Polymorphisms of methylenetetrahydrofolate reductase and the risk of prostate cancer: a nested case-control study.

It has been proposed that folate and polymorphisms of the enzyme methylenetetrahydrofolate reductase (MTHFR), which regulates influx of folate from DNA synthesis and repair to methylation reactions, are involved in the aetiology of cancer. To relate the MTHFR 677C-->T and 1298A-->C polymorphisms to the risk of prostate cancer, taking into consideration prospective plasma levels of folate, vitamin B12 and homocysteine. The design was a case-control study of 223 prostate cancer cases and 435 matched controls nested within the population-based Northern Sweden Health and Disease Cohort. Neither the MTHFR 677C-->T nor the MTHFR 1298A-->C polymorphism was statistically significantly associated with the risk of prostate cancer in univariate analysis by conditional logistic regression. After adjustment for MTHFR 1298A-->C, plasma folate, vitamin B12, homocysteine, body mass index and smoking, the odds ratios were, for the 677 CT genotype, 1.52 [95% confidence interval (CI) 1.02-2.26], and for TT, 0.91 (95% CI 0.41-2.04). Our previously reported observation of a possible increase in the risk of prostate cancer at high plasma folate levels was attributable in this study to subjects having the MTHFR 677C-->T polymorphism. We found that the MTHFR 677C-->T polymorphism is not likely to have a major role in the development of prostate cancer, although it may possibly increase the risk in combination with high plasma folate levels. Further investigation in larger studies is warranted.

Pigment epithelium-derived factor regulates the vasculature and mass of the prostate and pancreas.

Angiogenesis sustains tumor growth and metastasis, and recent studies indicate that the vascular endothelium regulates tissue mass. In the prostate, androgens drive angiogenic inducers to stimulate growth, whereas androgen withdrawal leads to decreased vascular endothelial growth factor, vascular regression and epithelial cell apoptosis. Here, we identify the angiogenesis inhibitor pigment epithelium-derived factor (PEDF) as a key inhibitor of stromal vasculature and epithelial tissue growth in mouse prostate and pancreas. In PEDF-deficient mice, stromal vessels were increased and associated with epithelial cell hyperplasia. Androgens inhibited prostatic PEDF expression in cultured cells. In vivo, androgen ablation increased PEDF in normal rat prostates and in human cancer biopsies. Exogenous PEDF induced tumor epithelial apoptosis in vitro and limited in vivo tumor xenograft growth, triggering endothelial apoptosis. Thus, PEDF regulates normal pancreas and prostate mass. Its androgen sensitivity makes PEDF a likely contributor to the anticancer effects of androgen ablation.

Safety of controlled-onset extended-release verapamil in middle-aged and older patients with hypertension and coronary artery disease.

BACKGROUND: Our purpose was to study the safety of controlled-onset, extended-release (COER) verapamil in patients with hypertension or coronary artery disease, with a focus on elderly patients. METHODS: Adverse event data were pooled from 7 double-blind, multicenter, randomized trials including 1999 patients with hypertension or chronic stable angina pectoris. There were 1042 patients who received COER verapamil 180 to 540 mg once daily in the evening for up to 10 weeks, 373 patients who received placebo, and 584 who received an active comparator agent. Data were analyzed according to the following groups: all patients, patients with hypertension, patients with angina, older patients (>/=65 years old), and younger patients (<65 years old). Adverse event rates were compared across the treatment groups by the Fisher exact test. RESULTS: In all patients combined, the incidence of constipation (13% vs 2%), dizziness (6% vs 2%), and back pain (3% vs 1%) was higher in patients treated with COER verapamil than with placebo. Patients with hypertension had more back pain (4% vs 1%) and constipation (12% vs 1%) with COER verapamil than with placebo, whereas patients with angina had more bradycardia (2.6% vs 0%), dizziness (8% vs 2%), and constipation (15% vs 3%). Older patients treated with COER verapamil had more bradycardia, constipation, dizziness, and fatigue and had fewer headaches compared with younger patients treated with COER verapamil. Second- or third-degree atrioventricular block was not observed after administration of COER verapamil in any subgroup. CONCLUSION: These data demonstrate that COER verapamil has an acceptable safety profile that is largely unrelated to age in patients with hypertension or coronary artery disease.

Orbofiban: an orally active GPIIb/IIIa platelet receptor antagonist.

A key role has been established for platelet activation and thrombus formation in the pathogenesis of acute coronary syndromes, and restenosis after percutaneous interventions. Antiplatelet agents that have a wider spectrum of activity than aspirin, and clopidogrel would be expected to provide improved antithrombotic protection. Preclinical studies were used to predict clinical efficacy of orally active GPIIb/IIIa antagonists such as xemilofiban, sibrafiban, lefradafiban, and orbofiban. While clinical trials have shown potent and sustained platelet inhibition, outcomes of trials with these first generation GPIIb/IIIa compounds have been disappointing. The active moiety of orbofiban is a potent and specific inhibitor of fibrinogen binding to GPIIb/IIIa, leading to inhibition of platelet aggregation to a wide variety of agonists. Studies comparing inhibition of aggregation and bleeding suggest that chronic inhibition of platelet aggregation can be achieved without major bleeding side effects. Thrombus formation is prevented in canine models of thrombosis. Orbofiban is approximately 28% bioavailable with a t(1/2) of 18 hr. The high bioavailability, long half-life, and potential safety suggest orbofiban would be suitable for chronic oral administration. Clinical data demonstrate that orally administered orbofiban has the desired pharmacodynamic effect of inhibiting platelet aggregation but does not demonstrate clinical benefit when examined in large-scale trials.

Oral glycoprotein IIb/IIIa inhibition with orbofiban in patients with unstable coronary syndromes (OPUS-TIMI 16) trial.

BACKGROUND: Although intravenous glycoprotein IIb/IIIa inhibitors are beneficial in patients with acute coronary syndromes, prolonged oral IIb/IIIa inhibition might provide an additional reduction in recurrent events. METHODS AND RESULTS: Investigators at 888 hospitals in 29 countries enrolled 10 288 patients with acute coronary syndromes, which was defined as ischemic pain at rest within 72 hours of randomization, associated with positive cardiac markers, electrocardiographic changes, or prior cardiovascular disease. Patients received aspirin and were randomized to receive, for the duration of the trial, (1) 50 mg of orbofiban twice daily (50/50 group), (2) 50 mg of orbofiban twice daily for 30 days followed by 30 mg of orbofiban twice daily (50/30 group), or (3) a placebo. The primary composite end point was death, myocardial infarction, recurrent ischemia requiring rehospitalization, urgent revascularization, or stroke. The trial was terminated prematurely because of an unexpected increase in 30-day mortality in the 50/30 orbofiban group. Mortality through 10 months was 3.7% for the placebo group versus 5.1% in the 50/30 group (P=0.008) and 4.5% in the 50/50 group (P=0.11). There were no differences in the primary end point (22.9%, 23.1%, and 22.8%, for the placebo, 50/30, and 50/50 groups, respectively). Major or severe bleeding (but not intracranial hemorrhage) was higher with orbofiban; it occurred in 2. 0%, 3.7% (P=0.0004), and 4.5% (P<0.0001) of patients, respectively. Exploratory subgroup analyses found that patients who underwent percutaneous coronary intervention had a lower mortality and a significant reduction in the composite end point (P=0.001) with orbofiban. CONCLUSIONS: -Fixed-dose orbofiban failed to reduce major cardiovascular events and was associated with increased mortality in this broad population of patients with acute coronary syndromes; however, a benefit was observed among patients who underwent percutaneous coronary intervention.

Pharmacodynamic efficacy, clinical safety, and outcomes after prolonged platelet Glycoprotein IIb/IIIa receptor blockade with oral xemilofiban: results of a multicenter, placebo-controlled, randomized trial.

BACKGROUND: Parenteral administration of platelet glycoprotein IIb/IIIa (GP IIb/IIIa) receptor blockers can reduce ischemic complications of coronary angioplasty. Orally active GP IIb/IIIa blockers may allow more sustained receptor antagonism with the potential for long-term secondary prevention. The pharmacodynamic efficacy, clinical safety, and outcomes after prolonged receptor blockade with an orally active GP IIb/IIIa antagonist are not known. The Oral Glycoprotein IIb/IIIa Receptor Blockade to Inhibit Thrombosis (ORBIT) Trial is a multicenter, placebo-controlled, randomized trial of xemilofiban, an oral platelet GP IIb/IIIa blocking agent, administered to patients after percutaneous coronary intervention. METHODS AND RESULTS: After successful elective percutaneous coronary intervention, 549 patients were randomized to receive either placebo or xemilofiban in a dose of 15 or 20 mg. Stented patients randomized to placebo also received ticlopidine 250 mg orally BID for 4 weeks. Patients who received abciximab during the coronary intervention and who were randomized to receive xemilofiban were administered a reduced dosage (10 mg TID for 2 weeks) followed by the randomized maintenance dose of 15 or 20 mg BID for 2 more weeks. All patients received 325 mg aspirin PO QD. Ex vivo platelet aggregation in response to 20 micromol/L ADP and 4 microg/mL collagen was measured over time after the initial dose of study drug and at days 14 and 28 of long-term therapy in 230 patients. All patients were followed clinically for 90 days. Xemilofiban inhibited platelet aggregation to both ADP and collagen with peak levels of inhibition that were similar at 14 and 28 days of long-term oral therapy. Plasma levels of xemilofiban correlated with the degree of platelet inhibition. Peak platelet inhibition on day 1 correlated with the subsequent occurrence of insignificant or mild bleeding events. Although this study was not powered to evaluate differences in clinical outcomes, a trend (P=0.04) was observed for reduction of cardiovascular events at 3 months in patients not treated with abciximab who received the highest dose (20 mg) of xemilofiban studied. CONCLUSIONS: Xemilofiban inhibited platelet aggregation and was well tolerated during 28 days of long-term oral therapy. The observed trend in reduction of cardiovascular events in follow-up awaits confirmation in the larger-scale phase III study (EXCITE trial) currently in progress.

Sustained platelet glycoprotein IIb/IIIa blockade with oral xemilofiban in 170 patients after coronary stent deployment.

BACKGROUND: Inhibition of platelet aggregation with parenteral glycoprotein (GP) IIb/IIIa receptor blockers can reduce the ischemic complications of angioplasty. Sustained efficacy and safety of protracted GP IIb/IIIa blockade with an orally administered agent have not previously been determined. This study is the first randomized, dose-ranging, single-blind, placebo-controlled trial of xemilofiban, an oral platelet GP IIb/IIIa receptor antagonist, administered to patients after intracoronary stent deployment. The pharmacodynamic efficacy of xemilofiban-induced platelet inhibition and clinical safety of this agent was evaluated during chronic therapy. METHODS AND RESULTS: After elective intracoronary stent deployment, patients were randomized to receive placebo (250 mg ticlopidine P.O. BID) or xemilofiban in doses of 5, 10, 15, or 20 mg P.O. BID. All patients received 325 mg aspirin P.O. QD. Inhibition of ex vivo platelet aggregation in response to 20 micromol/L ADP and 4 microg/mL collagen was measured over time after the initial dose of study drug and at 1 and 2 weeks of chronic therapy. Study drug was discontinued after 2 weeks, and all patients were followed clinically for > or = 30 days. Oral xemilofiban resulted in a dose-dependent inhibition of platelet aggregation in response to both agonists that was sustained through 2 weeks of chronic therapy. Doses of xemilofiban required to achieve > or = 50% inhibition of platelet aggregation were > or = 10 mg, and the duration of inhibition was 8 to 10 hours. No significant hemorrhagic episodes or blood transfusions were observed in this trial. CONCLUSIONS: Oral xemilofiban in doses of > or = 10 mg produced > or = 50% inhibition of platelet aggregation in response to ADP and collagen for 8 to 10 hours after dosing. Platelet inhibition was sustained through 2 weeks of chronic therapy. The optimal duration of oral GP IIb/IIIa blockade to effectively suppress recurrent ischemic events after coronary intervention remains to be determined.

First chronic platelet glycoprotein IIb/IIIa integrin blockade. A randomized, placebo-controlled pilot study of xemilofiban in unstable angina with percutaneous coronary interventions.

BACKGROUND: Clinical studies have demonstrated the efficacy of intravenous administration of agents that block platelet glycoprotein IIb/IIIa receptors in the setting of percutaneous coronary revascularization. Although the optimal duration of treatment has not been determined, more prolonged receptor blockade has been associated with increased efficacy. Orally active glycoprotein IIb/IIIa receptor antagonists may be advantageous and required for chronic therapy. METHODS AND RESULTS: Thirty patients with unstable angina who were undergoing percutaneous coronary interventions were randomized to placebo or Xemilofiban 35 mg orally before and 20 to 25 mg TID for 30 days after angioplasty. Bleeding events, platelet aggregation, and pharmacokinetic and hematologic parameters were assessed during hospitalization and at 2 and 4 weeks after drug initiation. Xemilofiban produced a rapid, sustained, marked inhibition of platelet aggregation. ADP-induced platelet aggregation at 2 hours after the initial dose at 2 and 4 weeks was 15%, 8%, and 11% in the Xemilofiban group compared with 80%, 68%, and 69% in the placebo group. Among 20 patients randomized to Xemilofiban there was 1 death after emergency coronary bypass surgery complicated by severe bleeding diathesis, and 3 patients had major bleeding events. Patients on Xemilofiban for 30 days reported episodes of mild mucocutaneous bleeding. CONCLUSIONS: Xemilofiban, an orally active glycoprotein IIb/ IIIa receptor inhibitor, produced rapid, sustained, extensive inhibition of platelet aggregation for a period of up to 30 days. At the dose initially tested, however, acute major bleeding and mucocutaneous bleeding during chronic administration were encountered.

Novel delivery system for verapamil designed to achieve maximal blood pressure control during the early morning.

Because the risk of cardiovascular events appears to be greatest in the early morning, this period is a time during which adequate blood pressure (BP) control appears to be most desirable. In this study, a controlled-onset extended-release system (COER-24) that delivers verapamil in a manner designed to achieve maximal levels of drug during the early morning surge in BP was compared with placebo. Ninety-five patients with mild to moderate hypertension were studied. Of this group, 49 patients (mean age 57.6 +/- 1.4 years; 35 men and 14 women) were randomized to take verapamil COER-24 240 mg at 10 PM, and 46 subjects (mean age 55.8 +/- 1.5 years; 29 men and 17 women) were randomized to take placebo. Ambulatory BP monitoring was performed after a 4-week initial placebo period and was repeated after 4 weeks of treatment with verapamil or placebo. Verapamil COER-24 resulted in significant (p < 0.001) decreases in mean whole-day systolic and diastolic BP (-8.2/-6.3 mm Hg; baseline 152/93.0 mm Hg) when compared with placebo (+0.3/-0.9 mm Hg; baseline 150.3/93.2 mm Hg). From 6 AM to noon, verapamil COER-24 resulted in a change in systolic and diastolic BP of -11.6/-9.0 mm Hg, which was significantly (p < 0.001) greater than the change that occurred with placebo (-0.5/-1.0 mm Hg) during the same period. In the last 4 hours of the dosing interval (6 PM to 10 PM), verapamil COER-24 caused significantly greater (p < 0.001) decreases in BP (-7.4/-4.8 mm Hg) than did placebo (+2.7/+1.0 mm Hg). These data demonstrate that the COER-24 system, when administered in the late evening, achieves maximal BP reduction during the early morning hours. Moreover, BP reductions were sustained throughout the 24-hour period.

Differential dose-response to oral xemilofiban after antecedent intravenous abciximab. Administration for complex coronary intervention.

BACKGROUND: Placebo-controlled randomized trials of parenteral platelet glycoprotein (GP) IIb/IIIa receptor antagonists have demonstrated reduced ischemic complications of coronary angioplasty. Orally active GP IIb/IIIa blockers are being developed to allow more sustained receptor antagonism with potential for long-term secondary prevention. Sequential therapy with abciximab followed by an oral IIb/IIIa antagonist has not previously been reported. The clinical safety and pharmacodynamics of a sequential therapeutic strategy are unknown. METHODS AND RESULTS: Of 74 consecutive patients enrolled in a placebo-controlled, dose-ranging pharmacokinetic/pharmacodynamic study of xemilofiban, a new oral nonpeptide GP IIb/IIIa antagonist, after elective intracoronary stent placement, 17 patients received abciximab during stent deployment as a weight-adjusted intravenous bolus and 12-hour infusion at the discretion of the investigator. Ex vivo platelet aggregation in response to 20 mumol/L ADP and 4 micrograms/mL collagen was measured over time after the first dose of either xemilofiban (5, 10, 15, or 20 mg) or placebo (ticlopidine) administered 8 to 18 hours after termination of abciximab and again after 1 week of twice-daily oral administration of study drug. At baseline, patients who had received abciximab had lower platelet aggregation in response to both agonists (P < .001). A significant dose-response relationship to xemilofiban was observed. Patients who had received abciximab had lower ADP-induced (P < or = .010) and collagen-induced (P < or = .029) platelet aggregation after xemilofiban. This pharmacodynamic interaction was no longer evident at 1 week. No significant clinical bleeding events or blood product transfusions were observed in this trial. CONCLUSIONS: Both the magnitude and the duration of pharmacodynamic response to xemilofiban were enhanced by prior abciximab treatment. The potentiated pharmacodynamic response was not evident after 1 week. This observation has implications for the safety and efficacy of sequential parenteral-oral GP IIb/IIIa blockade therapy and may be useful in deriving dose regimens for orally administered compounds.

Nocturnal dosing of a novel delivery system of verapamil for systemic hypertension. Verapamil Study Group.

To evaluate the efficacy and safety of a novel delivery system of physiologic pattern release (PPR)-verapamil administered nocturnally to patients with stages I and II hypertension using ambulatory blood pressure (BP) monitoring, we performed a multicenter (17 centers), double-blind, randomized, placebo-controlled, parallel-group trial with placebo and 120, 180, 360, and 540 mg of verapamil in 287 randomized patients. The delivery system has a delay in the release of verapamil for 4 to 6 hours, and then delivers the drug from an osmotic pumping system for approximately 12 hours. Patients were dosed at 10 P.M. The primary end point was change from baseline in trough diastolic BP assessed by ambulatory BP monitoring from 6 to 10 P.M. after 8 weeks of therapy, whereas secondary measures included changes from baseline in peak, early morning (6 to 10 A.M.) systolic and diastolic BP, trough clinic BP, and 24-hour average daytime (8 A.M. to 8 P.M.) and nighttime (8 P.M. to 8 A.M.) BP. The 180, 360, and 540 mg verapamil doses achieved statistically significant reductions in trough (6 to 10 P.M.) diastolic BP (-3.9 +/- 1.0, -7.8 +/- 1.2, and -10.6 +/- 1.1 mm Hg, respectively). Reductions in peak early morning (6 to 10 A.M.) diastolic BP were greater (-4.6 +/- 0.9, -13.3 +/- 1.2, and -19.0 +/- 1.2, for 180, 360, and 540 mg, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Placebo-controlled evaluation of three doses of a controlled-onset, extended-release formulation of verapamil in the treatment of stable angina pectoris.

This double-blind, placebo-controlled, parallel-group, multicenter study was designed to evaluate the safety and efficacy of a new controlled-onset, extended-release formulation of verapamil hydrochloride called physiologic pattern release (PPR) verapamil. The study was conducted at 24 sites (13 United States, 5 Canada, 6 overseas; see Appendix). Following a 1- to 3-week single-blind placebo lead-in period, 278 patients with chronic stable angina pectoris (247 males, 31 females, mean age 60.8 years, range 32 to 78) were randomly assigned to 1 of 4 once-daily, fixed-dose treatment groups: verapamil 180, 360, or 540 mg, or placebo. PPR verapamil at all doses significantly increased (p < 0.05) time to moderate angina and symptom-limited exercise duration, and verapamil 360 mg significantly increased (p < 0.05) time to > or = 1 mm ST-segment depression, after 4 weeks of treatment when assessed 24 hour after the previous dose. Larger doses of verapamil were associated with proportionately greater improvements in exercise tolerance. Frequency of anginal attacks was also reduced by verapamil. The most frequently observed adverse events were dizziness, headache, constipation, and nausea. The incidence of constipation was high (20.9%) within the 540 mg treatment group. This verapamil formulation can be clinically titrated within a 180 to 540 mg dosing range, permitting effective once-daily administration for the treatment of chronic stable angina.

Comparison of EMIT versus bioassay to evaluate inactivation of tobramycin by piperacillin.

We evaluated and compared the sensitivity of enzyme multiplied immunoassay (EMIT) and bioassay techniques in detecting the degree of inactivation of tobramycin by piperacillin in serum specimens. Specimens were prepared to contain initial tobramycin concentrations of 10 micrograms/ml and piperacillin concentrations of 62.5, 125.0, 250.0, and 500 micrograms/ml. The samples were stored at room temperature (25 degrees C), in the refrigerator (4 degrees C), and in the freezer (-10 degrees C) for up to 7 days. Tobramycin concentrations were determined by the two assay methods at the conclusion of 1, 3, and 6 h and 1, 3, 5, and 7 days of storage. The percentage of tobramycin activity as measured by EMIT and bioassay differed throughout the study period. Statistical analysis revealed that the assay method was the only significant variable to contribute to the variability observed in the differences of tobramycin concentration. Our results suggest that the bioassay technique is more sensitive than the EMIT assay for detecting the degree of inactivation of tobramycin by piperacillin. The EMIT assay overestimates tobramycin concentrations, which may be due to measurement of active and inactive tobramycin.

Compatibility of intravenous drugs in a coronary intensive care unit.

In a coronary intensive care unit (CCU) it is often necessary to utilize extensive pharmacologic interventions and multiple intravenous medications in order to stabilize a critically ill patient. However, the necessity of several intravenous infusions often presents the problem of compatibility of these medications when infused within a common line. The pharmacist must possess adequate skill to identify potential incompatibilities by retrieving information on the physical and chemical compatibilities of various intravenous medications. In a critical care setting, time is an important factor, and information that can be obtained rapidly and reliably is vital for the pharmacist to prevent the administration of an irritating substance or a medication that has undergone deterioration as a result of chemical inactivation. A compatibility table containing the most commonly used drugs in a CCU has been developed based on currently available literature, including standard reference texts, about these medications. The table outlines the potential for interactions, within a single intravenous line, when several drugs are infused concurrently. In addition, a review of the concepts of physical and chemical incompatibility is presented. The stability of an admixture is defined utilizing requirements established in the USP NF monographs and manufacturers' specifications. The resulting table concisely organizes vital information in a form that allows rapid, accessible information to the pharmacist in a critical care setting, where it is most needed.

Lower incidence of doxorubicin-induced cardiomyopathy by once-a-week low-dose administration.

A review of the literature investigating an alternative method of administering doxorubicin on a weekly basis demonstrates a lower incidence of doxorubicin-induced cardiomyopathy, as judged by endomyocardial biopsy techniques and by an apparent lower incidence of CHF as compared to older reports in the literature utilizing conventional tri-weekly administration. However, none of these studies has utilized objective methods for verifying cardiac function. The precise reason why weekly administration may induce lesser degrees of damage to the myocardium is not clearly understood. However, it appears that the lower serum concentrations obtained with this dosing regimen result in lower myocardial tissue concentrations of the drug. Though the initial data are encouraging, larger clinical trials are necessary to establish a lower incidence of cardiotoxicity with weekly low-dose doxorubicin administration. Such studies, if specifically designed to evaluate changes in myocardial function, will resolve the questions and hopefully establish the advantages of this encouraging new therapeutic modality.

Overflow urinary incontinence due to carbamazepine.

We describe the first well documented case of overflow urinary incontinence owing to prolonged carbamazepine treatment for temporal lobe seizures. Carbamazepine increased the bladder capacity to 1,700 ml. and was accompanied by symptoms of urgency and frequency. After carbamazepine was discontinued and the patient was given primidone the voiding symptoms disappeared. Post-voiding catheterization of the bladder showed minimal residual urine volume. In a review of urological adverse reactions of anticonvulsant drugs that are effective in the management of temporal lobe seizures we found that only primidone and phenobarbital have not been convincingly associated with such side effects. However, phenytoin and clonazepam have been linked with urinary incontinence, and valproic acid with enuresis.