration of medication based on birthweight is often required in newborn resuscitation. Actual weighing is often delayed because of the emergency situation. Therefore drugs are given according to weight estimates by physicians or nurses. The purposes of this study were to develop a measuring tape using the infant's length and head circumference to determine body weight and to evaluate the performance of the tape measurements to staffs' estimates. Weight, length, and head occipitofrontal circumference (OFC) measurements of 200 newborn infants were collected. By regression analyses, the best log curve for both length and OFC versus weight was determined. From these data, a measuring tape was constructed with the corresponding weights marked for both length and OFC. Forty-five newborn infants with gestational ages of 26 to 40 weeks were studied. Prior to actual weighing, estimates of the birthweights were obtained and recorded from the tape measurements using both the length and OFC and staffs' estimates. For infants less than 2 kg, the average percent error was less by the tape length (1.2%) and OFC (0.7%) compared with staffs' estimates (-7.2%). The tape was also useful in estimating weights of small for gestational age infants. The tape OFC (7.8% error) was more accurate than staffs' estimates (26% error) in these growth-retarded infants. The clinical precision of the tape was 3% with an intrameasurer variability of 5%. We conclude that estimating the birthweight in infants using our tape method is a practical and more accurate way than staff estimates, especially for low birthweight and small for gestational age infants.


Evaluation of a fetal risk-scoring system. A population of 2029 pregnant women (929 primiparas; 1100 multiparas) has been used to examine aspects of the calculation of obstetric risk scores from the presence of individual risk factors. The findings have been related to fetal outcome in these pregnancies and the following conclusions were reached: (1) the use of Bayes theorem for the calculation of a risk score is superior to the simple addition of weighted risk factors; (2) the diagnostic efficiency of a risk score is somewhat reduced when the data base used for calculation of the score is derived from a population different from that of the current pregnancy; (3) there is almost total overlap of risk scores in women with satisfactory and unsatisfactory fetal outcome. It is concluded that risk scores can be used to identify a small group of women at particularly high risk; in the remainder of the population scores are unhelpful except perhaps to indicate the women who do not require an intensive program of antenatal care.


Ultrasonically measured biparietal diameter and abdominal circumference: intra- and interobserver variation in the third trimester. Serial ultrasound measurements of the fetus under investigation is an important indicator of fetal growth, and thus fetal health. To assess how reliable those measurements are, a videotape was made, and, utilizing an ultrasound machine that allowed the placement of callipers on the videotape, the dispersion of the measurements obtained by 17 sonographers was noted. In the individual fetus in the third trimester of pregnancy, a 95% confidence interval of 3.5 and 2 weeks was found, respectively, for the measurements of the abdominal circumference and biparietal diameter (inter- and intraobserver variation combined).


Creation of a neonatology facility in a developing country: experience from a 5-year project in China. In 1983, Project HOPE was invited by Zhejiang Medical University to collaborate in developing a neonatal intensive care unit (NICU) at the Children's Hospital in Hangzhou, China. The initial approach involved renovating facilities, purchasing equipment and supplies, placing short-term consultants in the unit as teachers, and bringing selected leaders to the United States for brief fellowships. An evaluation at 18 months disclosed poor organization and leadership, inconsistent clinical care, and unsatisfactory utilization and maintenance of facilities and equipment. Therefore the strategy was revised to include long-term physician and nursing consultants, establishment of ties with HOPE Biomedical Engineering projects, and development of formal education programs. The unit was transferred to the Chinese after 4 years and an evaluation 1 year after transfer revealed an actively functioning independent NICU with evolving effective leadership, established purchasing and preventive maintenance programs, and continuing formal education activities. Unsatisfactory progress was found with the development of a transport system, some laboratory capabilities, adherence to admission and discharge policies, and various other administrative issues. Although the goal of establishing an independent NICU was realized, perhaps the most lasting accomplishment was the establishment of a facility and a format for development of a transportable education program aimed at improving neonatal care practices throughout a larger region of China.


Neonatal thrombosis with anticardiolipin antibody in baby and mother. The anticardiolipin antibody is associated with increased risk of thrombosis, which is manifested with various clinical presentations, including vascular thrombosis, recurrent fetal wastage, and neurologic defects. We report a case of neonatal thrombosis occurring in the renal vein and inferior vena cava associated with moderate positive anticardiolipin antibody titer in the baby while the maternal serum showed even stronger anticardiolipin antibody of immunoglobulin G class. Subsequent follow-up over the 4 months postpartum period showed a disappearance of the antibody in the baby, whereas the mother's antibody persisted. This case illustrates the fact that the maternal anticardiolipin antibody can be transferred to the fetus and may be a risk factor for thrombosis in the neonates. Anticardiolipin antibody syndrome should be considered in the differential diagnosis of neonatal thrombosis.