Pharmacokinetics of intravenous bepridil in patients with coronary disease

The pharmacokinetics of intravenous bepridil (1-[2-(N-benzylanilino)-1-(isobutoxymethyl)ethyl]pyrrolidine ) were studied in 16 patients undergoing cardiac catheterization for evaluation of coronary disease, all with normal base-line hemodynamic and renal functions. Ten patients received 3 mg/kg and six patients received 4 mg/kg of bepridil infused over a period of 30 min. Plasma bepridil concentrations were measured by HPLC and analyzed by model-dependent and model-independent methods. The mean (+/- SD) maximum plasma bepridil concentrations at the end of the infusion were 2047 +/- 820 ng/mL (3 mg/kg) and 2478 +/- 1426 ng/mL (4 mg/kg). Postinfusion bepridil concentrations were best described by a two-compartment open model. The model-dependent harmonic mean distribution and elimination half-lives were 1.7 h (range: 1.1-2.2 h) and 19.7 h (range: 8.0-61.9 h), respectively. The harmonic mean elimination half-life from model-independent analysis was 14.9 h (range: 7.4-64.0 h). The arithmetic means of other model-independent kinetic parameters were systemic clearance, 0.524 +/- 0.215 L X kg-1 X h-1; Vd, 15.3 +/- 10.9 L/kg; and Vdss, 10.1 +/- 6.0 L/kg. Model-dependent and model-independent estimates of half-life and clearance agreed reasonably well. Bepridil was well tolerated, effecting little or no change in central hemodynamics or EKG intervals. The extensive distribution and relatively slow clearance of bepridil account for its long elimination half-life. Intravenous bepridil appears to be a safe calcium (II) antagonist that is suitable for once-a-day dosing.     

Colonoscopy and bacteraemia: an experience in 50 patients

There is little consensus concerning the incidence of bacteraemia during colonoscopy and the need for antibiotic prophylaxis in susceptible patients. Hepatic abscesses in one patient which may have been related to prior colonoscopic examinations led the authors to carry out a prospective study of 50 patients undergoing colonoscopy. Multiple blood cultures were carried out to maximise the positive yield of transient bacteraemia and to attempt to determine the time when bacteraemia is most likely to occur. Five patients had positive blood cultures. In two patients S epidermidis was isolated, but only from the precolonoscopic blood sample. In three subjects enteric organisms were cultured from blood samples obtained during the procedure. In one of these three the same organism was cultured from the preendoscopic blood sample so that in only two patients (4%) could the bacteraemia be attributed to the colonoscopy. These results would suggest that the risk of bacteraemia during colonoscopy is low.     

Effect of goldenseal (Hydrastis canadensis) and kava kava (Piper methysticum) supplementation on digoxin pharmacokinetics in humans.

Phytochemical-mediated modulation of P-glycoprotein (P-gp) and other drug transporters may give rise to many herb-drug interactions. Serial plasma concentration-time profiles of the P-gp substrate, digoxin, were used to determine whether supplementation with goldenseal or kava kava modified P-gp activity in vivo. Twenty healthy volunteers were randomly assigned to receive a standardized goldenseal (3210 mg daily) or kava kava (1227 mg daily) supplement for 14 days, followed by a 30-day washout period. Subjects were also randomized to receive rifampin (600 mg daily, 7 days) and clarithromycin (1000 mg daily, 7 days) as positive controls for P-gp induction and inhibition, respectively. Digoxin (Lanoxin, 0.5 mg) was administered p.o. before and at the end of each supplementation and control period. Serial digoxin plasma concentrations were obtained over 24 h and analyzed by chemiluminescent immunoassay. Comparisons of area under the curve (AUC)((0-3)), AUC((0-24)), C(max,) CL/F, and elimination half-life were used to assess the effects of goldenseal, kava kava, rifampin, and clarithromycin on digoxin pharmacokinetics. Rifampin produced significant reductions (p < 0.01) in AUC((0-3)), AUC((0-24)), CL/F, t(1/2), and C(max), whereas clarithromycin increased these parameters significantly (p < 0.01). With the exception of goldenseal's effect on C(max) (14% increase), no statistically significant effects on digoxin pharmacokinetics were observed following supplementation with either goldenseal or kava kava. When compared with rifampin and clarithromycin, supplementation with these specific formulations of goldenseal or kava kava did not appear to affect digoxin pharmacokinetics, suggesting that these supplements are not potent modulators of P-gp in vivo.     

Anthracycline-based combined chemotherapy in the mouse model.

Our research was aimed at establishing if and how selenium (Se) ion, N-acetylcysteine (NAC), sodium salt of monoketocholic acid (MKH) and superoxide-dismutase (SOD), administered in the experimental animal model, could affect the possible cytotoxicity associated with anthracycline-based combined chemotherapy with doxorubicin, vincristine and prednisolone (DVP). The following biochemical parameters were investigated: the extent of lipid peroxidation (LPx), and the activity of peroxidase (Px), catalase (CAT), glutathione-peroxidase (GSHPx), and xanthine-oxidase (XOD). A statistical increase in LPx activity was obtained by SOD, MKH, DVPSe and DVPMKH. All chemotherapeutic agents reduced Px activity in a statistically significant manner. There was no statistical significance for the results regarding the effects of the administered substances on GSHPx activity. The results for DVP, SOD, MKH, DVPSOD, DVPSe and DVPMKH showed reduced XOD activity which was statistically significant, which was lowest in the case of MKH, while NAC and Se reduced the activity of this enzyme but statistically non significant. NAC, Se, DVP, MKH and DVPMKH caused a reduction in CAT activity, while DVPSOD and DVPSe caused an increase of the latter.     

Current status of colorectal cancer chemoprevention

Chemoprevention refers to suppression or reversal of the carcinogenic process using pharmacologic or nutritional agents. Colorectal carcinogenesis is a protracted, multistep process that offers opportunities for prevention. Aspirin and selective cyclooxygenase-2 inhibitors (coxibs) have been evaluated for the prevention of sporadic adenoma recurrence. Aspirin was shown to reduce adenoma recurrence rates in patients with prior colorectal neoplasms; however, the optimal dosage remains unclear. Recent studies of coxibs indicate that these agents are effective in reducing sporadic adenoma recurrence, but chronic use can result in serious cardiovascular toxicity. These data underscore the need for chemopreventive agents with acceptable risk-to-benefit ratios. In this regard, nitric-oxide-releasing aspirin shows chemopreventive efficacy in preclinical models and holds promise for reduced toxicity in humans. Furthermore, ongoing chemoprevention trials are evaluating nutritional supplements, such as folic acid and selenium, and results are eagerly awaited.     

Probing insulin's secondary structure after entrapment into alginate/chitosan nanoparticles.

The aim of the present study was to probe the structural integrity of insulin after being entrapped into chitosan/alginate nanoparticles produced by ionotropic polyelectrolyte pre-gelation. By manipulating the alginate:chitosan mass ratio and the pH during nanoparticle production, desired nanoparticles with a mean size of 850 (+/-88)nm and insulin association efficiency of 81 (+/-2)% were obtained. Insulin secondary structure was assessed by Fourier transform infrared (FTIR) and circular dichroism (CD) after entrapment into nanoparticles and after release from the particles under gastrointestinal simulated conditions. FTIR second-derivative spectra and area-overlap compared to an insulin standard confirmed that no significant conformational changes of insulin occurred in terms of alpha-helix and beta-sheet content. Far-UV-CD spectra corroborated the preservation of insulin structure during the nanoparticle production procedure. The presented nanoparticulate system is a promising carrier for insulin oral delivery since it preserves insulin structure and therefore also, potentially, its bioactivity.     

Activity measurements of the high-energy pure beta-emitters 89Sr and 90Y by the TDCR efficiency calculation technique.

The absolute activities of the pure beta-emitters 89Sr and 90Y have been determined by a direct method, namely the triple-to-double coincidence ratio (TDCR) efficiency calculation technique. This undertaking has extended further the number of radionuclides that have been standardized by this non-extrapolation liquid scintillation (LS) method. Both measurements were carried out within the framework of international key comparisons under the auspices of the International Bureau of Weights and Measures (BIPM). The TDCR results agreed well with those of other participating national laboratories, most using alternative (tracer) methods.     

100 years of ‘Allergy’: can von Pirquet's word be rescued?

Summary It is 100 years since Clemens von Pirquet wrote his classic paper introducing the term 'allergy'. Although the word is no longer used in the way he intended, his concept of 'changed reactivity' laid the foundation for the modern science of immunology.