Digoxin bioavailability: formulations and rates of infusions

22 patients with atheromatous narrowing of the left coronary trunk underwent surgery between 1969 and 1974. Most of these patients had severe and incapacitating angina pectoris. The clinical features are readily explained by the size of the diffuse anatomical lesions, which are to be found on the left coronary trunk as well as on the three coronary vessels themselves. This series has not confirmed the serious risk of surgery in such cases, as there were no operative deaths. Secondary mortality was low (9%), and the 20 survivors (average length of follow-up: 26 months) were mostly (18/20) in an excellent condition functionally. These facts have lead us to advise surgery whenever possible.     

Comparative pharmacokinetics and bioavailability of two cotrimoxazole preparations

The objective of this study was to assess both pharmacokinetic properties and bioavailability of a newly developed cotrimoxazole preparation (Bioprim tablets, 80 mg of trimethoprim/400 mg sulfamethoxazole), in comparison with a reference preparation commercially available (Bactrim tablets, 80 mg of trimethoprim/400 mg of sulfamethoxazole). The pharmacokinetics and bioavailability of cotrimoxazole from these preparations were compared in an open randomized crossover study in 12 healthy males. Plasma concentrations of trimethoprim and sulfamethoxazole were measured by HPLC after protein precipitation. Noncompartmental pharmacokinetic analysis was performed on the plasma concentration-time data. The obtained pharmacokinetic values (Cmax, tmax, beta, t1/2 beta, CL, Vd, AUC36, AUC infinity) of both trimethoprim and sulfamethoxazole determined in our study agreed with values reported in the literature. Westlake's and Nonparametric probability tests with the 90% confidence intervals, for both trimethoprim and sulfamethoxazole gave the differences within 80 and 120%, for all necessary measures (Cmax, tmax and AUC infinity). Statistical analysis of the data has shown that the preparations have similar pharmacokinetic profiles and therefore can be considered equally bioavailable.     

Comparative bioavailability of two sustained-release theophylline formulations in the dog

OBJECTIVES: The large surface area of the carbon core of diesel exhaust particles may contribute to the adsorption or condensation of such volatile carcinogenic organic compounds as benzene. The attention of this study focused on determining the distribution of benzene between the gas and particulate phases in the breathing zone of bus garage workers. METHODS: Benzene and suspended particulate matter were evaluated jointly in the air of a municipal bus garage. Personal passive monitors were used for benzene sampling in the breathing zone of the workers. Active samplers were used for sampling diesel exhaust particles and the benzene associated with them. The benzene levels were measured by gas chromatography. RESULTS: Diesel engine exhaust from buses was the main source of air pollution caused by benzene and particles in this study. The concentration of benzene in the gas and particulate phases showed a wide range of variation, depending on the distance of the workplace from the operating diesel engine. Benzene present in the breathing zone of the workers was distributed between the gas and particulate phases. The amounts of benzene associated with particles were significantly lower in summer than in winter. CONCLUSIONS: The particulate matter of diesel exhaust contains benzene in amounts comparable to the concentrations of carcinogenic polycyclic aromatic hydrocarbons (PAH) and the usually found nitro-PAH. The concentration of benzene in the gas phase and in the suspended particulate matter of air can serve as an additional indicator of exposure to diesel exhaust and its carcinogenicity.     

Serum concentrations and bioavailability of rifampicin and isoniazid in combination

The bioavailability of rifampicin and isoniazid from formulations containing these drugs in combination has been compared to that from formulations containing either drug alone. No formulation-related differences in either rates or extent of bioavailability were found after administration of each formulation. Mean peak serum concentrations of rifampicin (8.2-11.7 mug/ml) occurring 2 to 4 h after doses of 600 mg, and isoniazid (3.6-4.8 mug/ml) occurring 0.5 to 1 h after doses of 300 mg, were similar to those reported in the literature.     

Factors to be considered in the evaluation of bioavailability and bioequivalence of topical formulations

In this paper, an attempt is made to find functional definitions of bioavailability and bioequivalence for topical products and to examine critical factors that influence topical bioavailability and bioequivalence. A physical model approach for quantifying the problem and increasing our understanding is presented here. The key assumptions are (1) that the target site is in the lower epidermis (basal layer) or in the dermis, and (2) that it is the thermodynamic activity (i.e., the free drug concentration, C*, of the active drug species) at the target site that is the true correlate of drug effectiveness. Studies initiated to implement the physical model approach involved first validating a 'three-tiered' model for finite dose drug uptake/transport in skin with experimentally determined input parameters (partition coefficient, K, and steady-state permeability coefficients, P, for the stratum corneum, viable epidermis, and dermis). Hydrocortisone was used as the model drug with hairless guinea pig skin as the model membrane. The physical model is used to show, via the C* concept, how formulation factors may influence bioavailability and bioequivalence. Finally, a method is presented for predicting the efficacy of topical formulations employing appropriate in vitro data and physical model calculations.     

The pharmacokinetics and electroencephalogram response of remifentanil alone and in combination with esmolol in the rat

PURPOSE: The goal of this study was to determine if the co-administration of esmolol (ES), a short acting cardioselective beta-blocker, significantly alters the pharmacokinetics and/or pharmacodynamics of remifentanil (REMI), an ultra short-acting opioid, in the rat. METHODS: Sprague-Dawley rats (N = 8, Wt. = 325 +/- 15 g) were surgically implanted with stainless steel cerebrocortical EEG electrodes three days before the study. Each rat was dosed with REMI (15 micrograms/kg/min), and REMI & ES (15 micrograms/kg/min and 600 micrograms/kg/min) for 21 minutes in a random crossover design. Six serial blood samples were collected over 25 minutes into test-tubes containing 0.5 ml acetonitrile. Blood samples were extracted with methylene chloride and analyzed by a validated GC-MS assay. EEG was captured and subjected to power spectral analysis (0.1-50 Hz) for spectral edge (97%). RESULTS: No significant differences (p < 0.05) were found in clearance (REMI = 287 + 73 ml/min/leg vs. REMI & ES = 289 +/- 148 ml/min kg) or Vd (REMI = 286 +/- 49 ml/kg vs REMI & ES = 248 + 40 ml/kg). A linked sigmoid Emax PK-PD model was used and the pharmacodynamic parameters were not statistically different. Mean Emax and EC50 after REMI were 18.0 +/- 6.0 Hz and 32 +/- 12 ng/ml; and after REMI + ES were 19 + 4.8 Hz and 26 + 8.6 ng/ml. CONCLUSIONS: At the doses tested, there is no pharmacokinetic or pharmacodynamic interaction between remifentanil and esmolol in the rat.     

Lung bioavailability of chlorofluorocarbon free, dry powder and chlorofluorocarbon containing formulations of salbutamol

The objective of the study was to reanalyze the iron content in 74 foods or food products selected on the bases of an iron content above 3 mg-100 g or because of their frequent and significant inclusion in the average Mexican diet. The items were purchased in the largest food supply center in Mexico City and analyzed in the laboratories of the National Institute of Nutrition using the 2.2(1) dipyridine (alpha alpha 1 dipyrydil technique. The new values, 61% (45/74) of them smaller and 26% (19/74) higher than those previously included in the Institute's data base, are presented.     

The effect of COMT inhibition by tolcapone on tolerability and pharmacokinetics of different levodopa/benserazide formulations

Current practice of family planning in China is based on the population policy and strategy of the country. Comprehensive contraceptive methods are provided in family planning clinics at all levels. Among the methods used, intrauterine devices and tubal sterilization are most popular. Vasectomy is popular in some provinces. Oral pills, injectables and subdermal implants occupy a small proportion. Incidence of abortion is high due to failure of methods and unprotected intercourse. Attention is paid to the adoption of emergency contraception to prevent unwanted pregnancy. Improvement in quality of care is the key to a successful family planning program. Basic research is essential for development of new contraceptive technology.     

Effect of cimetidine, bicarbonate and glucose on the bioavailability of different formulations of praziquantel

The effects of cimetidine, bicarbonate and glucose on the bioavailability of the two brands of praziquantel (CAS 55268-74-1) available in Egypt were studied in normal healthy volunteers. Brand 1 when coadministered with cimetidine showed elevated concentration of the drug at all time intervals. The difference was statistically significant at 3, 4, 6 and 8 h following treatment. On the other hand coadministration of cimetidine with brand 2 (Distocide) showed elevated concentration of the drug 1 h post treatment. Analysis of the pharmacokinetic parameters revealed insignificant difference comparing brand 1 versus brand 1 plus cimetidine. Significant differences were observed between the elimination rate constant Ke (h-1) for brand 2 (0.017 +/- 0.004) alone versus brand 2 plus cimetidine (0.006 +/- 0.001). Coadministration of bicarbonate or glucose with either brand 2 or brand 1 tended to depress the serum concentration of praziquantel. Possible explanations of these findings are discussed.     

The use of clemastine ("Tavegil'') administered parenterally in acute allergic episodes

A case is reported in which anticoagulant therapy for thrombophlebitis and pulmonary embolism produced bilateral massive intrarenal hematomas (pseudotumors). The role of radiologic investigation (nephrotomography, renal scan and selective high dose arteriography) was found to identify and localize the intrarenal hematomata and exclude underlying renal pathology. Although an abnormal kidney is more likely to bleed, this case presentation demonstrates that even carefully monitored anticoagulation within the therapeutic range can induce massive intrarenal hemorrhage in previously normal kidneys. The renal architecture returned to normal on late follow-up examination on simple conservative management.     

Comparative bioavailability of two atenolol tablet formulations in healthy male volunteers after a single dose administration

The bioavailability of 2 atenolol tablet formulations (Angipress from Laboratórios Biosintética, and Atenol from Wellcome ICI Laboratory, Brazil) were compared in 18 healthy male volunteers who received a single 50 mg dose of each atenolol formulation. The study was conducted following an open randomized 2-period crossover design with a 14-day washout interval between doses. Plasma samples were obtained over a 24-hour interval and atenolol concentrations were determined by HPLC with fluorimetric detection. From the plasma atenolol concentration vs time curves the following pharmacokinetic parameters were obtained: AUC(zero-24) (area under the concentration vs time curves from 0-24 h), ke (terminal elimination constant), t1/2 (terminal first order elimination half-life), AUC (area under the concentration vs time curves extrapolated to infinity), Cmax (maximum achieved concentration), Tmax (time to achieve Cmax) and Cmax/AUC. All these variables were analyzed using both parametric and nonparametric statistics. Geometric mean Angipress/Atenol individual percent ratios were 99.6% for AUC(zero-24), 99.7% for AUC, 98.0% for Cmax, 102.8% for t1/2, 97.2% for ke and 97.8% for Cmax/AUC, with all their 90% confidence intervals within the bioequivalence range 80-125%, thus showing similar patterns of absorption and disposition. Arithmetic mean for individual Tmax differences was 0.8 h, and the 90% confidence interval did not include the zero value. Based on these results and in accordance with the European Union and the US Food and Drug Administration bioequivalence requirements we conclude that both atenolol formulations are bioequivalent for both the extent and the rate of absorption.     

The pharmacokinetics and efficacy of long-term low-level and split-dose administration of albendazole through in-feed formulations against ovine and caprine parasitic gastroenteritis

Two trials were conducted against natural and experimentally induced parasitic gastroenteritis in sheep and goats using an in-feed formulation of albendazole to evaluate its therapeutic and prophylactic efficacy. In the first trial, albendazole was incorporated in feed pellets to deliver an average daily dose of 0.7 mg/kg body weight in order to evaluate its prophylactic efficacy. In the second trial, feed pellets were offered to deliver an average total dose of 8.0 mg/kg body weight in two equal split doses in order to evaluate its curative efficacy. Sustained plasma concentrations of the active compound, albendazole sulphoxide, and its metabolite albendazole sulphone, sufficient to prevent establishment of infection, were achieved when the animals were allowed to feed on medicated pellets for 10 consecutive days. The bioavailability of the metabolites of albendazole following the administration of a therapeutic dose in two split doses of the in-feed formulation was sufficient to remove established adult nematodes. The concentrate feed pellets could be used for self-medicating small ruminants for therapeutic use as well as for prophylaxis based on their strategic use appropriate to the epidemiology of the parasitic disease.     

Pharmacokinetics of tramadol and bioavailability of enteral tramadol formulations. 2nd communication: drops with ethanol

The pharmacokinetics and the absolute bioavailability of tramadol hydrochloride (CAS 36282-47-0) after oral administration of Tramal drops (with ethanol) were determined in a balanced cross-over study in 8 (4 male and 4 female) volunteers in comparison with the intravenous injection. Each fasting volunteer received two single doses of 100 mg tramadol-HCl, one by oral (1 ml of drops) and one by intravenous route (2 ml of a solution for injection). The formulations were administered in the morning; the washout period was one week. Serum and urine concentrations of tramadol-HCl were determined by gas chromatography-mass spectrometry and gas chromatography, respectively, and the pharmacokinetic evaluation was carried out model-dependently. Only the extent of bioavailability and the renal clearance were calculated model-independently. The extent of the absolute bioavailability (F) of tramadol after oral administration of the drops, based on AUC data, was 66.3% (point estimate; n = 8) with a 95% confidence interval of 58.1-75.6% (ANOVAlog). The areas under the serum concentration curves of tramadol-HCl calculated by curve fitting (AUC), which agreed very well with the model-independently determined areas (AUC), were 2390 +/- 712 h.ng/ml (p.o.) and 3490 +/- 510 h.ng/ml (i.v.) (mean +/- SD; n = 8). After oral administration the means of the serum concentration peaks were 308 +/- 89 ng/ml (cmax) and 1.20 +/- 0.39 h (tmax), the half-life of absorption was 0.34 +/- 0.18 h (t1/2,ka) and the lag time 0.23 +/- 0.01 h (t0). The biological half-life in the terminal phase (t1/2,beta) was 5.5 +/- 0.9 h and agreed well with the value of 5.2 +/- 0.8 h determined after i.v. injection. There were large differences between the volunteers in the distribution rate. For the slower distribution half-life (t1/2,alpha) mean values of 1.2 +/- 0.7 h (p.o.; n = 6) and 1.9 +/- 0.7 h (i.v.; n = 6) were obtained. The values determined after i.v. injection for the total distribution volume and the total and renal clearance were 216 +/- 21 l (Vd,beta), 487 +/- 71 ml/min (Cltot) and 77 +/- 20 ml/min (Clren), respectively. These results show that after administration of the drops (with ethanol) the active ingredient tramadol is rapidly absorbed and that the extent of the absolute bioavailability is about the same as after oral administration of tramadol capsules.     

Enantioselective assays in comparative bioavailability studies of racemic drug formulations: nice to know or need to know?

The importance of enantiospecific assays in studying pharmacokinetic/pharmacodynamic (PK/PD) and drug-drug interactions of racemic drugs is widely recognized. Use of such assays in comparative bioavailability studies, however, remains controversial. This commentary proposes a PK/PD-based rationale for deciding whether an enantioselective assay is important in such studies. Racemic drugs are divided into three major categories: those with negligible or nonenantioselective first-pass metabolism (category I), those where the first-pass metabolism of the less-active enantiomer is predominant (category II), and those where the first-pass metabolism of the more active and/or toxic enantiomer is predominant (category III). In addressing the need for assay selectivity, a simple analogy is made between these drug categories and the protein-binding phenomenon. Enantioselective assays are not essential for category I drugs, or for category II drugs in the majority of cases. A special consideration, however, is needed for those category II drugs that undergo racemic inversion that may be influenced by the dose level and/or the residence time of the drug formulation in the gastrointestinal tract. It is with category III drugs that enantioselective assays become important, especially when metabolism, distribution, and/or elimination processes of the active or toxic enantiomer are saturable, leading to variable enantiomeric ratios in the plasma. Factors contributing to these ratio changes include routes of administration, dose level, and input rate differences. In put rate differences are particularly relevant to bioavailability evaluation of category III drugs.     

Comparative bioavailability of two oral formulations of ipriflavone in healthy volunteers at steady-state. Evaluation of two different dosage schemes

Because of the relative lack of overlapping toxicity, carboplatin (PPL) and cisplatin (CDDP) can be easily combined for treatment of ovarian cancer to increase total platinum dose intensity. Ifosfamide (IFO), one of the most effective single agents in ovarian cancer, has a low hematological toxicity when administered in continuous infusion. From January 1991 to December 1993, 34 patients with advanced ovarian cancer, previously untreated with chemo- or radiotherapy, were enrolled in a phase I-II study with the aim of determining the maximum tolerated dose (MTD) of CDDP (on day 8 of a 28-day cycle) in combination with PPL (300 mg/m2 on day 1) and IFO (4,000 mg/m2/24 h by continuous infusion on day 1). The initial dose level of CDDP was 40 mg/m2, which was continuously increased by 10 mg/m2 up to the MTD defined as one dose level below that inducing dose-limiting toxicity (DLT) in at least two-thirds of treated patients; no dose escalation was allowed in the same patient. Grade 3-4 leukopenia and thrombocytopenia were observed in 54 and 49% of patients, respectively. The DLT was reached at 70 mg/m2 and therefore the dose recommended for the phase II study was 60 mg/m2. Complete (CR) plus partial response was observed in 88% of patients with a 21% pathological CR. With a minimum follow-up of 32 months (median 40 months), median progression-free survival and overall survival were 21 and 39 months, respectively. In conclusion, the combination of CDDP, PPL, and IFO provides an effective regimen for ovarian cancer with an acceptable toxicity profile.     

The bioavailability of febantel in dehydrated camels

PURPOSE: This investigation compared the Vickers hardness and microstructures of four recently marketed, palladium-based alloys for metal-ceramic restorations. MATERIALS AND METHODS: Wax patterns simulating copings for maxillary central incisors were invested in a fine-grained, carbon-free, phosphate-bonded investment. Following burnout, the palladium alloys were fused with a gas-oxygen torch, centrifugally cast, and bench-cooled. Representative castings were embedded in transparent metallographic resin and sectioned to yield two mirror-image specimens. The specimens were evaluated in either the as-cast condition or following heat treatment simulating the firing cycles for Vita VMK porcelain. Vickers hardness measurements (n = 50) were made using a 1-kg load, and photomicrographs of polished and etched specimens were obtained with a scanning electron microscope. RESULTS: The measured values of microhardness for the as-cast alloys were in excellent agreement with values reported by the manufacturer. The hardness in the as-cast condition was significantly greater for the Pd-Cu-Ga-In alloy, compared with the other three alloys, which did not contain copper. For the three high-palladium (> or = 75 wt%) alloys, there were small (4%-8%) decreases in hardness following heat treatment, whereas a larger decrease (13%) in hardness occurred for the Pd-Ag-In-Sn alloy after heat treatment. The porcelain firing cycles caused microstructural homogenization for all four alloys, and the relatively thick near-surface oxidation region in the Pd-Cu-Ga-In and Pd-Ag-In-Sn alloys was not observed in the two heat-treated Pd-Ga-Ag-In-Au alloys. CONCLUSIONS: The multiphasic microstructures of these alloys may have some significance for the in vitro and clinical corrosion behavior and the metal-ceramic bond strength. The hardness for the three high-palladium alloys may be controlled by submicroscopic precipitates that remain unaltered by heat treatment. The significantly greater hardness for the Pd-Cu-Ga-In alloy may cause greater difficulty for finishing castings in the dental laboratory compared with the other three alloys studied. The strengthening mechanism for the Pd-Ag-In-Sn alloy has significant temperature dependence, which might be exploited to achieve optimum mechanical properties.     

The use of microdialysis in pharmacokinetics and pharmacodynamics

Microdialysis is a new in vivo sampling technology applied to the study of pharmacokinetics and drug metabolism in the blood and soft tissues of living systems. A small-diameter probe containing a dialysis membrane is implanted into tissue and perfused with a suitable fluid. Low-molecular-weight substances passively diffuse through the semipermeable membrane along a concentration gradient, resulting in the collection of purified dialysate samples. The advantage of this approach over blood sampling and dissection of tissues is the ability to sample blood and extracellular fluid with minimal tissue damage or alteration of fluid balance. Sampling several tissues simultaneously and continuously in animal models allows data to be obtained that more directly reflect interactions of drugs at their sites of activity and detoxification. Techniques such as this will have a tremendous impact on preclinical and clinical pharmacologic research.