Seasonal variations in pineal 5-methoxytryptophol (5-ML) concentrations and in the daily pattern of pineal 5-ML and melatonin in the desert rodent Jaculus orientalis: effect of prolonged illumination during the night. Seasonal variations in daytime pineal 5-methoxytryptophol (5-ML) and in the daily pattern of both pineal 5-ML and melatonin concentrations were measured by radioimmunoassay in male and female jerboas, Jaculus orientalis. Pineal 5-ML content was found to be low in winter and spring and showed a short but marked increase in summer. A clear daily rhythm was present in pineal 5-ML in September, with high concentrations during daytime and low concentrations during nighttime. In May there was a considerable drop in the daytime values and a marked decrease in the amplitude of the rhythm, while in December the daily rhythm completely disappeared. On the contrary, a clear daily rhythm was observed for pineal melatonin in September, December, and May with high values during nighttime and low values during daytime; no differences in the amplitude of the rhythm could be observed. Illumination during early night prevented both the nocturnal decrease of 5-ML and the increase of melatonin in September; in May illumination had no clear effect on 5-ML, while it prevented the normal increase of melatonin. These results suggest a possible desynchronization between the regulation of 5-ML and melatonin synthesis and release, and stress the complexity of the mechanisms involved in the environmental synchronization of seasonal functions.


Regulation of the androgen receptors in the harderian gland of the male Syrian hamster: influence of photoperiod, castration, and chronic melatonin treatment. Male Syrian hamsters that were exposed for 8 weeks to short photoperiod (LD 10:14) or treated with melatonin in the late afternoon under long photoperiod conditions (LD 14:10) had a significantly higher content of androgen receptors in the Lipidex-purified soluble fractions isolated from the Harderian glands as compared to the long photoperiod (LD 14:10) exposed controls. Simultaneous computer-assisted analyses of all series of saturation and competition experiments revealed that the numerical value of the apparent Kd, as determined by using the synthetic androgen R-1881 (methyltrienolone), was not different between the experimental groups, and ranged from 0.050 to 0.067 nM. Of the principal natural androgens, testosterone (T) was most potent in inhibiting methyltrienolone binding to the receptor (Ki values from 0.33 to 0.55 nM), and 5 alpha-dihydrotestosterone (DHT) and delta 4-androstenedione (AD) were less effective (Ki values between 1 and 1.9 nM). In the hypothalami and pituitaries of the same animals, used in parallel control assays, DHT was twice as potent as T. Short-term castration (24 hr post-orchidectomy) did not result in significant changes in the receptor binding characteristics. Following 8 weeks exposure to a long photoperiod (LD 14:10) the Bmax values demonstrated a four-fold increase in castrated animals (179 fmoles/mg protein vs. 47 fmoles/mg protein) over intact controls. The relative binding affinity of the major androgens under these conditions remained unchanged, with the exception of AD, where a five-fold increase in the numerical Ki values (decrease in the binding affinity) was recorded (Ki = 9.6 nM).(ABSTRACT TRUNCATED AT 250 WORDS)


Interruption of nocturnal pineal melatonin synthesis in spontaneous recrudescent Djungarian hamsters (Phodopus sungorus). The duration of nighttime synthesis of the pineal hormone melatonin is believed to determine the breeding season in many mammalian species. Hamsters exposed to short days undergo gonadal involution followed by a return to normal function, suggesting a developed insensitivity to regressive photoperiods. This recrudescence may be due to either exhaustion of the pineal or to target-desensitization. Both theories have been tested previously but failed to explain this phenomenon. We performed an experiment in the Djungarian hamster (Phodopus sungorus), a well-characterized photosensitive species with a type C melatonin pattern (prolonged peak during majority of dark phase), in an attempt to resolve this issue. Among age-matched male hamsters exposed to short days for either 16 weeks (involuted) or 38 weeks (spontaneous recrudescent), marked phase differences in diurnal pineal melatonin rhythms were observed. Furthermore, in recrudescent hamsters the melatonin pattern was divided into two parts, possibly no longer recognizable as a typical short-day rhythm.


A phase-dependent delay of the chick pineal rhythm in rate of thymidine incorporation by brief exposure to ouabain. Cultured chick pineal glands show a persistent rhythm in the rate of cumulative incorporation of thymidine into DNA [Wainwright and Wainwright, 1989]. In this study we have examined the effects of a pulse-exposure to ouabain in the dark on the first day of culture upon thymidine incorporation during the second and third days of culture in the dark with ouabain-free medium. The phase of the rhythm in rate of thymidine incorporation was delayed by a 4-hr exposure to 100 microM ouabain commencing in the final hour of the photoperiod, but not by a 2-hr exposure or by 10 microM ouabain. This effect was phase-dependent and not seen when exposure to ouabain began earlier in the photoperiod. The phase delay caused by ouabain was not due to a persistent direct inhibition of the process of thymidine incorporation. The phase-shift due to exposure to ouabain was superimposed on a phase delay caused by renewal of culture medium 4 hr after explanting the glands into culture.


A new biodegradable elastin-fibrin material; its use in urological, digestive and cardiovascular surgery. A new original artificial connective matrix mainly made of elastin and fibrin-like product is used to reinforce damaged tissues and to close and restore a loss of substance in several domains of surgery: all sites in the digestive system and urinary tract; besides, it can substitute for the pericardium in iterative heart operations. In all cases, the original tissue is restored ad integrum while the biodegradable material disappears completely, without any complications.


Polymeric membranes for silicon based (bio)sensors. During the last decade, chemical and biochemical sensor research has benefited from the availability of new technologies and materials. New embodiments of classical devices have resulted from the use of e.g., solid state technology for the realization of the transducers. In this paper we describe several examples of membrane deposition techniques used in connection with planar, silicon based electrochemical transducers. Casting and electrochemical deposition of glucose oxidase containing membranes are described for the fabrication of glucose enzyme electrodes. Photolithographic patterning of polyacrylamide hydrogel and of siloxane based gas permeable membrane is used for the realization of an amperometric oxygen sensor and an ISFET-based pCO2 device. The last example is that of a free-chlorine sensor for which the photolithographic patterning of the polyHEMA hydrogel layer is described.


Effect of pretreatment with epoxy compounds on the mechanical properties of bovine pericardial bioprosthetic materials. Early failures of bovine pericardial heart valves are due to leaflet perforation, tearing and calcification. Since glutaraldehyde fixation has been shown to produce marked changes in leaflet mechanics and has been linked to development of calcification, bovine pericardium fixed with the four hydrophilic epoxy formulations and their mechanical properties are studied in this paper. We measured the thicknesses, shrinkage temperatures, stress relaxations and stress-strain curves of bovine pericardiums after different treatments with (1) non-treatment (fresh), (2) glutaraldehyde (GA), (3) epoxy compounds followed by the posttreatment with GA (EP 1#, EP 2#), and (4) epoxy compounds (EP 3# and EP 4#). Results of this study showed that the hydrophilic epoxy compounds are good crosslinking agents. There are no significant differences of shrinkage temperature and ultimate tensile stress among all tissue samples pretreated with GA, EP 1# and EP 2#. However, the stress relaxations of tissue-samples pretreated with epoxy compounds followed by the posttreatment with GA (EP 1# and EP 2#) are significantly slower than that pretreated with GA, and the strains at fracture of EP 1# and EP 2# are also significantly larger than that of GA or epoxy compounds. These facts show that the bovine pericardium pretreated with the epoxy compound followed by the posttreatment with GA (EP 1# and EP 2#) possesses greater tenacity and potential durability in dynamic stress.


Bioactive polymers 55. Synthesis and characterization of a macromolecular drug based on 5-acetylamino-2-sulfamoyl-1,3,4-thiodiazole. The paper studies the coupling reaction by covalent bonding of acetylamino-2-sulfamoyl-1,3,4-thiodiazole (AcAA) on the poly(acrylic acid-costyrene) copolymer (PAcA-S) in homogeneous system, in the presence of dicyclohexylcarbodiimide (DCC) as activator. The influence of some factors on coupling efficiency (the drug/support ratio, time, volume of solvent), as well as the mathematical model correlating the amount of coupled drug with these parameters is established. Maximum amounts of drug (28%) are chemically bound when employing maximum values of the parameters mentioned (i.e., AcAA/PAcA-S ratio = 2 mole/mole; time = 50 h; THF volume = 60 ml). Physicochemical and spectral analyses evidence the existence of some chemical bonds of the -CO-NH-SO2-type between the macromolecular support and the drug. In vivo tests have demonstrated the gradual hydrolysis of the chemical bonds as well as the release of the drug, due to the diuretic effect produced.


Nursing in child psychiatric milieus: Part I: What nurses do. Because of the reduced length of inpatient hospitalization and the increasing emphasis on biopsychiatric treatments, milieu psychiatry is in decline. However, certain aspects of the therapeutic milieu are essential to the operation of child inpatient units. Children with acute psychiatric illness need a safe, structured, and supportive environment. Nurses are the professional group responsible for instituting and maintaining this type of environment, yet their specific functions are vaguely stated and often intuitively derived. A useful way to delineate and describe what nurses do is to organize nursing behaviors into five therapeutic processes: (a) safety, (b) structure, (c) support, (d) involvement, and (e) validation. By delineating essential milieu dimensions in this way, the form and purpose of nursing interventions are clarified.


Nursing in child psychiatric milieus: Part II: Mapping conceptual footholds. In the first part of this paper, child inpatient nursing practice was organized into five therapeutic processes (safety, structure, support, involvement and validation). Using this organization of nursing care, three specific practice question are now addressed. One, how will nursing blend their traditional psychosocial orientation with biological psychiatry? Two, how might nurses best respond to the pressure to reduce the length of hospitalization yet still effectively intervene with troubled children? Three, does the traditional milieu therapy model have clinical utility for child inpatient nurses in the 1990's. It is suggested that nursing practice is best supported by multiple midrange theories which clarify children's behavior and give theoretical support to specific nursing interventions.


[Translocation mechanism of presecretory protein across the cytoplasmic membrane of Escherichia coli]. Translocation of presecretory proteins across the cytoplasmic membrane of Escherichia coli requires several Sec proteins and two kinds of energies, adenosine triphosphate (ATP) and a proton motive force. In vitro assay system established for the analysis of protein translocation revealed that ATP and the proton motive force play different roles in protein translocation. SecA, a peripheral membrane protein, was shown to be essential for in vitro protein translocation. SecE and SecY, both of which are integral membrane proteins, were purified from E. coli cells overproducing these proteins, and reconstituted into proteoliposomes. The reconstituted proteoliposomes exhibited protein translocation activity in the presence of ATP and SecA, indicating that SecE and SecY as well as SecA are indispensable components of protein translocation machinery. In this paper, the molecular mechanism of protein translocation across the membrane of E. coli is discussed based on the recent data obtained by both in vitro and reconstitution systems.


[Structural alterations of the N-linked sugar chains of glycoproteins produced by tumor cells and their clinical application]. Enrichment of complex type N-linked sugar chains containing the Gal beta 1----4GlcNAc beta 1----6(Gal beta 1----4GlcNAc beta 1----2)Man group was found to be the structural background of Warren-Glick phenomenon. This alteration is induced by enhanced expression of N-acetylglucosaminyltransferase V in malignant cells. The phenomenon is positively correlated with the tumorigenicity and the potency of blood-borne metastasis of tumor cells. Further investigation of the surface sugar chains of lectin mutants of mouse B16 melanoma revealed that the occurrence of sialylated tetraantennary sugar chains is essential for the metastasis of tumor cells.


[Hypoglycemic activity of polysaccharide fraction from rhizome of Rehmannia glutinosa Libosch. f. hueichingensis Hsiao and the effect on carbohydrate metabolism in normal mouse liver]. The ethanol precipitate fraction (RG-WP) obtained from the hot water extract from rhizome of Rehmannia glutinosa Libosch. f. hueichingensis Hsiao is mainly composed of pectin-like polysaccharide, and exhibited hypoglycemic activity in normal and streptozotocin-induced mice by intraperitoneal administration of the fraction. The results obtained after chemical modification and proteinase treatments of RG-WP suggest that the activity exists in the polysaccharide moiety. Furthermore, the effect of RG-WP on the activities of enzymes responsible for the glucose metabolism in the liver of normal mouse was studied to elucidate the mechanism of the hypoglycemic activity. Administration of RG-WP to normal mice significantly increased the activities of hepatic glucokinase and glucose-6-phosphatase dehydrogenase, but decreased those of hepatic glucose-6-phosphatase and phosphofructokinase. RG-WP stimulated the secretion of insulin and reduced the glycogen content in the liver of normal mouse.


The effect of a bereavement group experience on bereaved children's and adolescents' affective and somatic distress. Losing loved ones through death is a common experience for children. Children living in urban centers may be at greater risk for death of family members as a result of increased daily stress and poverty. Children who experience permanent loss of family members without support to grieve are at greater risk for mental health problems. Manifestations of grief that frequently occur in children are psychosomatic complaints and affective distress. This study investigates the prevalence of loss by death among two groups of inner city youths, and the impact of a bereavement group experience on subjects' affective distress and somatic complaints. A significant difference was found between pretest and post-test scores on somatic complaints for the elementary school aged group.


Multiple family therapy for adolescents: a case illustration. Psychiatric hospitalization of adolescents is on the rise, with the concurrent trend toward shorter stays and increased need for expedient, effective treatment modalities. Involving families or troubled adolescents in all phases of treatment is believed to be essential and aids both in successful reintegration of the patient into the community and prevention of relapse. Psychiatric nurses can practice innovative therapies to meet the needs of hospitalized adolescents and their families. Clinical observations have shown multiple family therapy for adolescents to be a valuable component of care.


[Crystal morphological and habit investigations of crystalline drugs. I. Phenytoin]. Crystal morphology and crystal habit of phenytoin crystals were studied by the immersion method using a polarizing microscope. Several kinds of phenytoin materials, which had been confirmed to be lying on the same orientation by measuring key refractive indices, were photographed under crossed polars. The relationship between the patterns of retardation colors and the shapes of the phenytoin crystals were analyzed quantitatively using the chart indicating the relation of thickness to retardation colors, and concurrently several necessary facial angles were measured. On the basis of these results as well as edge angles measured under a microscope a stereographic projection was drawn finally, and an orthorhombic symmetry, an axial ratio and some facial angles were determined. Several kinds of crystal habits observed from the photographs were drawn by the classic crystallographic habit drawing method using the stereographic projection.


Sibling incest: a descriptive study of family dynamics. This study investigates the characteristics of families in which a member was identified as a victim of sibling incest. Four agencies in a southeastern city provided a convenience sample of 14 family case records from November 1986 through April 1988 for review. Sixteen children were identified as victims of sibling incest, including three boys and 13 girls between the ages of 2 and 10 years (mean = 6.75 years). Perpetrators included 1 girl and 14 boys between the ages of 13 and 17 years (mean = 15.06 years). The incestuous relationship had a major impact on families, especially the children. Many offenders and victims, in addition to experiencing emotional, school, and legal problems, were removed from their homes.


[Preparation of phenyl treated packing materials for high-performance liquid chromatography: evaluation by retention behaviour of carbamazepine and diphenylhydantoin]. The retention behavior and selectivity of 30 kinds of phenyl-modified porous glasses and silicas, prepared from solutions of phenyldimethylchlorosilane, diphenylmethylchlorosilane or triphenylchlorosilane in xylene, were studied by high-performance liquid chromatography using carbamazepine and diphenylhydantoin as model compounds. From the elemental data for carbon, the maximum number of bonded phenyl groups per gram (mean pore diameter, 15 nm, specific surface area, 217 m2/g, pore volume, 0.85 ml/g) on the diphenyl-bonded glass surface was calculated to be 0.159 x 10(21). Using various acetonitrile-0.01 M potassium dihydrogen phosphate mixtures as eluents, carbamazepine and diphenylnydantoin were separated on all the gels studied, but the degrees of resolution of the two compounds were different. With an increase in specific surface area on the glasses or silicas, the k' values of the solute increased.


[Determination of the main metabolite (desethyl KBT-3022) of a new antiplatelet agent, KBT-3022 in plasma by gas chromatography]. A highly sensitive, accurate and reproducible gas chromatographic method for the determination of a main metabolite, 2-[4,5-bis(4-methoxy-phenyl)thiazol-2-yl] pyrrol-ylacetic acid (desethyl KBT-3022) of a new antiplatelet agent, ethyl 2-[4,5-bis(4-methoxyphenyl)thiazol-2-yl]pyrrol-1-ylacetate (KBT-3022), in the human or dog plasma has been developed. Desethyl KBT-3022 in the plasma was extracted with a mixture of n-hexane and dichloromethane (1:1), and was derivatized using pentafluorobenzyl bromide. The obtained pentafluorobenzyl derivative of desethyl KBT-3022 in the plasma was separated by high-performance liquid chromatography. After the separation, the pentafluorobenzyl derivative of desethyl KBT-3022 was detected by gas chromatography. Gas chromatography was performed with a Ultra 1 column (12 m x 0.22 mm i.d., film thickness 0.33 microns), using an electron capture detector. 2-[2-(4,5-Bis(4-methoxyphenyl)thiazol-2-yl)pyrrol-l-yl]propionic acid was used as an internal standard. The detection limit of desethyl KBT-3022 in the plasma was 0.2 ng/ml. The coefficients of variation were below 5.3%. This method was applied to the determination of the plasma concentration of desethyl KBT-3022 after oral administration of KBT-3022 to dogs.


Preparing to parent the adolescent: a theoretical overview. Early adolescence (ages 11-14 years) occurs at the time most parents are in middle adulthood. The tasks of both early adolescent and middle adulthood stages are numerous and complex. As a societal unit, the family is challenged to meet one another's needs for cohesion, adaptability, and satisfaction. Family communication and the family's ability to resolve conflicts are proposed as facilitating factors to meet these challenges.


[Elucidation of biosynthetic process and regulation mechanism of bioactive peptides and their receptors]. To elucidate the mechanism of proinsulin induction by glucose, we determined the amount of proinsulin messenger ribonucleic acid (mRNA), the subcellular distribution of proinsulin mRNA and the transcriptional activity of proinsulin gene in isolated pancreatic islets of rat. From these results, we concluded that the stimulation of proinsulin synthesis was mainly regulated at the translational level. To elucidate the primary structure of vasoactive intestinal peptide (VIP) precursor, we determined the nucleotide sequence of VIP complementary deoxyribonucleic acid (cDNA). The entire amino acid sequence of the VIP precursor indicates that the precursor protein contains not only VIP but also PHI-like peptide. We also found that the induction of pro-VIP synthesis was achieved by enhancing the transcription rate of VIP gene. We also isolated fibroblast growth factor (FGF) receptor cDNA. The nucleotide sequence of FGF receptor cDNA indicates that the receptor is a transmembrane protein that contains extracellular immunoglobulin-like domains and an intracellular tyrosine kinase domain. We also found that the receptor had two isoforms of the extracellular domains and that the expression of the isoforms was regulated tissue-specifically.


[Prostaglandins: synthetic and pharmacological studies and development]. The therapeutic use of prostaglandins (PGs) which contain various biological activities and are unstable was successfully achieved. PGs were produced in a large scale according to the Corey method and could be stabilized by the formation of a clathrate compound with cyclodextrin, which enabled the production of marketable form of highly pure PGs. Diligence in the development of native PGs and their structural analogs for human therapy resulted in the following six drugs now being on the market in Japan: PGF2 alpha as the first drug of PGs in the world which induces labor; PGE2 as an orally active labor inducing drug; PGE1 for the treatment of peripheral vascular diseases; gemeprost for therapeutic abortion in the middle-term; ornoprostil, as an oral anti-ulcer agent; limaprost for the treatment of peripheral vascular diseases as an oral agent.


[Syntheses and central depressant activity in mice of uracil derivatives. Studies on development of new sedative-hypnotics. II]. Fifteen kinds of uracil derivatives, which were substituted with functional groups such as benzyl (Bn), methoxymethyl (MOM), n-propyl (Pr) or allyl (A) group at the N1 and/or N3 position of uracil, were synthesized. Sedative-hypnotic activity, pentobarbital (PB)-induced sleep prolongation and acute toxicity as indices of their pharmacological activities were evaluated using mice. Spontaneous activities of mice treated with N1-benzyluracil (N1-BnU, 7), N3-benzyluracil (N3-BnU, 8), N1,N3-dibenzyluracil (DBnU, 9), N1-benzyl-N3-allyluracil (BnAU, 14) and N1-allyl-N3-benzyluracil (ABnU, 15) were measured. Ten kinds of uracil derivatives showed hypnotic activity. ED50's values of ABnU (15) and N1-propyl-N3-benzyluracil (PrBnU, 13) were 155 and 172 mg/kg, i.p., respectively. Those effects were more potent than that of barbital (179 mg/kg, i.p.) Ten kinds of uracil derivatives tested significantly prolonged the PB-induced sleeping time. N3-BnU (8) increased the spontaneous activity of mice at a dose of 80 mg/kg, i.p., while ABnU (15) depressed the spontaneous activity at a dose of 160 mg/kg, i.p. The other compounds did not show any significant effect on the spontaneous activity of mice. LD50's values of ABnU (15), PrBnU (13) and N1-methoxy-methyl-N3-benzyluracil (MOMBnU, 11) were 199, 229 and 363 mg/kg, i.p., respectively. LD50's values of the other derivatives were more than 480 mg/kg, i.p. These results indicate that the benzyl group at the N3 position of uracil is important for exhibiting sedative-hypnotic activity of uracil derivatives, and that ABnU (15) has the most potent central depressant activity among the uracil derivatives tested.


[Studies on zwitter-ionization of drugs. I. Synthesis and pharmacological activities of N-alkylcarboxylic acid derivatives of 4-(2-chlorodibenz-[b,f][1,4]oxazepin-11-yl)piperazine, 4-(2-chlorodibenzo[b, f]-[1,4]thiazepin-11-yl)piperazine, and 4-(11H-dibenz-[b,e]azepin-6-yl)piperazine]. The piperazine N-alkylcarboxylic acids of 2-chlorodibenz[b,f][1,4] oxazepine (3a), 2-chlorodibenzo[b,f] [1,4] thiazepine (3b), and dipenz[b,e] azepine (3c) from the corresponding piperazines (1a-c, R1 = H) were synthesized via the piperazine N-alkylcarboxylates (2a-c). The pharmacological activities of the piperazine N-alkylcarboxylic acids (3a-c) were evaluated. Compared with the parent compounds (1a-c), 3a-c (n = 1-5) showed weak inhibitory activities on the uptake of noradrenaline and 5-hydroxytryptamine (5-HT) into hypothalamus vesicles and moderate antagonistic actions to 5-HT2 and H1 in several tissues.


[Elucidation on abnormal behavior of glycyrrhizin salts in high performance liquid chromatography determination for quasi-drug products]. Glycyrrhizinates such as monoammonium and dipotassium glycyrrhizinates which are extracted from licorice, converted to easily water-soluble salts and refined have been formulated in many quasi-drug products as an anti-inflammatory agent. A quantitative analysis of glycyrrhizinates in quasi-drug products has usually and successfully been carried out by high performance liquid chromatography (HPLC). However, a slightly higher value than the actual content has sometimes been observed in daily analysis. As the result of our various studies to investigate these phenomena, we finally found that a minor constituent in commercial glycyrrhizinates, which was identified as monomethyl glycyrrhizinate, was hydrolyzed after they were formulated in quasi-drug products and converted to glycyrrhizin which in turn was determined by HPLC as a higher value.


[Pharmacological study on kefir--a fermented milk product in Caucasus. I. On antitumor activity (1)]. The antitumor activity of kefir (YK-1), a fermented milk product in Caucasus, was investigated. YK-1 at oral doses of 100 or 500 mg/kg inhibited the proliferation of solid tumor of Ehrlich ascites carcinoma transplanted subcutaneously in mice. YK-1 did not show an inhibitory effect on the ear swelling induced contact dermatitis caused by picryl chloride (PC-CD). However, YK-1 inhibited the immunosuppression in Ehrlich carcinoma-bearing mice and with the frozen and dried ascites of the tumor-bearing mice containing immunosuppressive substances (EC-sup) in PC-CD-induced mice. And also, YK-1 activated the immunosuppressive activity of spleen cells of mouse treated with EC-sup. These results suggest that YK-1 may have antitumor activity against Ehrlich carcinoma and activate the immunosuppression with it.


[Disposition analysis by fast inverse Laplace transform (FILT)]. A curve fitting program, MULTI (FILT), in which an algorithm of fast inverse Laplace transform is incorporated, was introduced into the area of drug disposition. The reliance of MULTI (FILT) was verified by the Monte Carlo simulation based on compartment models. MULTI (FILT) was applied to the analysis of the local dispositions of drugs through the liver, including the construction of new dispersion model, the effect of albumin in perfusate, and the effect of perfusion rate. The elimination in the lung and the enterohepatic circulation were also evaluated using MULTI (FILT) in a simple manner.


[Stability studies on 6-amidino-2-naphthyl 4-[(4,5-dihydro-1H-imidazol-2-yl)amino]benzoate dimethanesulfonate (FUT-187) in aqueous solution]. FUT-187 (I), 6-amidino-2-naphthyl 4-[(4,5-dihydro-1H-imidazol-2-yl)amino] benzoate dimethanesulfonate, is a new synthesized proteinase inhibitor. Decomposition kinetics and photoreactivity of I in aqueous solution were studied. In aqueous solution, I was hydrolyzed to its moieties, [4-(4,5-dihydro-1H-imidazol-2-yl)amino]benzoic acid (IABA) and 6-amidino-2-naphthol (AN). The hydrolysis followed a pseudo-first order reaction. I was stable under acidic condition between pH 2 and pH 3 and decomposed by irradiation from xenon light to form IABA, AN and compound II. The structure of II was studied by nuclear magnetic resonance, infrared, mass and ultraviolet spectra and identification tests. It was shown that II was 6-amidino-2-hydroxy-1-naphthyl[4-(4,5-dihydro-1H-imidazol-2-yl)amino]- phenyl ketone, benzophenone derivative, produced by photorearrangement reaction of I.


[Application of the limulus amebocyte lysate test to measurement of endotoxin in therapeutic human plasma protein fraction. Comparison with the rabbit pyrogen test]. We applied the limulus amebocyte lysate (LAL) test to the detection of bacterial endotoxins in therapeutic human plasma protein fraction (PPF) and compared the LAL-test with the rabbit pyrogen test. Two endotoxin-specific LAL-reagents were used for the colorimetric method and turbidimetric kinetic method. The amounts of added endotoxin to the PPF were correctly estimated by either method. The results of four independent assays for the 53 samples of PPF corresponded well with each other (correlation coefficient: 0.851-0.959, regression coefficient: 0.898-1.151). The amounts of endotoxin in the PPF estimated by the LAL-test significantly correlated with the rise of body temperature in rabbits (correlation coefficient: 0.547-0.642, and 0.911-0.934 for the endotoxin added samples). These results suggest that the LAL-test could be used as an alternative method for the rabbit pyrogen test to PPF.


[Studies on early stage changes of peroxide lipid in isoproterenol-induced myocardial injury]. The amount of peroxide lipid in vivo in the early stage of the experimental model of myocardial infarction in a rat induced by the administration of isoproterenol (Isp) was measured as the value of malonic dialdehyde (MDA). The model of myocardial infarction was made by giving 75 mg/kg of Isp to the rat weighing 270 +/- 10 g. After the administration of Isp, the amounts of lipid in the serum and in the myocardial tissue were measured, and a blood chemistry test (glutamic oxaloacetic dehydrogenase, glutamic pyruvic transaminase, lactate dehydrogenase, free fatty acid, creatine kinase) was simultaneously carried out on the serum. The value of the amount of peroxide lipid in the serum began to elevate 3 h after the administration of Isp and reached a maximum value at 6 h. The value of the amount of peroxide lipid in the tissue began to elevate 30 min after the administration and reached a maximum at 3 h. Each blood chemistry disclosed the elevation 30 min after the administration. As mentioned above, the production of peroxide lipid in vivo on the myocardial disorder in the early stage after the administration of Isp and the biochemical changes showed a significant correlation. From these results it is suggested that the myocardial disorder induced by the administration of Isp has already developed at 30 min after the administration.


[Structures of isomers of ursodeoxycholic acid: 3 beta,7 alpha- and 3 beta,7 beta-dihydroxy-5 beta-cholan-24-oic acids]. Isomers of ursodeoxycholic acid, 3 beta,7 alpha- and 3 beta,7 beta-dihydroxy-5 beta-cholan-24-oic acids (3 beta 7 alpha U and 3 beta 7 beta U) crystallize in the orthorhombic space group P2(1)2(1)2(1) containing one molecule and in the monoclinic group P2(1) containing two independent molecules in an asymmetric unit. The cell dimensions are a = 28.032(17), b = 9.973(5), c = 8.049(6) A for 3 beta 7 alpha U, and a = 11.771(8), b = 27.999(12), c = 6.637(2) A, beta = 90.78(6) degrees for 3 beta 7 beta U, respectively. Both structures were solved by the direct method and refined to the residual values of 0.065 (3 beta 7 alpha U) and 0.059 (3 beta 7 beta U). The conformations of the D rings of each molecule are different from each other: 3 beta 7 alpha U intermediate, 3 beta 7 beta U (A and B) half-chair form. In the crystal, 3 beta 7 alpha U molecules are connected by a hydrogen bond extended nearly parallel to the bc plane and 3 beta 7 beta U molecules are connected by the helical hydrogen bond system or by the zigzag one parallel to the ac plane.


[Antimutagenic activities of hexane extracts of the fruit extract and the kernels of Prunus mume Sieb. et Zucc]. Antimutagenic activities of hexane extracts obtained from the fruit extract (UE) and the Kernels (KE) of P. mume were examined. These extracts showed inhibitory activities to known mutagens, 2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide, benzo[alpha]pyrene and aflatoxin B1 in the Ames assay using Salmonella typhimurium TA100 and TA98 strains. The UE and KE fractions were then separated by silicic acid column chromatography with a stepwise elution method using ether-hexane. The location of the active substances in the fractions was also determined by thin-layer chromatography. Consequently, it was found that the effective substances for the desmutagenicity were fatty acids, and identified by gas liquid chromatography, mainly as oleic acid, linoleic acid and linolenic acid in UE, and mainly as oleic acid and linoleic acid in KE, respectively.


[Preparation of water-soluble hydronaphthoquinone derivatives and its application to the determination of hydrogen peroxide in clinical chemistry]. Several 1-alkoxy-2,3-dichloro-4-hydroxynaphthalene derivatives were prepared. These compounds were oxidized by hydrogen peroxide in the presence of a peroxidase to give 2,3-dichloro-1,4-naphthoquinone, which then reacted with various alkyl benzoylacetates to develop blue coloration with absorption maximum at greater than 600 nm. The color development reaction can be applied to the determination of appropriate serum constituents such as cholesterol.


Radical-induced oxidation of oxahydrindene (hexahydrobenzofuran) portion of 22,23-dihydroavermectin B1a: identification of autooxidation products. Three products resulting from free-radical-induced oxidation of the oxahydrindene portion of 22,23-dihydroavermectin B1a (H2B1a) are 5-oxo-H2B1a, 8a-oxo-H2B1a, and 5,8a-bisoxo-H2B1a. The last of these compounds has not been reported previously.


In vitro and in vivo anticalcification effects of novel bishydroxyiminophosphonates. Some geminal bisphosphonates are used clinically for a number of important bone- and/or calcium-related diseases; however, side effects and lack of selectivity impede their wide use. This work reports the synthesis and evaluation of bishydroxyiminophosphonates (e.g., adipoyl- and suberoylbisphosphonate dioximes). These compounds significantly inhibited hydroxyapatite formation and dissolution in vitro and the calcification of bioprosthetic tissue implanted subdermally in rats. The compounds reported in this paper are less active than the structurally related bisacylphosphonates. The results of this work indicate that the introduction of oxime groups adjacent to the phosphonic function in long-chain bisphosphonates confers calcium interaction capabilities and that complete ionizability of a bisphosphonate may enhance its biological activity.


Steady-state pharmacokinetics of haloperidol and reduced haloperidol in schizophrenic patients: analysis of factors determining their concentrations in hair. Profiles of the steady-state concentrations of haloperidol (HL) and its major metabolite, reduced haloperidol (RHL), in plasma versus time were determined in 10 Japanese patients whose schizophrenic symptoms were clinically controlled by fixed, oral maintenance doses (4-30 mg/day, three times a day) for greater than 4 months. These data were used to determine the pharmacokinetic factor(s) that correlate best with HL and RHL concentrations in hair. The concentrations of HL and RHL in plasma or hair were simultaneously measured by high-performance liquid chromatography with an electrochemical detector. The observed values of minimal and maximal concentrations in plasma (Cmin and Cmax, respectively) varied widely among patients: 3.0-22.9 and 6.2-32.7 ng/mL for HL and 2.8-21.4 and 5.7-33.3 ng/ml for RHL, respectively. The ratio of the area under the plasma concentration-time curve (AUC) of RHL for 1 day to that of HL also ranged widely from 0.39 to 1.99 (1.04 +/- 0.48, mean +/- standard deviation). When the concentration of HL or RHL in hair was compared with the daily dose of HL and respective AUC, Cmax, or trough concentration in the plasma in the morning, the parameter that best correlated with the concentration of HL in hair was AUC. The concentration of RHL in hair correlated with all three parameters, but the correlation with AUC was better than that with Cmax. Therefore, the concentrations of these substances in hair were considered to be representative of their mean amounts in the body.


Effect of impurities on estradiol crystallization in a sustained-release implant. During the development of a silicone rubber implant for the delivery of estradiol 17-beta some batches of implants made from a certain lot of commercial estradiol inexplicably developed surface crystals of estradiol after several days of storage. An impurity profile was obtained for 28 lots of estradiol by a newly developed HPLC method. One or more impurities may have had a role in the spontaneous crystal growth on the surface of the implants, because the one lot of estradiol that initially had surface crystals on aging produced acceptable implants after multiple recrystallizations. Attempts to isolate suspected impurities for characterization were unsuccessful. During the manufacture of the implants, temperatures sufficient to melt the estradiol (mp, 173-179 degrees C) were used. It was expected that, upon implant cooling, melted impure estradiol would form a thermodynamically more active (i.e., noncrystalline) physical form. This metastable form could have migrated to the implant surface, where ambient conditions favored crystallization. Because melted estradiol of a higher purity tended to crystallize more readily, it was less likely to form a glass upon cooling. The phenomenon of surface crystallization was limited to one lot of estradiol with the highest level of impurities. Data from differential scanning calorimetry studies supported this conclusion.


Cholinergic agents: effect of methyl substitution in a series of arecoline derivatives on binding to muscarinic acetylcholine receptors. Arecoline, arecaidine, and a series of derivatives, differing by the presence or absence of methyl groups at positions on the periphery of the molecule, were prepared, and their binding to muscarinic acetylcholine receptors was tested. On the basis of this study, muscarinic agonism for arecoline series is governed by strict structure-activity relationships, as previously observed for other agonist series. Only minor changes in nitrogen substitution were tolerated in the present series of arecoline derivatives.


Application of a pharmacokinetic model with multiple enterohepatic cycles to a new inotropic drug after infusion and oral administration. A pharmacokinetic model with multiple, unequal, enterohepatic recirculations was developed to fit the experimental data of a new inotropic drug after intravenous infusion and oral administration. Optimized model parameters were used to derive theoretical values of the area under the curves of concentration versus time that were in good agreement with the experimental values.


Pharmacokinetics and the effect of probenecid on the renal excretion mechanism of diprophylline. The mechanism of renal excretion of diprophylline (DPP) and the effect of probenecid on the active transport of DPP in renal tubules were investigated in rats. The concentration of DPP in plasma increased in proportion to the doses of 10, 30, and 60 mg/kg. The pharmacokinetic parameters and the urinary excretion of DPP did not change significantly with the dose. These findings indicate that DPP possesses dose-independent pharmacokinetics. Pharmacokinetic parameters for tubular secretion of DPP, as determined by a single-injection renal clearance method, were 21.25 micrograms/mL for the Michaelis-Menten constant and 102.38 micrograms/min for maximum velocity. Coadministration of probenecid decreased the total body clearance of DPP but did not change in the steady-state volume of distribution of DPP. The effect of probenecid concentration on the steady-state renal clearance of DPP was evaluated by continuously infusing probenecid at various rates. The renal clearance of DPP decreased as the probenecid concentration increased, a result indicating that probenecid inhibits the tubular secretion of DPP. However, probenecid did not inhibit the renal secretion of DPP completely, probably because of the existence of probenecid-insensitive transport systems for DPP in the renal proximal tubule. The Michaelis-Menten constant, maximum velocity, and glomerular filtration rate, as calculated with the competitive inhibition model for renal clearance of DPP, correlated well with estimated values after a single intravenous administration, as described earlier. The competitive inhibition constant of probenecid was 15.86 micrograms/mL.


Racemization and intramolecular nucleophilic substitution reactions of ibutilide. The kinetics and mechanisms of the racemization and cyclization reactions of ibutilide are described. The cyclization reaction yields a bell-shaped rate-pH curve consistent with a change in rate-determining step. It is hypothesized that the hydroxyl group leaves to form a carbocation intermediate; this is followed by nucleophilic attack by the amine. This mechanism is supported by kinetic analysis, aniline trapping of carbocation intermediate, and observation of all four stereo-isomers of the resulting quaternary ammonium compound. Whereas racemization can also progress through the carbocation intermediate, a direct SN2 mechanism appears to be the major route for the racemization reaction.


Pharmacokinetic analysis of maprotiline and its demethylated metabolite in serum and brain of rats after acute and chronic oral administration of maprotiline. Compartmental model analysis by simultaneous curve fitting was used to ascertain the pharmacokinetic relationship between maprotiline (MAP) and its demethylated metabolite desmethylmaprotiline (DMAP) in the serum and brain of rats after single or multiple oral administrations of MAP. The extent of bioavailability and the fraction metabolized to DMAP after acute oral administration were 0.202 and 0.065, respectively, indicating first-pass metabolism of MAP. Although the estimated transfer rate constants to and from the brain (k(in) and k(out)) of MAP were higher than those of DMAP, the k(in):k(out) ratio for MAP was similar to that for DMAP. These findings indicate the equivalent ability of MAP and DMAP to penetrate into the brain after acute oral administration. The estimated values of bioavailability and fraction metabolized to DMAP increased 2.6 and 1.7 times, respectively, after chronic administration of MAP. These findings are attributable to inhibited distribution in tissue. The k(in) and k(out) values of MAP decreased, whereas those of DMAP showed no marked change. Therefore, the k(in):k(out) ratio for MAP decreased, whereas that for DMAP did not change. These results suggest that the permeability of MAP into the brain might be affected and that of DMAP is not modified by chronic administration of MAP.


Determination of pivaloylcarnitine in human plasma and urine by high-performance liquid chromatography with fluorescence detection. A high-performance liquid chromatographic (HPLC) method was developed for the determination of pivaloylcarnitine, one of the major metabolites of pivaloyloxymethyl (+)-(6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2- pentenamido]-3-carbamoyloxymethyl-8-oxo-5-thia-1-azabicyclo[4.2.0] oct-2- ene-2-carboxylate hydrochloride hydrate (S-1108), an oral cephem antibiotic, in human plasma and urine. Fluorescence detection was done with 3-bromomethyl-6,7-dimethoxy-1-methyl-2(1H)-quinoxalinone as the labeling reagent. Pivaloylcarnitine and cyclopropylacetylcarnitine, the internal standard, were selectively fractionated from plasma or urine on a disposable cation-exchange column. Derivatization was completed in 20 min at 40 degrees C in the presence of N,N'-diisopropylethylamine as the catalyst. A column-switching device was used to remove the excess reagent for HPLC analysis. The recovery of pivaloylcarnitine was greater than 98%, and average within-day and between-day coefficients of variation were less than 5% at concentration ranges of 0.05-2 micrograms/mL for plasma and 5-500 micrograms/mL for urine. Detection limits were 0.02 micrograms/mL for plasma and 1 micrograms/mL for urine. The urinary recovery of pivaloylcarnitine was 94% after the administration of S-1108, a result that suggested that S-1108 was almost quantitatively converted to pivalic acid and then conjugated with carnitine.


Pharmacokinetic profile of glycyrrhizin in healthy volunteers by a new high-performance liquid chromatographic method. An improved high-performance liquid chromatographic method was developed for the quantification of glycyrrhizin and its metabolites in human plasma. The improved method was selective and made it possible to determine precisely glycyrrhizin at levels as low as 500 ng/mL. The pharmacokinetic behavior of glycyrrhizin and its metabolites after oral and intravenous administration of glycyrrhizin to normal subjects was investigated. After oral administration of glycyrrhizin (100 mg) to three normal subjects, the major metabolite of glycyrrhizin (glycyrrhetic acid) appeared in plasma (less than 200 ng/mL), but glycyrrhizin was not found. On the other hand, glycyrrhizin was found in urine, and the amount excreted was 1.1-2.5% of the dose. This finding suggests that glycyrrhizin is partly absorbed in the intact form from the gastrointestinal tract. The concentration of glycyrrhizin in plasma after intravenous administration of glycyrrhizin (40, 80, and 120 mg) showed biexponential profiles during the 24-h period after administration of each dose. The glycyrrhizin metabolites, glycyrrhetic acid and glycyrrhetic acid-3-O-glucuronide, were not detected in either plasma or urine. The terminal half-life of glycyrrhizin, the apparent volume of the central compartment, the steady-state distribution volume, and the total body clearance in three dosing experiments were 2.7-4.8 h, 37-64 mL/kg, 59-98 mL/kg, and 16-25 mL/kg/h, respectively. Glycyrrhizin was not detected in plasma after oral administration of the usual therapeutic dose of glycyrrhizin, and no dose dependency of the drug was observed in the dose range of 40-120 mg.


Pharmacokinetic analysis of ester prodrugs of valproic acid. The pharmacokinetics of five monoester prodrugs of valproic acid (VPA) were investigated: propyl valproate (P-VPA), butyl valproate (B-VPA), isobutyl valproate (IB-VPA), isoamyl valproate (IA-VPA), and hexyl valproate (H-VPA). In addition, the anticonvulsant activity of these compounds was evaluated and compared with that of VPA and valpromide (VPD). The pharmacokinetics of VPA and its five ester derivatives were determined after intravenous administration of equivalent doses (400 mg of VPA) to six dogs. The five ester prodrugs of VPA were biotransformed to VPA; the biotransformation was complete for P-VPA, B-VPA, and H-VPA but was only partial for IB-VPA and IA-VPA. Because of the rapid conversion of the prodrugs to the parent drug, levels of VPA in plasma after administration of the prodrugs peaked at 6-26 min after dosing and did not yield an in vivo sustained-release dosage profile. Of the five ester prodrugs of VPA, only P-VPA demonstrated anticonvulsant activity. P-VPA also was less neurotoxic than VPA and VPD; therefore, it has a better protective index.


Molecular connectivity: treatment of the electronic structure of amino acids. A molecular connectivity model of atomic charges on the second-row atoms in alpha-amino acids is discussed. A correlation was found between the valence delta (delta v) index from molecular connectivity theory and the charges on atoms that belong to the same class, whereas different classes of carbon atoms had the same slopes on the Q versus sigma v matrix, where Q is the calculated charge distribution. A similar correlation was found for nucleotide bases.


Electrochemical determination of partition coefficients of drugs. An electrochemical method for the determination of partition coefficients of drugs that can exist as ions in aqueous solutions is presented. The method involves cyclic voltammetry at the polarizable interface between two immiscible electrolyte solutions. Because n-octanol is an unsuitable solvent for electrochemical purposes, 1,2-dichloroethane, which has electronic properties similar to those of n-octanol, was used in the measurements. The values obtained could be correlated with the values for n-octanol-water partition taken from the literature by an approach based on the linear solvation relationship: log P1 = a log P2 + b; in this relationship, a and b are constants and P1 and P2 correspond to the two different organic and aqueous phase partition equilibria. Furthermore, aqueous diffusion coefficients of drugs were determined from voltammograms.


Formation of a tablet: a site and bond percolation phenomenon. The concepts of percolation theory are used to elucidate the formation of a tablet by compression of particulate matter. The process of compaction can be considered as a combination of site and bond percolation phenomena. Because of effects of different particle size and shape of the particles in a powder bed and effects of brittle fracture and plastic flow, moisture content of the powder, and finite size of the tablet, no sharp percolation thresholds are expected. Thus, it is interesting to test the validity of the fundamental equation of percolation theory: the power law X = S(p - pc)q, where X is the system property, S is the scaling factor, p is the site occupation or bond formation probability, and q is the critical exponent. This model is, in certain cases, only rigorously valid close to the percolation threshold (range, [+/- 0.1 pc]). Combination of the Heckel equation with an equation derived earlier for the properties (X) of tensile strength (sigma t) and deformation hardness (P) yields a power law with q = 1, S'(sigma t) = sigma tmax/(1 - pc), and S(P) = Pmax/(1 - pc). With respect to the simplifying assumptions made, the power law agrees well with the experimental results obtained. Substantial improvements in the interpretation of the compression-compaction process are possible with these findings, and some interpretations differ from previous ones in earlier publications.


Relationship of film properties to drug release from monolithic films containing adjuvants. The rate of drug release from a polymeric matrix system was influenced by the physical and chemical properties of the monolithic films. The model drugs, salicylic acid and chlorpheniramine maleate, and two poly(methyl methacrylate) copolymers of different permeabilities (Eudragit RL and Eudragit RS), with and without additional adjuvants, were used to form monolithic matrix films for controlled drug release. Adjuvants, including polyethylene glycols (PEG 400 and PEG 8000) and poly(vinylpyrrolidones) (PVP-K15 and PVP-K90), were incorporated into films of Eudragit RL PM and Eudragit RS PM. The moisture permeation constant, glass transition temperature (Tg), tensile strength, and drug release profiles were determined for each acrylic resin slab to correlate the physicochemical and physicomechanical film properties to observed drug release. Faster rates of drug diffusion were observed with the addition of PEG 400 to the films, because of its plasticizing effect and the resultant increased moisture permeability of the matrix. An exception existed with the Eudragit RL PM film containing salicylic acid where drug-polymer interactions inhibited drug diffusion. The small changes in moisture permeability, Tg, and tensile strength observed with incorporation of the PVPs had an insignificant influence on the dissolution results for salicylic acid from Eudragit RS PM films. Increases in the tensile strength and Tg after addition of PVP to the Eudragit RS PM matrix support the observed decreased rate of diffusion for chlorpheniramine maleate. The pores formed by migration of the hydrophilic adjuvants from the films altered the diffusion kinetics of the matrix, compared with that of the nonporous polymer, when only the antihistamine was present.


Kinetics of transdermal penetration of an organic ion pair: physostigmine salicylate. Physostigmine salicylate was delivered from a series of solvents consisting of isopropyl myristate, isopropyl alcohol (IPA), and their mixtures across dermatomed human skin. The apparent steady-state fluxes over the time range of the test, obtained separately for physostigmine and its corresponding salicylate, indicate a consistent trend toward higher values for the salicylate in the series tested. The ratios of salicylate fluxes to physostigmine fluxes ranged from 1.1 to 3.34, the higher ratios being obtained at a volume fraction of IPA exceeding 0.7. Ionization of the ion pair at the pH of the hydrated stratum corneum immediately after its partitioning into the membrane, followed by differential diffusion of the species across the membrane, is consistent with the kinetics of penetration. It is proposed that the apparent volume of distribution of physostigmine is larger than that of salicylate and, hence, a smaller concentration difference across the diffusion barrier exists for physostigmine. This hypothesis can explain the lower flux of physostigmine to conform to Fick's first law of diffusion and the assumption of equal molar transfer to the skin of both species. The hypothesis implies that if steady state appears to have been reached for the faster migrating salicylate over the time range tested then the apparent steady state of physostigmine is not a true one. Increasing the salicylate content in one of the donor solutions by eight times over that of physostigmine decreased the saturation concentration of physostigmine but not in its flux. Increasing the physostigmine content by 6.5 times over that of salicylate in the same donor solution did not change either the flux or the salicylate concentration but decreased the permeability coefficient of physostigmine.(ABSTRACT TRUNCATED AT 250 WORDS)


Transdermal drug delivery systems of albuterol: in vitro and in vivo studies. In vitro and in vivo experiments were conducted with double- and single-layer albuterol transdermal pads designed for once-a-day application. In the in vitro experiments, dissolution of albuterol from pads and permeation of albuterol through hairless mouse skin were monitored. In the in vivo experiments, pads were applied to the chest area of four female rhesus monkeys (Macaca mulata), and an albuterol aqueous solution was injected into the saphenous vein of the same animals in a crossover design. The amount lost from pads applied to monkeys was monitored by analysis of pad residue. Blood samples were withdrawn at regular intervals and analyzed by a high-performance liquid chromatography-fluorescence method. Skin irritation due to the pad was measured by a modified Draize score test. The amounts released from the two formulations were similar. The amount released was, however, dependent on the technique used and decreased in the following manner: pad dissolution greater than in vivo amount lost from pads applied to monkeys greater than in vitro permeation through hairless mouse skin. The pharmacokinetic parameters determined after intravenous and transdermal administration were as follows: terminal half-life, 2.26 +/- 0.45 h; apparent volume of distribution, 1935 +/- 37.2 mL.kg-1; and total body clearance, 612.0 +/- 118 mL.h-1.kg-1. The average concentrations in serum after application of single- and double-layer pads were 44.60 +/- 16.40 and 62.50 +/- 8.00 ng/mL, respectively. Further, the amount lost from pads applied to monkeys correlated with the respective amount absorbed in monkeys, as calculated from the average concentration in serum and clearance.(ABSTRACT TRUNCATED AT 250 WORDS)


A time hierarchy-based model for kinetics of drug disposition and its use in quantitative structure-activity relationships. By using the time hierarchy of the processes determining the fate of drugs in biosystems (absorption, transport, distribution, protein binding, and elimination), a one-compartment open model is formulated at a subcellular level for the disposition phase of pharmacokinetics. The resulting disposition function describes the kinetics of the intracellular disposition of drugs as determined by their hydrophobicity, acidity or basicity, affinity to proteins, and rate parameters of elimination. Structure-activity relationships, based on the function with incorporated extrathermodynamic relations, fit the literature data well (fixed-time bioactivity-hydrophobicity profiles, kinetics of microbial degradation of organic compounds, and kinetics of analgesic effects of fentanyl derivatives in rats). Application of the approach, creating a basis for the construction of model-based quantitative structure-time-activity relationship, to biosystems of varying complexity is discussed.


Solid-state structure of orphenadrine hydrochloride and conformational comparisons with diphenhydramine hydrochloride and nefopam hydrochloride. The solid-state structure of (+-)-orphenadrine hydrochloride [(CH3)2NCH2CH2OCH(o-CH3C6H4)(Ph).HCl], a skeletal muscle relaxant drug, was determined by single-crystal X-ray diffraction analysis. Orphenadrine hydrochloride gave crystals belonging to the monoclinic P2(1)/n space group, and at low temperature (92 K), the following parameters were found: a = 6.923 (4), b = 7.508 (5), c = 33.22 (3) A, V = 1720 (3) A3, Z = 4, R(F) = 0.109, and Rw(F) = 0.131. Data were collected from poor crystalline material because of the low volume of the needle-shaped crystals (0.025 x 0.025 x 0.15 mm3). A molecular mechanics model was calculated by using an input structure based on atomic coordinates of the crystallographically determined molecular structure. The resulting molecular mechanics model and the structure determined by X-ray crystallography have the same molecular conformation. Whereas both solid-state (+-)-orphenadrine hydrochloride and diphenhydramine hydrochloride [(CH3)2NCH2CH2OCH(Ph)2.HCl] have synclinal N-C-C-O and antiperiplanar NC-C-O-CAr2 torsion angles, the former has a helical arrangement for Ar2CH, as expected, and the phenyl rings in the latter are disposed in a nonhelical, "open-book" arrangement.


A compartment model for percutaneous absorption: compatibility of lag time and steady-state flux with diffusion model. The lag times and steady-state flux predicted by a specific case of the compartment model, which was recently proposed to generate finite-dose percutaneous permeation pharmacokinetics, are compared with those predicted by the diffusion model. When the intercompartmental transfer rate constants are defined so that the three statistical moments of the compartmental model (the mean residence times of a drug in the vehicle and that in the skin and the variance of residence time in the vehicle) are identical to those in the diffusion model, the lag times and steady-state flux values predicted by the two models are the same.


A theoretical analysis of a new drug delivery system: a cylindrical device with a vertical opening on its surface. A theoretical analysis of a proposed drug delivery device is presented. The device is of cylindrical shape with an opening on its side surface. Analytical expressions for the temporal variations in the amount of drug released and the size of the unreleased portion of the device are derived. The result of numerical simulation reveals that an approximately zero-order mechanism can be obtained, provided that the device is designed appropriately. The applicability of the analytical expressions derived is justified by examining the release of sodium salicylate embedded in polyethylene. The present work is a generalization of analyses suggested previously for some similar devices.


Lecithin organogel as matrix for transdermal transport of drugs. Organogels obtained by adding small amounts of water to a solution of lecithin in organic solvents were studied as matrices for the transdermal transport of drugs. Gels obtained from isopropyl palmitate and cyclooctane were used (molar ratios of water to lecithin of 3 and 12, respectively). Preliminarily histological studies showed that the gels have no harmful effect when applied to the skin for prolonged periods. Data relative to the stability of the organogels with time are also presented. Scopolamine and broxaterol were used as model drugs, and the transdermal experiments were done with a Franz diffusion cell and human skin obtained from plastic surgery. The transport rate of scopolamine obtained with the lecithin gels was about one order of magnitude higher than that obtained with an aqueous solution of the drug at the same concentration. In contrast, the transport rates of scopolamine obtained with the microemulsion solution prior to gelation (molar ratio of water to lecithin, 0) were not different from those obtained with the gel. The same variations in transport rates were observed for broxaterol, in which case the flux through the skin was directly proportional to the concentration of drug in the gel. At a concentration of broxaterol of 75 mg/mL in the donor gel, the flux was 47 micrograms.h-1.cm-2. Because preliminary results showed that transdermal transport is successful with amino acids and peptides also, it is concluded that lecithin gels may be efficient vehicles for the transdermal transport of various drugs.


Rate-limiting steps in oral absorption of a leucotriene D4 antagonist in the beagle dog. Oral administration of a leucotriene D4 antagonist drug (1) in the Beagle dog at doses of 2, 20, 100, 300, and 800 mg/kg resulted in dose-dependent bioavailability values (4-50%). To understand the dose dependence of the absorption of 1 in the dog, initial rates of absorption of 1, which were estimated from Loo-Riegelman analysis of the concentration in blood data, were analyzed in terms of dissolution and absorption rates. From the Loo-Riegelman plots, the initial rates of absorption of 1 were estimated as 8.2, 41.9, 41.1, 76.1, and 72.8 micrograms.mL-1.h-1, respectively, for the doses given earlier. These data, which indicate leveling of the initial absorption rates at high doses, were consistent with an absorption model in which the dissolution rate is the rate-controlling step in the intestinal absorption of 1 at doses less than 100 mg/kg. The powder dissolution rate of 1 in 17 mM bile salt solution was estimated as 14 and 700 micrograms.mL-1.h-1 for amounts of 1 equivalent to the amounts given to dogs at 2- and 100-mg/kg doses, respectively. After consideration of the volume of distribution and the volume of intestinal fluid in the dog, the value of the initial dissolution rate was much lower than the initial absorption rates at the 2-mg/kg dose. Oral administration of 1 at 2 mg/kg in a 3% polysorbate 80 solution enhanced both the rate and the extent of absorption of the compound. These results confirm the validity of the conclusion that the intestinal absorption of 1 is limited by dissolution rate at low doses.


Epithelial transport of drugs in cell culture. VII: Effects of pharmaceutical surfactant excipients and bile acids on transepithelial permeability in monolayers of human intestinal epithelial (Caco-2) cells. The effects of anionic (sodium dodecyl sulfate and sodium dioctyl sufosuccinate) and nonionic (polysorbate 80 and polyoxyl 40 hydrogenated castor oil) synthetic surfactants and bile acids (sodium taurocholate, sodium taurodeoxycholate, and sodium taurodihydrofusidate) on epithelial integrity were studied in monolayers of human intestinal epithelial (Caco-2) cells grown on microporous polycarbonate filters. The effects of the surfactants on intracellular enzyme activity, cell monolayer permeability, and morphology were studied. The effects on permeability were studied by two methods: measurements of transport of marker molecules (mannitol and polyethylene glycol) and measurements of transepithelial electrical resistance. All surfactants demonstrated concentration-dependent effects on intracellular enzyme activities, permeability, and morphology. The effects of the anionic surfactants were more pronounced than those of the nonionic surfactants. The effects on transepithelial electrical resistance correlated with intracellular dehydrogenase activity. Fluxes of marker molecules were the most sensitive measure of epithelial integrity. The results indicate that the hydrophilic marker molecules permeate the epithelial monolayers through different pathways at different concentrations of the surfactants. The effects of the surfactants were reversible at intermediate concentrations, even though the morphology of the monolayers had changed. The results agree with published data obtained with experimental animals and indicate that Caco-2 cells can be used to study the concentration-dependent effects of surfactants and other pharmaceutical additives on intestinal epithelial permeability.


Variability of inversion of (R)-flurbiprofen in different species. The anti-inflammatory activity of 2-arylpropionic acids like flurbiprofen appears to be due to the S enantiomers only. A unique characteristic of the metabolism of this class of drugs is inversion of configuration. The present study examines whether chiral inversion occurs after administration of the optically pure flurbiprofen enantiomers to various species (i.e., dogs, guinea pigs, rats, and gerbils). Concentrations of the enantiomers in plasma were analyzed by a stereoselective high-performance liquid chromatographic assay with a chiral alpha 1-acid glycoprotein column. Pharmacokinetic parameters of the flurbiprofen enantiomers were evaluated with a two-compartment computer model. Inversion of (R)-flurbiprofen to its optical antipode occurred to a variable extent in the dog [fraction inverted (Fi) = 0.39; n = 3] and the guinea pig (Fi = 1.00; n = 3) and to a much lower extent in the rat (Fi = 0.02; n = 3) and the gerbil (Fi = 0.05; n = 3). After intravenous administration of (S)-flurbiprofen to dogs, guinea pigs, rats, and gerbils, (R)-flurbiprofen was not detected in plasma (limit of quantification was 0.05 microgram/100 microL of plasma).


Synthesis and anti-inflammatory activity of fluorinated phenyl styryl ketones and N-phenyl-5-substituted aryl-3-p-(fluorophenyl) pyrazolins and pyrazoles. Various N-phenyl-5-substituted aryl-3-p-(fluorophenyl) pyrazolins and pyrazoles were synthesized by cyclization of the corresponding 4-(fluorophenyl) styryl and 4-(fluorophenyl) dibromostyryl ketones. These compounds were characterized by elemental analysis and UV, infrared, and nuclear magnetic spectral data. All substituted p-(fluorophenyl) styryl ketones [250 mg/kg orally (po)] possessed anti-inflammatory activity, as reflected by their ability to provide protection (51-70%) against carrageenin-induced edema in rat paw. Indomethacin (10 mg/kg, po) and dehydrozingerone (70 mg/kg, po), used as standard reference drugs, provided 97 and 60% protection, respectively. All compounds (0.20 mM) showed ability to denature bovine serum albumin, as observed in in vitro inhibition studies. Inhibition ranged from 7 to 59% for substituted p-(fluorophenyl) styryl ketones and from 12 to 21% for pyrazoles. No correlation was found between the anti-inflammatory activity of p-(fluorophenyl) styryl ketones or substituted pyrazoles and their effectiveness at inhibiting bovine serum albumin denaturation. The low toxicity of p-(fluorophenyl) styryl ketones was reflected by the dose that was lethal in 50% of the cases tested (2000-2500 mg/kg).


Simultaneous spectrophotometric determination in solid phase of aspirin and its impurity salicylic acid in pharmaceutical formulations. We report the simultaneous determination of aspirin and its hydrolysis product, salicylic acid, in solid phase by fluorescence spectrophotometry. Aspirin is often the most labile component in a combination-type analgesic compound. Therefore, its stability is often the initial concern in any formulation-screening program. Preliminary screening of a large number of potential formulations can be arduous, because most current methods of analysis generally consist of several steps: extractions or column separations followed by UV, colorimetric, or gas-liquid chromatographic assays. The method proposed here is quite suited to large numbers of assays because it is not time consuming, it is straightforward, and it is not subject to interference from the substances present in the pharmaceutical formulations. In addition, the method is nondestructive, not dependent on the sampling procedure, and, above all, quite sensitive.


Preparation of neurotensin analogue-containing poly(dl-lactic acid) microspheres formed by oil-in-water solvent evaporation. This report describes the preparation of injectable microspheres containing a neurotensin analogue (NA), which is a hexapeptide with neurotensin activity. NA, a hydrophilic drug, was successfully entrapped into poly(dl-lactic acid) microspheres prepared by a novel oil-in-water solvent evaporation method. The preparation method was investigated with regard to the partition of NA into the oily phase and the rapid phase separation of the polymer. Successful entrapment was achieved with the following conditions: (1) an alkaline water phase, (2) addition of fatty acid salt in the oily phase, and (3) addition of a water-miscible solvent in the oily phase. Under these conditions, NA was completely entrapped into the microspheres at poly(dl-lactic acid):NA molar ratios of greater than 3.


Preparation and evaluation of Eudragit gels. IV: Rectal gel preparations for sustained release and avoidance of first-pass metabolism of propentofylline. Formulations of a high-viscosity acrylic resin gel (Eudispert hv) containing propentofylline, a new cerebral microcirculation-improving agent, were prepared and tested for avoidance of the first-pass metabolism of propentofylline through the liver and for sustained release of propentofylline. The absolute bioavailability of propentofylline after oral administration was only 4% in rabbits. The relative bioavailabilities of propentofylline from polyethylene glycol (M(r), 2000) and Witepsol H-15 suppositories were approximately 8- and 16-fold, respectively, compared with oral administration. Furthermore, the absolute bioavailability of propentofylline from Eudispert hv hydrogel and xerogel preparations was approximately 100%. The results indicate that, in principle, drug loss caused by first-pass metabolism may be avoided completely by placing Eudispert hv hydrogel and xerogel formulations in the lower part of the rectum for long periods.


Acid-catalyzed hydrolysis of maltosyl-beta-cyclodextrin. Maltosyl-beta-cyclodextrin was hydrolyzed via two pathways in acidic solution: (1) ring opening to give noncyclic oligosaccharides and (2) cleavage of maltose in the branched residue to give glucosyl-beta-CyD and glucose. Ring opening was approximately 2-3 times faster than maltose cleavage because of the multiple hydrolysis sites of the beta-cyclodextrin (beta-CyD) ring (seven glycosidic linkages) compared with only one reaction site of the maltose residue in the branch. Values of the enthalpy and entropy of activation of the hydrolyses were positive and in the range reported for maltose, a result indicating that the hydrolyses proceeded according to the A-1 mechanism (i.e., unimolecular decomposition). The alpha-1,6-glycosidic bond of branched beta-CyDs connecting beta-CyD and branched sugar moieties resisted hydrolysis; this property is a potential pharmaceutical advantage because the parent beta-CyD, which has low aqueous solubility, would not precipitate after hydrolysis.


Reversible adsorption of nicotinic acid onto charcoal in vitro. The effects of various factors on the adsorption of nicotinic acid onto and desorption from activated charcoal were investigated in vitro. The affinity of nicotinic acid for charcoal was poor both in acidic and neutral media. Adsorption increased with increasing charcoal:drug ratios and decreasing incubation volume:charcoal ratios. Desorption of nicotinic acid from dried drug-charcoal complexes was investigated in a Sartorius dissolution apparatus. The rate of the rapid, initial desorption depended on the pH and the amounts of charcoal and drug. As equilibrium was reached in the dissolution chamber, the release rate of nicotinic acid decreased slowly, depending mainly on the flow of the medium. Thus, nicotinic acid preadsorbed onto charcoal was released in a sustained manner under "continuous flow" conditions. However, because of the poor affinity for nicotinic acid, charcoal may not be a suitable matrix for sustained release of nicotinic acid.


Polarographic study of the photodecomposition of nimodipine. Nimodipine, a calcium antagonist belonging to the dihydropyridine family, produces a well-defined polarographic peak due to the four-electron reduction of the nitro group. This peak was used to track the photodecomposition of nimodipine induced by UV light and daylight. Nimodipine was modified by UV irradiation with degradation following first-order kinetics. A degradation rate constant of 0.099 min-1, with a half-life of 7.78 min, for UV irradiation without a filter was obtained. Furthermore, a quantum yield of 1.32 x 10(-3) molecules/quantum absorbed was measured with a chemical actinometer. The UV degradation product, which was isolated and identified, showed that irradiation of nimodipine causes oxidation of the dihydropyridine ring and transmutation of the nitro group in the nitrobenzene moiety.


Pharmacodynamic system analysis of the biophase level predictor and the transduction function. This work deals with the pharmacodynamic problem of relating a drug effect E(t) to an observable pharmacokinetic (PK) predictor variable r(t), which may be a venous and/or arterial drug level, some other PK variable, or a drug infusion scheme. It is proposed that the relationship between E(t) and r(t) may, in many cases, be appropriately modeled as E(t) = N(F(r(t))) [for practical analysis reasons, F(r(t)) is denoted the biophase level, cb(t), the operator F() is accordingly denoted the biophase level predictor (BLP), and N() is denoted the transduction function (TF)]. This work proposes a method for determining the two fundamental components, BLP and TF, that define the E(t)-r(t) relationship. The BLP is determined by a hysteresis minimization (HM) technique with the following features: (1) the method considers errors in both HM variables; (2) the method is suitable for dealing with the important case in which the predictor variable is a drug infusion scheme; (3) the approach is noncompartmental in contrast to the effect-compartment approaches and it does not require a specific structured modeling of the cb(t)-r(t) relationship when dealing with drugs with linear PKs in a general operational sense; and (4) the method makes use of a dimensionless transformation of the hysteresis variable that eliminates numerical scaling problems so that a complex penalty function optimization approach can be avoided. The TF is determined by a cross validation procedure in conjunction with the BLP determined by HM. The method is demonstrated using pharmacodynamic data for several drugs, considering both concentration-based and drug input-based r(t) values. The significance of the information obtained from the determined BLP and TF is discussed, including the concepts of equilibration dynamics and overloading. The limitations and potential problems of the methodology are discussed.


Stereoselective pharmacokinetics of a novel uricosuric antihypertensive diuretic in rats: pharmacokinetic interaction between enantiomers. 5-Dimethylsulfamoyl-6,7-dichloro-2,3-dihydrobenzofuran-2-carboxyli c acid (DBCA), a promising uricosuric, diuretic, and antihypertensive agent, was administered intravenously to rats. The levels of DBCA in plasma and the areas under the curve of concentration versus time (AUC values) of the S(-)-enantiomer were higher than those of the R(+)-enantiomer. Total body clearance was significantly greater for the R(+)-enantiomer. This stereoselective elimination was due to a difference in the nonrenal clearance, which seemed to reflect hepatic metabolism or biliary excretion. Hepatic metabolism seemed more likely because AUC and the amount of urinary excretion of the N-monodemethylated metabolite of DBCA were greater for the R(+)-enantiomer. The plasma had higher free fractions of the S(-)-enantiomer, a result suggesting that this enantiomer is distributed more readily to the tissues, including the liver. This result indicates that protein binding was not responsible for the stereoselective metabolism of (R)-(+)-DBCA. Although there was no difference in the renal clearances of the enantiomers, the renal clearance of free (R)-(+)-DBCA exceeded that of the S(-)-enantiomer, a result indicating the preferential excretion of the R(+)-enantiomer into the urine. Comparison of the pharmacokinetics of individual enantiomers after intravenous administration of each enantiomer or its racemate showed that the enantiomers interact with one another; dosing with racemate delayed the elimination of each enantiomer because of mutual inhibition of hepatic metabolism and renal excretion for (R)-(+)-DBCA and of renal excretion for (S)-(-)-DBCA.


Effects of chronic ethanol ingestion on tissue elimination-phase kinetics of procainamide in rats. The effects of chronic ethanol ingestion on the pharmacokinetics of procainamide in various tissues were studied. Ethanol-treated rats received ethanol at 4 g/kg/day for an initial 7 days and then at 8 g/kg/day for the subsequent 21 days; control rats received isocaloric sucrose. After a single intravenous dose, the semilogarithmic procainamide concentration-time profiles observed in hearts and kidneys of both groups of rats were similar to the previously reported biexponential profiles of procainamide concentration in blood. This finding indicates a rapid distribution equilibrium of drug in both blood and these highly perfused tissues. The profiles of drug concentration in thigh muscle and fat of both groups of rats exhibited a drug-uptake phase during the initial 25-min period followed by a monoexponential decline in drug concentration. For all tissues, the slopes (beta values) of the curves of the drug concentration versus time were calculated on the basis of elimination-phase data, except for fat of control rats where the predominant elimination phase was not discernible. The beta values in hearts and thigh muscles of ethanol-treated rats were significantly higher than those in the corresponding tissues of control rats. These results are evaluated in light of previously reported effects of the same ethanol treatment on the distribution pharmacokinetics and the steady-state partition coefficients of the drug in these tissues. Possible mechanisms are proposed to account for these effects on the basis of the known diverse effects of chronic ethanol ingestion on the cellular compositions of individual organs and tissues.


Use of scavenging oxygen-derived free radicals to protect the rat against aspirin- and ethanol-induced erosive gastritis. Oxygen-derived free radicals are cytotoxic and produce tissue damage. The effect of the radical scavengers allopurinol and dimethyl sulfoxide (DMSO) on aspirin- and ethanol-induced acute gastric mucosal injury was studied in the rat. Orogastric instillation of aspirin at 200 mg/kg produced, after 4 h, gastric mucosal injury in 30% of rats without pyloric ligation [score, 3.1 +/- 0.8 mm2, mean +/- standard error of the mean (SEM); n = 10] and in 80% of rats with this ligation (score, 10.4 +/- 1.2 mm2, mean +/- SEM; n = 10). Gavage with 1 mL of 2 or 5% allopurinol or DMSO at 24 h before and again just before aspirin administration completely protected rats with or without pyloric ligation against injury. Orogastric instillation of ethanol (1 mL of a 40% solution) produced, after 1 h, gastric mucosal injury in all rats with or without pyloric ligation (24.1 +/- 1.7 and 14.1 +/- 1.3 mm2, respectively, mean +/- SEM; n = 10). Gavage with 1 mL of 5% allopurinol or DMSO at 24 h before and again just before ethanol administration completely protected rats with or without pyloric ligation against injury. Protection against the aspirin- and ethanol-induced injury was not associated with any significant effect on the H+ output. The results suggest that oxygen-derived free radicals are directly implicated in the mechanism of aspirin- and ethanol-induced acute gastric mucosal injury and that scavenging these free radicals protects against injury by maintaining the integrity of the gastric mucosa.


Measurement of haloperidol in human breast milk by high-performance liquid chromatography. A high-performance liquid chromatographic method was developed for the assay of haloperidol in human breast milk. The method involves rapid extraction of haloperidol and chromatography with a reversed-phase C18 column and a mobile phase of phosphate buffer (pH 4.0):acetonitrile (70:30, v/v). Moperone was used as the internal standard. Haloperidol and moperone were detected with ultraviolet detection at 254 nm. The sensitivity was 5 ng/mL of milk, and the standard curve was linear in the concentration range 5-250 ng/mL. The average interassay coefficient of variation for samples with drug in the concentration range 25-125 ng/mL was less than 8.8%. The absolute recovery of haloperidol by the method was greater than 94.4%. No interference with endogenous substances in human milk was observed. The method was used to determine haloperidol levels in breast milk from patients undergoing chronic haloperidol treatment.


Isolation and biological evaluation of potential cancer chemopreventive agents from ambrette musk residue. Two nitroaromatic compounds, 1-(1,1-dimethylethyl)-3,5-dimethyl-2,4-dinitrobenzene (1) and 1-[4-(1,1-dimethylethyl)-2,6-dimethyl-3,5-dinitrophenyl]ethanone or musk ketone (2), were isolated from ambrette musk residue, which is widely used in the food and cosmetics industry. The ability of 1 and 2 to induce increased activity of the detoxifying enzyme glutathione S-transferase was tested in A/J mice. Enzyme induction in the cytosols of liver, forestomach, lung, colon, and small intestinal mucosa was determined. Biological evaluation revealed that both compounds exhibit high activity as glutathione S-transferase inducers in liver and small intestinal mucosa. The effects of 1 and 2 on the levels of acid-soluble sulfhydryl in the five mouse tissues were also determined. Both compounds slightly elevated sulfhydryl levels in the small intestinal mucosa but significantly decreased the sulfhydryl levels in the other tissues. Because the ability of anticarcinogenic compounds to induce an increase in the detoxifying enzyme activity correlates with their tumor inhibitory activity, 1 and 2 may be potential cancer chemopreventive agents.


A new method for the estimation of the aqueous solubility of organic compounds. Using a semiempirical quantum chemical method (AM1), various properties (dipole moment, charge distribution, geometrical parameters, etc.) of 331 compounds were calculated. Various linear functions of these properties and their combinations were fitted to reproduce experimental aqueous solubilities. An 18-parameter function was derived that is reasonably simple, yet appears to be able to describe the aqueous solubilities of a wide range of organic compounds. The parameter set is essentially the one used in a recent similar study of octanol-water partition coefficients. The derived equation has important predictive value.


Pharmacokinetics of glycyrrhizin after intravenous administration to rats. A simple high-performance liquid chromatographic method was developed to study the pharmacokinetics of glycyrrhizin in the rat after bolus intravenous administration at a dose of 20, 50, or 100 mg/kg. The decline in the concentration of glycyrrhizin in plasma was generally biexponential at each dose, but the terminal disposition became much slower as the dose was increased. A greater-than-proportional increase in the glycyrrhizin concentration in plasma was observed with an increase in the dose, a result suggesting a dose-dependent glycyrrhizin disposition. The disposition of drug in plasma at each dose fitted well to a two-compartment pharmacokinetic model. The apparent total body clearance decreased significantly with increases in the dose. On the other hand, the apparent distribution volume after intravenous administration was unaffected by the dose. The results indicate that the pharmacokinetics of glycyrrhizin is nonlinear.


Synthesis and anti-inflammatory activity of 3-(benzylideneamino)coumarins in rodents. A series of substituted 3-(benzylideneamino) coumarins was synthesized and evaluated for anti-inflammatory activity against carrageenan-induced edema in rats. Halogenated derivatives 4g and 4c, at oral doses of 100 mg/kg, showed 75 and 60% antiedmatous activity, respectively (phenylbutazone antiedematous activity, 58%). The analgesic activity of 4g and 4c, based on inhibition of acetic acid-induced writhing in mice (67 and 62%, respectively, at oral doses of 100 mg/kg) was comparable with that of aspirin (58%). However, these derivatives were devoid of antipyretic activity and showed low activity against adjuvant-induced arthritis.


Warfarin sodium. Practitioner beware.

Warfarin sodium. Practitioner beware. The use of warfarin sodium in the US has increased dramatically over the last 40 years. Warfarin sodium or Coumadin is the most popular oral anticoagulant used in the US. The podiatric physician frequently encounters patients taking this agent and therefore needs to understand its potential impact. This article will familiarize the reader with the history, pharmacology, clinical applications, side effects, and frequent drug interactions encountered with warfarin sodium.


Rotational scarf (Z) osteotomy bunionectomy for correction of high intermetatarsal angles. A modification of the scarf osteotomy bunionectomy is described. The modification involves a change in the movement of the osseous fragments from lateral transposition to lateral rotation of the metatarsal head fragment around a stationary axis at the metatarsal base. Rotation of the distal fragment in this manner allows greater than 50% transposition and, therefore, higher intermetatarsal angle corrections can be obtained as compared to a transpositional scarf osteotomy. The configuration of the scarf osteotomy is more stable to the stress of weightbearing than the closing base wedge osteotomy, and this modification can provide a useful alternative to closing base wedge osteotomy for the correction of severe hallux valgus deformity.


Treatment of lower extremity infections in diabetics. The infected diabetic lower extremity has enjoyed a surge in popularity in the medical literature. There have been numerous papers outlining classification systems for ulcer depth, surgical approaches, and microbiology. Discussions on antibiotic use have usually been directed toward therapy of the "diabetic foot infections" as a group, without regard to differences in severity and location of these infections. These infections can vary from the most superficial of processes to a severe life- and limb-threatening sepsis. The author presents a review of the processes involved in the diabetic lower extremity infection and suggests a classification system for selection of empiric antibiotic therapy based on the severity of the infection.


Effect of rearfoot posts in reducing forefoot forces. A single-subject design. The purpose of this study was to assess the effectiveness of a semirigid foot orthosis with a varus wedge on forefoot vertical forces in a 24-year-old female with a compensated rearfoot varus deformity. The results of this study indicate that the use of total contact semirigid foot orthoses reduces the forefoot force-time integral during walking, whether a rearfoot varus wedge was or was not used. The authors recommend that total contact construction of the foot orthoses be considered when a reduction of the forces acting on the forefoot is the goal of treatment.


Current diagnostic and radiographic assessment of tendo Achillis rupture. The literature is replete with current clinical evaluation techniques of tendo Achillis rupture. An overview of the etiologies, diagnosis, radiographic evaluation, and treatment modes, either surgical or conservative, is presented with a brief description of two lesser known techniques: the knee flexion examination and needle test.


Ciprofloxacin in the treatment of Mycobacterium fortuitum infection of the peroneal tendons. A case report. In the case reported, M. fortuitum was sensitive in vitro to amikacin, erythromycin, tobramycin, and ciprofloxacin. Because the patient did not respond to long-term therapy with amikacin and erythromycin, an experimental antibiotic, ciprofloxacin, was tried. Only after extensive surgical debridement and 2 1/2 months of oral ciprofloxacin therapy was the infection eradicated and wound healing obtained. The authors conclude that a wound that has reopened, but remains indolent, exudes a clear, serous drainage and responds poorly to antibiotics should suggest a possible mycobacterial infection. Combination antibiotic therapy is recommended because of the high rate of relapse and development of resistance to drugs. Extensive surgical debridement of all infected tissue remains the primary treatment. The therapeutic value of ciprofloxacin and other newer antibiotics in the treatment of mycobacterial infection is promising.


Management of complications associated with an excision of a lipoma from the ankle. This case study demonstrates the following: close proximity of lipoma to underlined skin can compromise circulation; the size of the lipoma and the resulting redundant skin after the incision can lead to fluid development and impede the healing process; and a patient who is noncompliant and stands or walks excessively after the excision of a lipoma can cause buildup of a hematoma, which can compromise the incision site. Lipomas associated with the foot or ankle are rarely symptomatic. When they do cause pain and are surgically treated, possible complications because of their size and location must be considered. Finally, these complications could have been avoided if the redundant skin had been excised and a Penrose drain inserted to eliminate excess fluid buildup. Also, better communication should have been maintained with the patient during the entire postoperative course.


Loop memory of posterior chamber intraocular lenses of various sizes, designs, and loop materials. Looped intraocular lenses (IOLs) fixate by exerting centripetal pressure on the ocular tissues. The ability of the flexible loops to maintain pressure depends on their rigidity (i.e., resistance to flexion) and their "memory" (i.e., ability to restore original configuration after a long period of compression). We studied the memory of 30 different posterior chamber IOLs, with loops made of polypropylene (PP) and poly(methyl methacrylate) (PMMA), of various diameters, styles, and designs. The lenses were inserted into plastic wells, 9.5 mm in diameter, and immersed in water (37 degrees C) for one month. They were then placed on an open plate and allowed to re-expand for one month. Loop memory was calculated as the difference in diameter between the initial (pretest) measurement and measurements taken during the compression and release periods. The results showed that short (12.0 to 12.5 mm) IOLs had relatively better memory than longer (13.5 to 14.0 mm) IOLs. Those with PP loops expanded more and for longer periods than those comparable size and design with PMMA loops. One-piece, all-PMMA lenses exhibited the best loop memory. These lenses have the high rigidity of the PMMA material and the good memory of the design. Thus, the total IOL diameter can be reduced to 12.0 mm while providing long-term constant pressure on the capsular bag to maintain stable fixation.


Comparison of shape recovery ratios in various intraocular lens haptics. Since understanding the mechanical properties of intraocular lens (IOL) haptic materials can minimize decentration after surgery, we have examined shape recovery ratios of various intraocular lens haptics (polypropylene [PP], polyvinylidene fluoride [PVDF], extruded poly(methyl methacrylate) [PMMA]) currently on the market under conditions that approximate clinical use. The results using various Ascon lens-holding forceps and compression tests, during which the lenses were held in a cylindrical holder for seven days, one month, and three months, indicated that PVDF haptics had better shape recovery capability than PP and extruded three-piece PMMA haptics.


Aqueous humor analysis after Nd:YAG laser capsulotomy with the laser flare-cell meter. Using the laser flare-cell meter (Kowa FC-1000), we conducted a prospective study analyzing the effect of Nd:YAG posterior capsulotomy on the quantity of aqueous particles, aqueous flare, and intraocular pressure in 65 eyes (58 patients). Aqueous particles increased at six hours, followed by flare rise which was significant at 18 hours after capsulotomy. Only 22 eyes (34%) had a significant flare rise over prelaser values. Anti-inflammatory therapy was necessary in only one patient. The mean intraocular pressure value did not rise significantly after capsulotomy. Acute intraocular hypertension (AIOHT) (> 7 mm Hg increase) occurred between three and six hours after laser therapy in 12 patients (19%), was related in time to particle rise, and always responded to a single dose of acetazolamide. Acute intraocular hypertension was strongly correlated with elevated aqueous particles (P < .0001) and somewhat correlated with flare rise (P < .036), but was not correlated with the intraocular lens position (bag or sulcus fixation). Our findings strongly suggest that trabecular meshwork clogging by debris generated by the capsulotomy is the mechanism at the origin of AIOHT.


Effect of preoperative YAG laser anterior capsulotomy on the incidence of posterior capsule opacification: ten year follow-up. One hundred twenty-two patients, who were followed for ten years, had bilateral extracapsular cataract surgery with implantation of J-looped posterior chamber lenses between 1980 and 1981. On the first eye an anterior capsulotomy was performed with a pico-second YAG laser 12 to 20 hours before surgery; on the second eye a capsulotomy was performed manually at the time of surgery. Four of the eyes (3.27%) with laser capsulotomies had opacified posterior capsules after ten years; 61 of the eyes (50.00%) with manual capsulotomies had opacified capsules that had to be opened with a YAG laser.


Effect of neodymium:YAG laser photodisruption on intraocular lenses in vitro. Poly(methyl methacrylate) (PMMA) based intraocular lenses (IOLs) such as injection-molded PMMA and lathe-cut PMMA IOLs and soft IOLs such as silicone and poly(hydroxyethyl methacrylate)(polyHEMA) IOLs were tested for vulnerability to Nd:YAG laser photodisruption. The laser beam was focused on the posterior surface and inside of the IOLs in balanced salt solution. Cracks and central defects with radiating fractures were observed in PMMA IOLs; blistered lesions and localized pits were observed in silicone and polyHEMA IOLs, respectively. A molten edge surrounding the large hole, which was an indication of the thermal effect of the laser, was observed in the injection-molded PMMA while only a minute lesion was found in the polyHEMA IOL which contained 38% water. The size of the superficial damage of the IOL increased as the power of laser irradiation increased and PMMA IOLs showed greater damage than soft IOLs (P < .05).


Antiplatelet therapy and cataract surgery. To gain information about patients who continue antiplatelet therapy while having cataract surgery, we performed a prospective, nonrandomized study. Twenty-four of 60 phacoemulsification procedures were performed on patients who were receiving medications with antiplatelet activity prior to surgery and who continued to receive the medications for the duration of the study. The remaining 36 procedures were performed on patients who received no medications with antiplatelet activity prior to surgery. One patient in the antiplatelet therapy group had a limited peribulbar hemorrhage, and one patient not receiving antiplatelet therapy had a postoperative hyphema. Postoperative subconjunctival hemorrhages were more common in the antiplatelet therapy group (P = .001). No patient in the antiplatelet therapy group had late postoperative complications. No differences in postoperative visual acuity or intraocular pressure were observed between the groups. Our results demonstrate that phacoemulsification and posterior chamber intraocular lens implantation can be performed without serious complications in some patients who continue to use antiplatelet therapy. However, our sample sizes were too small to determine whether such therapy is associated with any increased risk of rare but serious hemorrhagic complications.