15667066
Oculohypotensive effects of foeniculum vulgare in experimental models of glaucoma.
PURPOSE
Evaluation of oculohypotensive activity of single drop application of aqueous extract of Foeniculum vulgare in experimental models of glaucoma.


METHODS
The evaluation of oculohypotensive activity of Foeniculum vulgare was done in rabbits with normal intraocular pressure (IOP) and with experimentally elevated IOP. The experimental increase in IOP was achieved using water loading and steroid induced glaucoma models.


RESULTS
The aqueous seed extract of Foeniculum vulgare exhibited 17.49, 21.16 and 22.03% reduction of intraocular pressure (IOP) in normotensive rabbits at 0.3%, 0.6% and 1.2% (w/v) concentrations respectively. The 0.6% concentration was further evaluated in acute and chronic models of glaucoma. A maximum mean difference of 31.20% was observed between vehicle treated and extract treated eyes in water loading model while a maximum mean IOP lowering of 31.29% was observed in steroid induced model of glaucoma.


CONCLUSIONS
The aqueous extract of Foeniculum vulgare possesses significant oculohypotensive activity, which was found to be comparable to that of timolol. Further investigations into the mechanism of action, possible toxicity and human clinical trials are warranted before the Foeniculum vulgare finds place in the arsenal of antiglaucoma drugs prescribed by physicians.
6343189
Mechanisms of angiotensin converting enzyme inhibitor-induced IOP reduction in normotensive rats.
Angiotensin converting enzyme inhibitors (ACEIs) have been shown to lower intraocular pressure (IOP). Since, the ACEIs cause increased tissue prostaglandin levels, we hypothesized that the mechanisms of ACEI-induced IOP reduction have similarity with those of prostaglandin analogs. The present study investigated the involvement of matrix metalloproteinases (MMPs) and cytokine activity modulation as the underlying mechanisms of ACEI-induced ocular hypotension. The IOP lowering effect of single drop of enalaprilat dehydrate 1% was evaluated in rats pretreated with a broad spectrum MMP inhibitor or a cytokine inhibitor. Effect of angiotensin receptor blocker, losartan potassium 2%, was also studied to evaluate involvement of angiotensin II receptor type 1 (AT1) in IOP lowering effect of ACEI. Topical treatment with single drop of enalaprilat resulted in significant IOP reduction in treated eye with mean peak reduction 20.3% at 3h post-instillation. Treatment with losartan resulted in a peak IOP reduction of 13.3%, which was significantly lower than enalaprilat, indicating involvement of mechanisms in addition to AT1 blockade. Pretreatment with a broad spectrum MMP inhibitor or a cytokine inhibitor significantly attenuated the enalprilat-induced IOP reduction with mean peak IOP reduction of 11.2% and 13.6% respectively. The IOP-lowering effect of enalaprilat seems to be attributed to reduced angiotensin II type 1 receptor stimulation and modulation of MMP and cytokines activities.
41765492
Effects of magnesium taurate on the onset and progression of galactose-induced experimental cataract: in vivo and in vitro evaluation.
Cataract, a leading cause of blindness, is characterized by lenticular opacities resulting from denaturation of lens proteins due to activation of calcium-dependent enzyme, calpain. Magnesium (Mg(2+)) plays an important role not only in maintaining a low lenticular calcium (Ca(2+)) and sodium concentration but also in preserving the lens redox status. Taurine has also been shown to reduce lenticular oxidative stress. Present study evaluated the anticataract effects of magnesium taurate in vivo and in vitro. Among the five groups of 9 Sprague Dawley rats each, two groups received 30% galactose diet with topical (GDMT) or oral treatment (GDMO) with magnesium taurate. Two groups received 30% galactose diet with topical (GDT) or oral vehicle (GDO). Remaining 1 group received normal diet (ND). Weekly slit lamp examination was done during 21 days experimental period and then all rats were sacrificed; Ca/Mg ratio and antioxidant parameters including reduced glutathione (GSH), catalase and superoxide dismutase (SOD) activities were measured in the isolated lenses using ELISA. In the in vitro study, 2 groups of 10 normal rat lenses were incubated in Dulbecco's Modified Eagle's Medium (DMEM) with galactose while 1 similar group was incubated in DMEM without galactose. In one of the groups, galactose containing medium was supplemented with magnesium taurate. After 48 h of incubation, lenses were photographed and Ca(2+)/Mg(2+) ratio and antioxidant parameters were measured as for in vivo study. The in vivo study, at the end of experimental period, demonstrated delay in the development of cataract with a mean opacity index of 0.53 ± 0.04 and 0.51 ± 0.03 in GDMO (p < 0.05 versus GDO) and GDMT (p < 0.01 versus GDT) respectively. Histopathological grading showed a lower mean value in treated groups, however, the differences from corresponding controls were not significant. Lenticular Ca(2+)/Mg(2+) ratio with a mean value of 1.20 ± 0.26 and 1.05 ± 0.26 in GDMO and GDMT was significantly lower than corresponding controls (p < 0.05) and in GDMT no significant difference was observed from ND. Lenticular GSH and catalase activities were significantly lower and SOD activity was significantly higher in all galactose fed groups. However, in GDMT, GSH and catalase were significantly higher than corresponding control with mean values of 0.96 ± 0.30 μmol/gm lens weight and 56.98 ± 9.86 μmol/g lens protein respectively (p < 0.05 for GSH and p < 0.01 for catalase). SOD activity with mean values of 13.05 ± 6.35 and 13.27 ± 7.61 units/mg lens protein in GDMO and GDMT respectively was significantly lower compared to corresponding controls (p < 0.05) signifying lesser upregulation of SOD due to lesser oxidative stress in treated groups. In the in vitro study, lenses incubated in magnesium taurate containing medium showed less opacity and a lower mean Ca(2+)/Mg(2+) ratio of 1.64 ± 0.03, which was not significantly different from lenses incubated in DMEM without galactose. Lens GSH and catalase activities were restored to normal in lenses incubated in magnesium taurate containing medium. Both in vivo and in vitro studies demonstrated that treatment with magnesium taurate delays the onset and progression of cataract in galactose fed rats by restoring the lens Ca(2+)/Mg(2+) ratio and lens redox status.
10346616
Mechanisms of cataractogenesis in the presence of magnesium deficiency.
Senile cataract is the most common cause of bilateral blindness and results from the loss of transparency of the lens. Maintenance of the unique tissue architecture of the lens is vital for keeping the lens transparent. Membrane transport mechanisms utilizing several magnesium (Mg)-dependent ATPases, play an important role in maintaining lens homeostasis. Therefore, in Mg-deficiency states, ATPase dysfunctions lead to intracellular depletion of K(+) and accumulation of Na(+) and Ca(2+). High intracellular Ca(2+) causes activation of the enzyme calpain II, which leads to the denaturation of crystallin, the soluble lens protein required for maintaining the transparency of the lens. Mg deficiency also interferes with ATPase functions by causing cellular ATP depletion. Furthermore, Mg deficiency enhances lenticular oxidative stress by increased production of free radicals and depletion of antioxidant defenses. Therefore, Mg supplementation may be of therapeutic value in preventing the onset and progression of cataracts in conditions associated with Mg deficiency.
39481152
Magnesium deficiency: does it have a role to play in cataractogenesis?
Magnesium is one of the most important regulatory cation involved in several biological processes. It is important for maintaining the structural and functional integrity of vital ocular tissues such as lens. Presence of high magnesium content especially in the peripheral part of lens as compared to aqueous and vitreous humor has been observed. Magnesium plays significant role as a cofactor for more than 350 enzymes in the body especially those utilizing ATP. Membrane associated ATPase functions that are crucial in regulating the intracellular ionic environment, are magnesium-dependent. Moreover, the enzymes involved in ATP production and hydrolysis are also magnesium-dependent. Magnesium deficiency by interfering with ATPase functions causes increased intracellular calcium and sodium and decreases intracellular potassium concentration. Furthermore, magnesium deficiency is associated with increased oxidative stress secondary to increased expression of inducible nitric oxide synthase and increased production of nitric oxide. Thus the alterations in lenticular redox status and ionic imbalances form the basis of the association of magnesium deficiency with cataract. In this paper we review the mechanisms involved in magnesium homeostasis and the role of magnesium deficiency in the pathogenesis of cataract.
44919999
Asymptomatic incomplete left ventricular apical rupture diagnosed by cardiac magnetic resonance imaging.
66-year-old man presented with a fever of 103 °F, cough, and dyspnea, despite 3 days' treatment of pneumonia. Chest radiography revealed a normal cardiac silhouette and a small left pleural effusion. A baseline electrocardiogram (ECG) showed normal sinus rhythm with profound ST-segment elevation in the anterolateral leads. An ECG obtained 2 months earlier was normal. An echocardiogram showed severe hypokinesis of the anterior, anteroseptal, and apical segments without evidence of a pericardial effusion. Coronary angiography revealed complete occlusion of the proximal left anterior descending coronary artery with severe distal anterior hypokinesis. 
 
Forty-eight hours after admission, the patient had recurrent fever. A repeat transthoracic echocardiogram (Fig. 1) revealed a thin, aneurysmal, left ventricular (LV) apex with pericardium apparently adherent to the apex. In addition, a moderate-to-large, echo-free pericardial effusion was noted. Out of clinical concern for a possible contained LV rupture, cardiac magnetic resonance imaging (CMR) was performed for definitive evaluation and tissue characterization. 
 
 
 
Fig. 1 Transthoracic echocardiogram (4-chamber view at end-systole) reveals an apex-sparing pericardial effusion and an aneurysmal left ventricular apex. 
 
 
 
The CMR (Figs. 2 and 3) revealed evidence of a large myocardial infarction (MI) with subsequent aneurysm formation involving the distal half of the left anterior descending artery distribution and the entire apex, with an extensive amount of thrombus in the apex. A “hinge-point” involving the lateral and anterolateral walls was noted, raising the concern of a possible contained rupture of the LV apex. A large, predominantly simple-appearing pericardial effusion was noted circumferentially, but the apex was spared. The pericardium was hyperenhanced on viability/ scar imaging in the regions of infarct, suggesting post-MI pericarditis. 
 
 
 
Fig. 2 Cine cardiac magnetic resonance imaging demonstrates a large aneurysmal area involving the distal half of the left anterior descending coronary artery distribution with an extensive amount of thrombus at the apex. A hinge-point involving the lateral ... 
 
 
 
 
 
Fig. 3 Viability/scar imaging reveals a transmural infarction of the affected area. The remainder of the left ventricular myocardium appears to be of full thickness and viable. There is also hyperenhancement of the pericardium in the infarct regions, ... 
 
 
 
A follow-up echocardiogram performed 1 week later showed a slight decrease in the size of the pericardial effusion. Repair of the LV was deferred until effective surgical suturing could be performed on the infarcted area. 
 
Eight weeks later, the patient underwent successful LV endoaneurysmorrhaphy with a Dacron patch. Intraoperatively, a 3- × 4-cm balloon-like aneurysm was found to be fused to the pericardial sac. The aneurysm was excised, and subsequent microscopic evaluation revealed necrotic myocardium and reactive connective tissue (Fig. 4). The patient had an uneventful hospital course and was discharged from the hospital in stable condition. At a follow-up visit 2 months later, he reported a substantial increase in exercise tolerance and a return to usual daily activities. 
 
 
 
Fig. 4 Photomicrograph illustrates necrotic myocardium and adjacent reactive connective tissue. (H & E, orig. ×100)
36066210
First-line therapy for ovarian cancer with carboplatin followed by paclitaxel-gemcitabine (SCOTROC5): a feasibility study and comparative analysis of the SCOTROC series.
BACKGROUND
We have conducted a series of four feasibility studies in stage Ic-IV ovarian cancer exploring six sequential first-line schedules with the same entry criteria in a total of 339 patients. Here we present the results of the sixth study, and an analysis of the overall series.


METHODS
In this trial patients received 4 cycles of carboplatin AUC 7 every 3 weeks, followed by 4 cycles of concurrent paclitaxel 175 mg/m(2) (day 1) and gemcitabine 1000 mg/m(2) (days 1 and 8) every 3 weeks. The primary end-point of the trial was feasibility of administering all cycles of planned chemotherapy to >60% of patients.


RESULTS
Fifty-four patients were recruited to the trial between June 05 and June 06. A total of 40 (74.1%) patients received all 8 cycles of treatment. Reasons for early discontinuation included toxicity (n=8) and disease progression (n=4). The overall response rate was 73.7%, and the median progression free survival (PFS) was 14.2 months with a median follow-up of 24 months. A comparative analysis of all six regimens from the SCOTROC series suggests that the sequential schedule in which paclitaxel was given weekly (median PFS 19.5m) is most effective.


CONCLUSION
The sequential schedule explored in this trial is feasible, but comparative efficacy analysis suggests that trials involving weekly paclitaxel should be prioritised for further study.
34975041
Treatment of hypertension in patients with diabetes: lessons from recent trials.
Hypertension plays a critical role in causing a high rate of cardiovascular events in patients with diabetes mellitus. Large trials show that lowering blood pressure in the patient with diabetes who has hypertension has profoundly favorable effects. This review discusses recent trials to answer the question of how low patients' blood pressure should go and which agents should be used to achieve this goal. The National Institutes of Health's guidelines, published in the Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, call for a blood pressure goal of <130/85 mmHg in patients with diabetes. Based on data from the recent trials, an even lower blood pressure of <130/80 mmHg in patients with diabetes and hypertension appears to be appropriate. Observational studies show that the lowest cardiovascular event rate is observed in patients with diabetes whose systolic blood pressure is <120 mmHg. Thus, goal blood pressure in patients with diabetes who have hypertension may need to be revised lower, to <120/80 mmHg. In patients with overt proteinuria of 1 g/d or more, mean arterial pressure of <92 mmHg is recommended. Available evidence justifies the use of angiotensin-converting enzyme (ACE) inhibitors as first-line agents and angiotensin receptor blockers in those patients who are intolerant to ACE inhibitors. Because the blood pressure goal is lower in patients with diabetes who are hypertensive, these patients require the use of multiple agents. Diuretics or long-acting calcium channel blockers are logical second choices because of their synergistic blood pressure reduction effect observed with ACE inhibitors. Alpha-blockers should be used with caution, however. In patients with renal disease, loop diuretics may be required to reduce sodium and volume overload and to improve blood pressure control.
30308813
Strategies and feasibility of hypertension control in a prevalent hemodialysis cohort.
BACKGROUND
There are few data to demonstrate the feasibility of long-term blood pressure (BP) control using short dialysis sessions as practiced in the US. Control of hypertension in hemodialysis patients may reduce the risk of cardiovascular events.


METHODS
Forty-two dialysis patients had BPs and weights recorded before and after dialysis for two consecutive weeks and were followed by one physician over three years. Patients were treated by ultrafiltration and conventional antihypertensive drugs and BPs were repeated at three years in the 32 survivors.


RESULTS
93% of the patients (39/42) were African-American. At inception, 85% of the patients were hypertensive with BPs of 154 +/- 23/83 +/- 14 mmHg and 137 +/- 22/74 +/- 14 mmHg pre- and post-dialysis, respectively. The response to ultrafiltration was dependent upon gender, with women having a greater BP reduction compared to men. At three-year follow-up, the BP had dropped significantly in the survivors a mean of 9.4/6.7 mmHg. Pre- and post-dialysis weights, post dialysis BP and interdialytic weight-gain were unchanged. The BP reduction was achieved by an increase in the number of antihypertensive medications from 0.91 +/- 0.86 medications to 1.41 +/- 1.16. Improved BP control did not worsen the efficiency of dialysis (Kt/V). The use of beta-blockers doubled during the period of follow-up. Compared to the USRDS average cardiovascular death rate, the risk of cardiovascular deaths was improved 80% over three years.


CONCLUSION
Long-term BP reduction can be achieved through the use of antihypertensive agents and volume control in a predominantly African-American hemodialysis population. This may impact cardiovascular mortality.
33440140
Supervised atenolol therapy in the management of hemodialysis hypertension.
BACKGROUND
Uncontrolled hypertension continues to be a common problem, particularly in noncompliant hemodialysis patients. Atenolol, a water soluble beta-blocker has a prolonged half-life in renal failure and may serve as a useful antihypertensive agent in these patients.


METHODS
Hypertension was diagnosed by ambulatory blood pressure monitoring for 44 hours during an interdialytic interval in eight chronic hemodialysis patients receiving no antihypertensive therapy. An average daytime blood pressure greater than 140/90 mm Hg or an average nighttime blood pressure greater than 120/80 mm Hg was used to define uncontrolled hypertension. Patients were then administered atenolol (25 mg) following hemodialysis three times a week. The efficacy of therapy was judged by ambulatory blood pressure monitoring three weeks after instituting atenolol therapy. Blood pressure loads above the threshold blood pressures during the day or night were also calculated and compared before and after three weeks of atenolol therapy.


RESULTS
The mean 44-hour ambulatory blood pressure (ABP) fell from 144 +/- 14/80 +/- 7 mm Hg to 127 +/- 13/69 +/- 10 mm Hg (P < 0.001). The heart rate fell from 85 +/- 11 to 70 +/- 11 beats per minute. The systolic and diastolic blood pressure load was reduced from 71 +/- 25% and 30 +/- 24% to 35 +/- 26% and 11 +/- 17%, respectively (P < 0.001). There was a persistent antihypertensive effect over 44 hours. The blood pressure reduction was achieved without any increase in intradialytic symptomatic or asymptomatic hypotensive episodes, reduction in delivered dialysis, or statistically significant changes in serum potassium or glucose.


CONCLUSIONS
A supervised administration of atenolol following hemodialysis effectively and safely controls hypertension in chronic hemodialysis patients. This therapy can be particularly valuable for noncompliant hemodialysis patients.