Comparative bioavailability of diltiazem in prolonged-release oral preparations.

This study was conducted to compare the bioavailability of two prolonged-release pharmaceutical forms containing 300 mg of diltiazem. The test formulation is a new design of tablets with a hydrophilic matrix, and the reference formulation is capsules containing prolonged liberation microgranules, in the same dose, that are commercially available in the pharmaceutical market. Diltiazem plasma concentrations were analyzed by high-performance liquid chromatography (HPLC), which involves solid-phase extraction for plasma sample preparation. Twelve healthy volunteers participated in the study, which had a single-dose, two-treatment, two-sequence-crossover, randomized design. The preparations were compared using pharmacokinetic parameters such as the area under the plasma concentration-time curve AUC(0-36), peak plasma concentration Cmax, and Cmax/AUC(0-36) ratio as a measure for the absorption rate. No statistically significant difference was observed for any of the parameters, and the 90% confidence intervals calculated for the ratio of the logarithmically transformed AUC(0-36) and Cmax/AUC(0-36) values of both formulations were within the bioequivalence limit of 0.80-1.25. Moreover, an in vitro study of dissolution according to USP 23 was conducted, and the in vitro parameters were calculated.

Beta-blocker use in patients with acute myocardial infarction treated by hospitalists.

It is well recognized that the administration of beta blockers to patients after myocardial infarction improves survival. This retrospective cohort and prospective study sought to define the usage of a large hospitalist group and enhance this usage by education and the utilization of a uniform discharge summary. All patients with a discharge diagnosis of acute myocardial infarction were included for analysis. The use of beta blockers by the hospitalist group was initially collected retrospectively and compared with two large cohorts. The data were presented to the hospitalist group. Prospective data collection then commenced. Retrospective analysis of the use of beta blockers showed a rate of 68% as compared with 21% and 34% in two large cohorts (P < .0001). After data were reviewed and conference occurred, prospective use of beta blockers increased to 90% (P < .0005). Patients with myocardial infarction were extremely likely to be treated with beta blockers by this hospitalist group. Review of previous usage and review of contraindications along with the use of a uniform discharge summary resulted in a significant increase in the use of these life-saving drugs.

Stability of capsules containing omeprazole in enteric coated pellets.

The aim of the present study was to comparatively evaluate the stability of capsules containing 20 mg of Omeprazole, in enteric coated pellets, from seven pharmaceutical laboratories on Argentine market. The stability test was performed under the conditions indicated by the ICH: 40 degrees C, 75% HR, with and without light, during a six month period. The remaining content of Omeprazole, total percentage of impurities and percentage of released active principle in vitro, were determined by HPLC. The organoleptic characteristics of the pellets were visually examined. The results obtained at six months indicate that, from the seven products studied, four were found to have a content of Omeprazole higher than 90% of the labeled amount, in both lighting conditions tested, and also comply with the USP23 specifications with respect to the release in vitro. We conclude that the progressive darkening of the pellets indicates, qualitatively, the level of degradation of the product and that the stability of Omeprazole depends on the correct formulation and the primary container.

Molecular characterization and LD(50) identify virulent isolates of Staphylococcus epidermidis from adult sepsis.

Staphylococcus epidermidis plays an important role in infections of patients with implanted prosthetic devices. The exact clinical significance of recovered S. epidermidis from clinical specimens is difficult to assess, as they are inhabitants of the normal skin. In this study, 11 adults with clinical sepsis and blood cultures that grew only S. epidermidis were the host population. Bacterial virulence in vivo was determined by using the mouse LD(50) assay where the intravenous lethality was determined for each patient isolate. Bacterial dose (CFU x 10(9)) that produced lethality in 50% of the animals at 12 h was the value used for comparison. Restriction fragment length polymorphism (RFLP) analysis of chromosomal DNA by pulsed-field gel electrophoresis (PFGE) was used for identification of individual strains and their clonal organization. Confirmation of species assignment was done by RFLP analysis of 16S + 23S rRNA gene regions (ribotyping). Plasmid profile analysis was also conducted. Four of 11 blood isolates from adults with S. epidermidis sepsis had indistinguishable or closely related DNA patterns and were considered clone A. The same clone was previously seen to account for the majority of sepsis in a neonatal intensive care unit. There were significant differences in virulence characteristics of the S. epidermidis isolates. Clone A isolates produced lethality by LD(50) in mice at a dose averaging 2.35; clone B isolate at a dose of 2.54, and the remaining isolates, representing six distinct clones, were lethal to mice at significantly larger doses (3.51-5.17, average 4.16). These data suggest that individual clones of S. epidermidis isolated from septic adults have detectable differences in virulence as defined by an animal bioassay, and the more virulent clone is widespread.

Relative bioavailability of atovaquone suspension when administered with an enteral nutrition supplement.

OBJECTIVE: To compare the relative bioavailability of a single atovaquone 750 mg suspension oral dose when administered in the fasting state, after a normal breakfast, and after an enteral nutrition supplement. DESIGN: Ten healthy volunteers received a single dose of atovaquone suspension 750 mg/5 mL while fasting. At 2-week intervals, the subjects were then randomized in a crossover design to receive the atovaquone dose within 1 hour of consuming a normal breakfast (fat content 21 g) and 16 oz. of Sustacal Plus (fat content 28 g). Blood samples were collected at seven time points after each atovaquone dose. HPLC was used to determine the atovaquone concentrations in plasma. RESULTS: Administering atovaquone suspension with either a normal breakfast or an enteral nutrition supplement, such as Sustacal Plus, significantly increased the oral relative bioavailability. The mean AUC0-24 after the fasting dose was 43.4 micrograms.h/mL. The mean AUC0-24 values with breakfast (103.8 micrograms.h/mL) and Sustacal Plus (118.8 micrograms.h/mL) were significantly greater compared with fasting (p < 0.0001). CONCLUSIONS: This study has shown that the new atovaquone oral suspension also has significantly greater bioavailability when administered after food or a nutrition supplement that has a moderate fat content. Patients who require atovaquone therapy can use Sustacal Plus without risk of reduced absorption.

Platelet depletion and severity of streptococcal endocarditis.

OBJECTIVE: To evaluate the importance of thrombocytopenia in streptococcal endocarditis using an animal model. DESIGN: A model of human septic endocarditis was established in rats (polyethylene catheters across the aortic valve and administration of Streptococcus sanguis, 5×10(7) colony forming units [cfu] intravenous). Thrombocytopenia at four levels was produced by antiplatelet serum. Secondary methods of producing thrombocytopenia were also evaluated. At sacrifice (96 h after platelet depletion and 72 h after infection), vegetations were removed, weighed, diluted, plated and counted. Potential mechanisms of the dose-response relationship between vegetation density and platelet count were evaluated. SETTING: Controlled research laboratory experiments. POPULATION STUDIED: Animal models of streptococcal endocarditis. MAIN RESULTS: The bacterial density of the aortic valve vegetations significantly increased as the platelet count decreased (P=0.0007). In severely thrombocytopenic animals (two-dose antiplatelet serum), data suggest increased vegetation embolism. Platelet depletion, which was minimal with chemical methods, was produced most effectively by antithrombocyte serum. Platelet surfaces in endocarditis were found to express elevated CD62p proteins (72.7% endocarditis, 34.7% control). Platelet protein fractions were evaluated in vitro by both streptocidal (P=0.19) and phagocytosis-stimulating assays. Platelet presence in mature aortic valve vegetations averaged only about 2%. CONCLUSIONS: In platelet depletion experiments using a rat model, a dose-response relationship of peripheral circulating platelet depletion to aortic valve vegetation density was found. The mechanism relating thrombocytopenia to endocarditis severity remains unresolved.

A comparative trial of zidovudine administered every four versus every twelve hours for the treatment of advanced HIV disease.

Zidovudine is approved for administration in doses given every 4 hours. Less frequent dosing has been used in many clinical trials, but the toxicity and efficacy of such regimens have not been formally compared with the approved regimen. In this multicenter, randomized, double-blind, controlled trial, the safety, tolerance and efficacy of 600 mg of zidovudine given daily in two or six divided doses were compared. Three hundred and twenty patients with a CD4 lymphocyte count < 250 cells/mm3 (mean, 104 cells/mm3) or a prior AIDS-defining illness were treated with zidovudine 100 mg every 4 hours (regimen A) or 300 mg every 12 hours (regimen B). Eighty-eight patients (56%) and 94 patients (58%), assigned to regimens A and B, respectively, completed the planned 48 weeks of treatment. Serious anemia (hemoglobin < or = 7.5 g/dl) occurred in 13% and 7% of patients treated with regimens A and B, respectively (difference, 6%, 95% confidence interval [CI], 2, 12%; p = .13). The mean duration of treatment and the frequency of neutropenia and symptomatic complaints including nausea and headache were similar in the two treatment groups. The number of patients experiencing a new opportunistic infection (18% versus 20% for regimens A and B, respectively), and the number of deaths (five in each group) did not differ significantly between groups. The effect of treatment on CD4 lymphocyte counts and HIV p24 antigenemia also was similar for both regimens. Zidovudine given at the more convenient dose of 300 mg twice daily has similar safety, and tolerance and appears to have similar efficacy to the currently approved regimen. Use of this regimen should help simplify the treatment of HIV disease.

Prospective study of histoplasmosis in patients infected with human immunodeficiency virus: incidence, risk factors, and pathophysiology.

Histoplasmosis is a common opportunistic infection in patients with human immunodeficiency virus (HIV) infection who reside in areas where Histoplasma capsulatum is endemic. We undertook a prospective study of a cohort of 304 HIV-Infected patients in Kansas City from October 1990 through March 1993 to define the incidence-specific risk factors, and pathophysiology of histoplasmosis. The annual incidence of histoplasmosis was 4.7%; 74% of the patients with histoplasmosis were symptomatic (all of whom had disseminated disease). A history of exposure to chicken coops, a positive baseline serology for complement-fixing antibodies to Histoplasma mycelium antigen, and a baseline CD4+ lymphocyte count of < 150/microL were associated with an increased risk for histoplasmosis. Histoplasmin reactivity and the presence of pulmonary calcifications were not useful markers for patients at high risk. Symptomatic infection occurred in 9.9% of patients with evidence of prior exposure to H. capsulatum, in 4.0% of patients without documented prior exposure, and in 3.0% of patients who were anergic; these findings suggest that the pathophysiology of histoplasmosis in patients with AIDS involves reactivation of latent infection in some cases and dissemination of exogenously acquired infection in other cases.

Contribution of the host to test results in assays of Staphylococcus epidermidis.

From two human populations (one pediatric and one adult), clinically diagnosed with Staphylococcus epidermidis (S. epidermidis) sepsis of similar severity, bacteria were isolated from pre-antibiotic blood samples and evaluated for virulence. The LD50 of the bacteria in a mouse model was performed, with evaluation of animals dying acutely following intravenous S. epidermidis administration. More simple assays of virulence were also performed, including bacterial adherence to a fibrin clot and carbohydrate specific lectin binding. The eight pediatric-host S. epidermidis isolates required a significantly larger dose to produce lethality in dosed animals (LD50) when compared to the 20 adult-host S. epidermidis isolates. The fibrin clot assay, a test that has corroborated bacterial virulence in endocarditis models, did not differentiate the groups: all but one of the 28 isolates were well above the adherence seen with the ATCC control, suggesting endocarditis-producing potential. Glycocalyx (slime) from eight of the more virulent isolates showed reactivity with a glucose-specific biotinylated lectin which was lacking in other isolates. Necropsy of mice dying at 12 hr showed S. epidermidis strain differences in specific organ effects. Overall, this study demonstrates the utility of the LD50 to provide a highly sensitive quantification of bacterial virulence. Necropsy of test animals dying acutely has showed an apparent organ tropism of some of these isolates which are usually considered harmless commensals.

Bacterial characterization in Staphylococcus epidermidis septicemia.

An analysis of the in vitro characteristics of Staphylococcus epidermidis strains isolated from patients with true S. epidermidis septicemia was undertaken. From a potential population of 921 cultures from adult patients with coagulase-negative bacteremia, highly defined selective criteria limited the population to 20 patients with S. epidermidis sepsis, from whose blood cultures the study organisms were isolated. Another population of 11 S. epidermidis blood isolates, clinically determined to be contaminants, were tested as a control group. In vitro assays performed on all isolates included slime quantification, hydrophobicity, surface hexoses, and capsule presence. Murine spleen phagocytosis of intravenously administered isolates was measured in vivo. The assayed quantity of cell-associated bacterial hexose sugars positively correlated with organism virulence to the host (p = 0.02). This bacterial population was also low in slime but varied as to the presence of capsule and ease of phagocytosis. Permanent catheter-bearing patients' bacteria were somewhat more hydrophobic (p = 0.07). We conclude that in vitro assays can differentiate bacteremic cultures from contaminants and that the characteristic that best relates to host toxicity in these S. epidermidis isolates was bacterial cell surface-associated carbohydrate.

Diagnosis of cellulitis in patients infected with the human immunodeficiency virus.

A prospective microbiological evaluation of cellulitis in 22 patients infected with the human immunodeficiency virus was performed. Patients with helper lymphocyte counts of less than 200 cells/mm(3) had a greater frequency of positive cultures. The most frequently isolated pathogens were Staphylococcus aureus and Streptococcus pyogenes, and initial antibiotic therapy should cover these Gram-positive cocci.

Reactivity of the glycocalyx of endocarditis-producing viridans group streptococci.

We correlated quantity of streptococcal polysaccharides and endocarditis production by those bacterial strains. To investigate this finding further, we studied the composition of the glycocalyx using a spectrophotometric assay and lectin analysis of exopolysaccharides from endocarditis- and non-endocarditis-producing strains of viridans streptococci. Identical weights of glycocalyx from the clinical endocarditis isolates produced significantly different absorbances as compared with the nonendocarditis isolates (P < 0.0012, Wilcoxon rank test). Lectin-binding experiments showed that endocarditis-producing streptococci contained increased amounts of glucose, galactose, sialic acid, and mannose. These data suggest that the glycocalyx of endocarditis-producing viridans streptococci is both qualitatively and quantitatively different from non-endocarditis-producing isolates. These differences can be measured in vitro.

In vitro assays of Staphylococcus epidermidis characteristics and outcome in an endocarditis model.

OBJECTIVE: Staphylococcus epidermidis adherence to indwelling polymers is important in prosthetic valve endocarditis. Earlier studies have related streptococcal endocarditis to isolates with high levels of cell-associated hexoses. The objective of the present study was to determine if a relationship exists between an S epidermidis isolate assay score and production/severity of experimental endocarditis. DESIGN: Groups of patient S epidermidis isolates were screened for surface hexoses and an animal model of endocarditis with isolates testing highest and lowest on the screen was produced. Disease severity produced by 'high hexose' versus 'low hexose' organisms was evaluated. Endocarditis responding variables were bacterial vegetation weight and log(10) colony forming units (cfu) and in survival tests, comparative time to death with different isolates. Bacterial characteristics were not measured. Baseline data showed a vegetation weight difference so that with a ß error of 0.20 and a two-tailed α error of 0.05, a significant difference would be noted using 30 animals. A total of 64 animals was used. POPULATION STUDDED: Bacterial isolates from two patient groups (n=42 and n=68) on which in vitro assays were run. An animal model of endocarditis (n=64) was used to evaluate four selected isolates for vegetation size, log(10) cfu/g, and survival time. MAIN RESULTS: In a group of S epidermidis endocarditis animals evaluated for time of death, a significantly more rapid death time resulted in the group dosed with the high hexose-scoring organism (P<0.025). Vegetations and log(10) cfu produced by test high hexose isolates averaged larger but were not significantly different. CONCLUSIONS: A significantly more rapid death rate occurs in untreated endocarditis using a high hexose isolate than with S epidermidis with low surface hexoses. Using bacterial vegetation and cfu as endpoints, however, experimental endocarditis using patient isolates of S epidermidis does not show the same strong correlation to bacterial surface hexoses as does streptococcal endocarditis.

[The pharmacokinetic study of a daily dose of theophylline]. / Estudio farmacocinético de una dosis diaria de teofilina.

Theophylline pharmacokinetics, administered in tablets containing 600 mg in a sustained-release hydrophilic matrix for a once daily intake, was evaluated after being administered to 6 healthy volunteers during 7 days at 8 pm. Plasmatic levels at -2, 0, 2, 3, 4, 6, 8, 10, 12, 14, 18 and 24 hours in relation with 8 pm intake, were obtained at the 7th day of administration. A plasmatic curve was obtained with a maximum concentration at 12 hours of 10.18 mcg/ml, a minimum concentration of 3.27 mcg/ml and an area under the concentration/time curve of 198.4 mcg.h/ml. These data make it evident that the tablet studied shows a release profile without excessive peaks and an average concentration at steady state within therapeutical range, and suggests its use in asthma.

Invasive polymycotic pneumonia in an uncontrolled diabetic.

We describe the clinical course of a patient with invasive polymycotic pneumonia due to Rhizopus arrhizus and Candida albicans. Both organisms were recovered from antemortem sputum cultures, and their clinical significance was confirmed by histologic examination of the lungs at autopsy. Circumstances leading to polymycotic infection are discussed, with special attention given to polymycotic infections involving Zygomycetes.

Association of cell-adherent glycocalyx and endocarditis production by viridans group streptococci.

To assess the role of glycocalyx production in the pathogenesis of endocarditis caused by viridans group streptococci in adult patients, glycocalyx production was examined for 49 blood culture isolates. The tryptophan assay, a quantitative spectrophotometric test, was used to measure cell-adherent glycocalyx production. Absorbance values of the isolates that produced endocarditis were significantly higher (means, 0.166 versus 0.060 [P less than 0.001]). At a breakpoint of absorbance of 0.120, the sensitivity of the test was 0.83, the specificity was 0.96, and the predictive value was 0.95. These data suggest that the in vitro tryptophan assay of glycocalyx production by viridans group streptococci has potential value as a predictor of clinical pathogenicity.