Correlation between pharmacokinetic parameters of rifampicin and its biologically active metabolite as related to estimation of the relative bioavailability of the antibiotic

In the bioavailability studies with drugs biotransformed to biologically active metabolities only the concentrations of the parent drug (PD) are usually taken into account even when the pharmacokinetic data on the metabolite(s) (M) are available. However, such data may be useful as an alternative source for the bioavailability determination. Moreover, the clinical outcomes often depend on both the PD and M concentrations. The aim of the study performed with two rifampicin formulations, tablets and dragee, was to correlate the pharmacokinetic parameters of the PD and 25-O-deacetylrifampicin, a microbiologically active M of rifampicin, and to examine whether the bioavailability parameters based on the PD and M concentrations were compatible. The serum concentrations of the PD and M were determined in 8 healthy volunteers by HPLC. Despite different patterns of the PD and M pharmacokinetic profiles the PD peak concentration (Cmax) and especially the AUC correlated with Cmax or the AUC of the M (r = 0.76 and 0.92 respectively). Moreover, the extent of the absorption expressed as the AUC ratio for the PD correlated with the AUC ratio for the M (r = 0.86). However, neither the time to reach the maximum (tmax), nor the Cmax/AUC ratio, a measure of the absorption rate, based on the PD pharmacokinetic data correlated with the respective parameters calculated with using the M concentrations. Thus, only the estimates of the extent of the absorption and not of the absorption rate based on the PD and M data may be considered as compatible.     

Tyrosine phosphorylation of the Kv1.3 potassium channel

Kv1.3, a voltage-dependent potassium channel cloned from mammalian brain and T lymphocytes, contains multiple tyrosine residues that are putative targets for tyrosine kinases. We have examined the tyrosine phosphorylation of Kv1.3, expressed transiently in human embryonic kidney (or HEK) 293 cells, by endogenous and coexpressed tyrosine kinases. Tyrosine phosphorylation is measured by a strategy of immunoprecipitation followed by. Western blot analysis, using antibodies that specifically recognize Kv1.3 and phosphotyrosine. Coexpression of the constitutively active tyrosine kinase v-src, together with Kv1.3, causes a large increase in the tyrosine phosphorylation of the channel protein. This phosphorylation of Kv1.3 can be reversed by treatment with alkaline phosphatase before Western blot analysis. Coexpression with a receptor tyrosine kinase, the human epidermal growth factor receptor, also causes an increase in tyrosine phosphorylation of Kv1.3. The effects of endogenous tyrosine kinases were examined by treating Kv1.3-transfected cells with the specific membrane-permeant tyrosine phosphatase inhibitor pervanadate. Pervanadate treatment causes a time- and concentration-dependent increase in the tyrosine phosphorylation of Kv1.3. This increased tyrosine phosphorylation of Kv1.3 is accompanied by a time-dependent decrease in Kv1.3 current, measured by patch-clamp analysis with cell-attached membrane patches. The pervanadate-induced suppression of current and much of the channel tyrosine phosphorylation are eliminated by mutation of a specific tyrosine residue, at position 449 of Kv1.3, to phenylalanine. Thus, there is a continual phosphorylation and dephosphorylation of Kv1.3 by endogenous kinases and phosphatases, and perturbation of this constitutive phosphorylation/dephosphorylation cycle can profoundly influence channel activity.     

Prevalence of malaria in Dakar, Senegal. Comparative study of the plasmodial indices in pregnant and non-pregnant women

One hundred ASA I orthopaedic surgical patients (four randomized groups) were anaesthetized using continuous propofol and intermittent fentanyl (TIVA), with controlled ventilation via a tracheal tube in groups 1 and 2, and a laryngeal mask airway (LMA) in groups 3 and 4. Neuromuscular blockers were used in groups 1 and 3 only. There were no significant differences between groups in total anaesthetic requirements, as assessed by cardiovascular variables and movement. Coughing interfered with surgery and made controlled ventilation difficult to manage. In contrast, movement not associated with coughing did not impair surgery or ventilation. Patients in group 2 (tracheal tube, no neuromuscular blocker) required more interventions for coughing than the other groups, while patients in group 4 (LMA, no neuromuscular blocker) needed more boluses for movement than groups 1 and 3. Groups 1 and 2 (tracheal tube) had significantly higher heart rates and mean arterial pressures than groups 3 and 4 for varying periods up to 5 min after insertion of the airway management device. There was no correlation between mean arterial pressure and plasma concentrations of catecholamines related to insertion of either the tracheal tube or LMA. The LMA was found to be a highly effective device for controlled ventilation in TIVA and easier to manage than the tracheal tube in the absence of neuromuscular blockers.     

The choice of the method for the surgical treatment of bladder exstrophy

129 children with exstrophy of the bladder underwent primary surgical reconstruction according to G. A. Bairov. Morphofunctional findings in these children gave grounds for determination of three degrees of the bladder congenital defects. 39 patients had defect of the 1st degree, 53 of the 2nd and 37 of the 3d degree. The results of plastic reconstruction of the bladder with local tissue support the validity of such procedure only for patients with the congenital defect degree I. For degree II the benefit is relative. In degree III plastic surgery in contraindicated.     

Efficacy of silicone punctal plugs as adjuncts to topical pharmacotherapy of glaucoma--a pilot study. Punctal Plugs in Glaucoma Study Group

BACKGROUND: The concept of enhancing the ocular hypotensive effects of topical antiglaucoma medications by impeding lacrimal drainage of medication has been insufficiently studied. This investigation sought to evaluate the effect of bilateral inferior punctal occlusion using silicone punctal plugs on the ocular hypotensive effect of topically applied timolol. METHODS: A randomized, double-masked, cross-over clinical trial was conducted, comparing the ocular hypotensive effect of timolol maleate 0.25 percent, both with and without occlusion of the inferior punctum with the Freeman silicone punctal plug. Following a 2-week washout of topical medication, 17 subjects with early primary open-angle glaucoma or ocular hypertension received one drop of timolol 0.25 percent in each eye with or without punctal plugs in place. Blood pressure, resting pulse rate, and intraocular pressure were measured both before timolol instillation and at intervals of 1, 2, 4, 8, and 12 hours following drop instillation. Following a 2-week washout period, the subjects were evaluated with the alternative treatment. RESULTS: There was no statistically significant difference (p = 0.648) in IOP levels between treatment groups. CONCLUSIONS: This pilot suggests that need for a longer-term study with larger numbers of subjects to evaluate the potential role of silicone punctal plugs to enhance the ocular bioavailability of topically applied antiglaucoma medications.     

Isolation of bacterial endotoxins from Pseudomonas putida 36 and Escherichia coli (vulgaris)

A prospective analysis of 69 patients who had been treated for nasopharyngeal carcinoma (NPC) by external radiotherapy was carried out. Biopsies from the posterior nasopharynx were performed and analyzed by in situ hybridization using an antisense Epstein-Barr Early RNA (EBER) radio-labelled riboprobe. None of the patients had evidence of disease in the nasopharynx. One patient was found to have nasopharyngeal carcinoma detected only by in situ hybridization. In the subsequent 18-month follow-up of these clinically- and biopsy-negative patients, only one patient developed relapse in the nasopharynx. In situ hybridization is a valuable tool for the detection of NPC and should be routinely available in histopathology laboratories where NPC is regularly diagnosed.     

Low dose desensitisation does not reduce the toxicity of sulphasalazine in rheumatoid arthritis

To investigate the apoptosis-inducing effect of glucocorticoid on gastric epithelial cell expressing different p53 genes, a human gastric epithelial cell line-GES-1 was transfected with either wild type or mutant p53 cDNA in vitro. The cells were treated with hydrocortisone in a concentration range of 0.2-0.8 g/L. Apoptotic cells were found in those transfectants. The apoptotic response of the wild-type p53-transfected GES-1 cells was much more marked than that of the mutant p53 transfected ones. It can be inferred that the glucocorticoid secreted not only suppress the immunological response during inflammation, but induce gastric epithelial cell apoptosis as well. If the gastric epithelial cell contains mutant p53 genes, the glucocorticoid confer a selective growth advantage which advance the malignant process.     

Stimulation of weak organic acid uptake in rat renal tubules by cadmium and nystatin

The uphill uptake of a weak organic acid, fluorescein, in superficial proximal tubules of the rat kidney was stimulated by CdCl2 (0.1 mM) or nystatin (20 microM) in the absence of metabolic substrates in the incubation medium. The stimulation could be observed during the initial period of incubation (up to 30 min) only and was prevented completely by ouabain (0.1 mM), fluoroacetate (1 mM), malonate (10 mM), alpha-cyano-4-hydroxycinnamate (0.1 mM), phenylpyruvate (1 mM), D-malate (2 mM) or phenazine methosulfate (20 microM). In the renal cortex fragment suspension, both Cd2+ and nystatin increased the ouabain-sensitive, basal oxygen consumption and inhibited the rate of glucose production from pyruvate, but not from lactate. In the presence of lactate (0.5-5 mM) in the incubation medium, Cd2+ and nystatin rather inhibited fluorescein uptake, while externally added pyruvate did not influence their stimulatory effects. Taken together, these data suggest that both activation of the tricarboxylic acid cycle and export of reducing equivalents from the mitochondria to the cytosol are necessary for the stimulatory effects of Cd2+ and nystatin on the weak organic acid uptake to develop.