Cardiotoxicity of verapamil in renal failure: a case report and review of the literature.

We present a case of a 76-year-old diabetic patient on verapamil with undiagnosed renal failure presenting with collapse and severe life threatening bradyarrhythmias. She responded well to inotropic support and calcium supplementation.

Leveraging prior quantitative knowledge in guiding pediatric drug development: a case study.

The manuscript presents the FDA's focus on leveraging prior knowledge in designing informative pediatric trial through this case study. In developing written request for Drug X, an anti-hypertensive for immediate blood pressure (BP) control, the sponsor and FDA conducted clinical trial simulations (CTS) to design trial with proper sample size and support the choice of dose range. The objective was to effectively use prior knowledge from adult patients for drug X, pediatric data from Corlopam (approved for a similar indication) trial and general experience in developing anti-hypertensive agents.

Preparation and performance evaluation of saquinavir laden cationic submicron emulsions.

The main purpose of the present study was to investigate different cationic submicron emulsions as potential delivery for oral administration. Different submicron emulsion based formulations were prepared by standard procedures incorporating Chitosan, stearylamine, and protamine as charge inducer. Saquinavir (SQ) laden emulsions were characterized in terms of globule size, zeta potential, entrapment efficiency, release profile, cytotoxicity, LDH release, and stability studies.

Pediatric antihypertensive trial failures: analysis of end points and dose range.

Historically, drugs prescribed for children have not been studied in pediatric populations. Since 1997, however, a 6-month extension of marketing rights is granted if manufacturers conduct Food and Drug Administration-defined pediatric trials. In nearly half of the drugs studied, there were unexpected results in dosing, safety, or efficacy compared with adult studies, including failure of half of the antihypertensive dose-response trials, which are pivotal for deriving dosing recommendations.

Leveraging prior quantitative knowledge to guide drug development decisions and regulatory science recommendations: impact of FDA pharmacometrics during 2004-2006.

The End-of-Phase 2A meetings are proposed to identify opportunities to make innovative medical products available sooner and to increase the quality of drug applications through early meetings between sponsors and the FDA. This article summarizes the overall experience across 11 pilot End-of-Phase 2A meetings since 2004. Four case studies are presented in more detail to demonstrate the various issues and methods encountered at these meetings.

Concentration-QT relationships play a key role in the evaluation of proarrhythmic risk during regulatory review.

The criterion for assessing whether a drug prolongs QT as described in the International Conference on Harmonization topic E14 guideline does not explicitly account for individual drug concentrations. The authors' experience with reviewing QT studies indicates that understanding the relationship, if any, between individual drug concentration and QT change provides important additional information to support regulatory decision making. Therefore, regulatory reviews of "thorough QT" studies routinely include a characterization of the concentration-QT relationship.

(S)-N-{3-[1-cyclopropyl-1-(2,4-difluoro-phenyl)-ethyl]-1H-indol-7-yl}-methanesulfonamide: a potent, nonsteroidal, functional antagonist of the mineralocorticoid receptor.

A novel, potent series of indole analogs were recently developed as MR antagonists, culminating in 14. This compound represents the first MR antagonist in this class of molecules, exhibiting picomolar binding affinity and in vivo blood pressure lowering at pharmaceutically relevant doses.

Antinociceptive and anthelmintic activity of Canna indica.

Dried, coarsely powdered leaves, flowers, rhizomes and seeds of Canna indica were successively extracted with benzene and methanol in Soxhlet apparatus. The effect of benzene and methanol extracts of various parts of C. indica on nociceptive response using writhing test and hot plate method in mice was examined.

Parenteral amino acid and metabolic acidosis in premature infants.

Background: Aggressive parenteral nutrition (PN) including amino acids is recommended for low-birth-weight infants to prevent energy and protein deficit. Their impact on acid-base homeostasis has not been examined.

Methods: We investigated the impact of dose and duration of parenteral amino acids, with cysteine, on acid-base parameters in 122 low-birth-weight infants.

Semi-mechanistic pharmacodynamic modeling for degarelix, a novel gonadotropin releasing hormone (GnRH) blocker.

An integrated semi-mechanistic pharmacodynamic (PD) model describing the relationship between luteinizing hormone (LH) and testosterone (T) after short-term administration of degarelix was developed. Data from three clinical studies involving, intravenous (IV) and subcutaneous (SC) dosing, in healthy male subjects were available. Degarelix pharmacokinetic (PK) data from all studies were modeled simultaneously.

A new equivalence based metric for predictive check to qualify mixed-effects models.

The main objective of any modeling exercise is to provide a rationale for effective decision making during drug development. The aim of the current simulation experiment was to evaluate the properties of predictive check as a covariate model qualification technique and, more importantly, to introduce and evaluate alternative criteria to qualify models.Original concentration-time profiles (yod) were simulated using a 1-compartment model for an intravenous drug administered to 25 men and 25 women.

3,3-Bisaryloxindoles as mineralocorticoid receptor antagonists.

Syntheses and SAR studies of 3,3-bisaryloxindole analogues provided potent mineralocorticoid receptor (MR) antagonists that were selective over other steroid nuclear hormone receptors.

5-Amidinobenzo[b]thiophenes as dual inhibitors of factors IXa and Xa.

Syntheses and SAR studies of 5-amidinobenzo[b]thiophene analogs provided compounds with low submicromolar factor IXa activity and equal or slightly better selectivity relative to factor Xa.

5-Amidinoindoles as dual inhibitors of coagulation factors IXa and Xa.

Structural features of a 5-amidinoindole inhibitor of factor Xa, which displayed modest inhibition of factor IXa were varied to increase potency and improve selectivity for factor IXa.

SAR and factor IXa crystal structure of a dual inhibitor of factors IXa and Xa.

Modifications to the P4 moiety and pyrazole C3 substituent of factor Xa inhibitor SN-429 provided several new compounds, which are 5-10nM inhibitors of factor IXa. An X-ray crystal structure of one example complexed to factor IXa shows that these compounds adopt a similar binding mode to that previously observed with pyrazole inhibitors in the factor Xa active site both with regard to how the inhibitor binds and the position of Tyr99.

Synthesis and biological evaluation of nonpeptide integrin antagonists containing spirocyclic scaffolds.

Analogues of isoxazoline alpha(v)beta(3) antagonist 1 designed to further restrict the four carbon alkyl tether were prepared by incorporating two spirocyclic scaffolds, 1-oxa-2-azaspiro[4,5]dec-2-ene and 1-oxa-2,7-diazaspiro[4,4]non-2-ene. Additional optimization provided potent antagonists of both alpha(v)beta(3) and alpha(5)beta(1) which are selective over GPIIb/IIIa.

Tuberous sclerosis: a presentation of less-commonly encountered stigmata.

The protean manifestations of the tuberous sclerosis complex have lent this condition to extensive review in textbooks and in the medical literature. This condition generally presents by virtue of its neurological manifestations. Osseous stigmata, when encountered, are generally asymptomatic and do not require specific treatment owing to their benignity.

Determination of celecoxib in pharmaceutical formulations using UV spectrophotometry and liquid chromatography.

A new UV spectrophotometric method (UV method) and a reversed phase liquid chromatographic method (LC method) for the quantitative estimation of celecoxib, a selective COX-2 inhibitor, in pure form and in solid dosage form were developed in the present study. The linear regression equations obtained by least square regression method, were Abs=4.949 x 10(-2).

Transvaginal sonographic diagnosis of live monochorionic twin ectopic pregnancy.

Ectopic pregnancy is a leading cause of pregnancy-related deaths; its incidence has progressively increased in recent years. Spontaneous twin ectopic pregnancy, however, is extremely rare. Among more than 100 reported cases of twin tubal pregnancies, only 5 cases in which fetal cardiac motion has been visualized in both embryos have been reported.

Alcohol consumption and hemostatic factors: analysis of the Framingham Offspring cohort.

Background: Moderate alcohol consumers have lower rates of cardiovascular disease than abstainers. One proposed mechanism is a beneficial effect on hemostatic parameters, but previous studies have provided conflicting results.

Methods And Results: We measured levels of fibrinogen, plasma viscosity, von Willebrand factor, factor VII, plasminogen activator inhibitor antigen-1, and tissue plasminogen activator antigen in a cross-sectional analysis of 3223 adults free of cardiovascular disease enrolled in the Framingham Offspring Study.

Inhibition of human endogenous retrovirus-K10 protease in cell-free and cell-based assays.

A full-length and C-terminally truncated version of human endogenous retrovirus (HERV)-K10 protease were expressed in Escherichia coli and purified to homogeneity. Both versions of the protease efficiently processed HERV-K10 Gag polyprotein substrate. HERV-K10 Gag was also cleaved by human immunodeficiency virus, type 1 (HIV-1) protease, although at different sites.

Low Incidence of Cerebrovascular Events in Patients with Incidental Atrial Septal Aneurysm.

OBJECTIVES: The purpose of our investigation was to describe the echocardiographic characteristics of an atrial septal aneurysm (ASA) and associated cardiac abnormalities, to determine whether any echocardiographic characteristics are associated with cerebrovascular events, and to compare the cerebrovascular risk of ASA when it is an isolated and incidental finding with ASA associated with other cardiac abnormalities and diagnostic indications, including a cardiac source of embolus. METHODS: In 1605 consecutive patients referred for transesophageal echocardiography during open heart surgery, we identified 78 patients with ASA as an incidental finding (Group I). During the same period, this anomaly was found in 39 of 8014 consecutive patients referred to the echocardiographic laboratory for various diagnostic reasons (Group II).

Inhibition of neointima formation by a nonpeptide alpha(v)beta(3) integrin receptor antagonist in a rabbit cuff model.

This study was performed to determine whether a highly selective nonpeptide alpha(v)beta(3) antagonist (SH306) would prove effective in inhibiting neointima formation in a rabbit cuff model. The animals were dosed with SH306, 5 mg/kg i.v.