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S E Bellibas

Publications and source records attributed to S E Bellibas.

6 recordsLinked to original sources
PubMed2001

Making the most of sparse clinical data by using a predictive-model-based analysis, illustrated with a stavudine pharmacokinetic study.

A small-scale clinical investigation was done to quantify the penetration of stavudine (D4T) into cerebrospinal fluid (CSF). A model-based analysis estimates the steady-state ratio of AUCs of CSF and plasma concentrations (R(AUC)) to be 0.270, and the mean residence time of drug in the CSF to be 7.04 h. The analysis illustrates the advantages of a causal (scientific, predictive) model-based approach to analysis over a noncausal (empirical, descriptive) approach when the data, as here, demonstrate certain problematic features commonly encountered in clinical data, namely (i) few subjects, (ii) sparse sampling, (iii) repeated measures, (iv) imbalance, and (v) individual design variation. These features generally require special attention in data analysis. The causal-model-based analysis deals with features (i) and (ii), both of which reduce efficiency, by combining data from different studies and adding subject-matter prior information. It deals with features (iii)--(v), all of which prevent 'averaging' individual data points directly, first, by adjusting in the model for interindividual data differences due to design differences, secondly, by explicitly differentiating between interpatient, interoccasion, and measurement error variation, and lastly, by defining a scientifically meaningful estimand (R(AUC)) that is independent of design.

Anti-HIV Agents↗
PubMed2001

Pharmacokinetics and pharmacodynamics of thalidomide in HIV patients treated for oral aphthous ulcers: ACTG protocol 251. AIDS Clinical Trials Group.

Thalidomide has increasing clinical benefits, including the healing of aphthous ulcers in patients with HIV. Unfortunately, pharmacological information addressing the pharmacokinetics (PK) of this compound in HIV patients is limited. Concern exists as to whether thalidomide may alter its own metabolism owing to in vitro data previously reported. Furthermore, no information is available defining the relationship between drug exposure and clinical response. This study evaluated the PK and pharmacodynamics (PD) of thalidomide in patients enrolled in AIDS Clinical Trials Group Protocol 251. Study patients had HIV infection and oral aphthous ulcers of at least 2 weeks'duration. Pharmacologic studies were completed in those subjects randomized to receive active thalidomide at a dose of 200 mg daily for the 4-week study period. PK studies involving serial sampling were carried out in 7 subjects following multiple dosing during study weeks 1 and 4. In addition, trough measurements were done in 20 subjects during each of the 4 study weeks to explore the relationship between time-averaged trough values and extent of clinical response. All samples were analyzed using a validated HPLC method, and parameters were determined using noncompartmental PK analysis. Thalidomide oral clearance averaged 0.14 +/- 0.08 and 0.12 +/- 0.05 l/h/kg on weeks 1 and 4 (p = 0.72), while the terminal elimination half-life averaged 5.7 +/- 1.5 and 7.3 +/- 1.7 hours (p = 0.12). The median time-averaged trough value for subjects deemed complete responders was 0.60, while the median value for noncomplete responders was 0.54. Adjusting for baseline CD4 count and initial index ulcer area, no significant effects were observed of increased thalidomide levels on response. In summary, this study provides steady-state PK data in HIV patients managed with thalidomide and suggests negligible effect of chronic dosing on drug clearance (comparing results from weeks 1 and 4). Furthermore, variable trough measurements between patients do not directly influence the effectiveness of thalidomide for oral aphthous ulcers.

Adult↗
PubMed1999

Failure to detect nelfinavir in the cerebrospinal fluid of HIV-1--infected patients with and without AIDS dementia complex.

OBJECTIVE: To assess the penetration of the HIV-1 protease inhibitor, nelfinavir, into cerebrospinal fluid (CSF). DESIGN: Nelfinavir, a commonly used HIV-1 protease inhibitor (PI), is highly effective for reducing plasma viral load. It is deployed clinically in combination with other antiretroviral agents, including nucleoside and nonnucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs). Despite its potency based on plasma HIV-1 RNA results, its effectiveness in reducing HIV-1 RNA levels (i.e., viral load) in the central nervous system (CNS) is less certain. We sampled the CSF as a surrogate for brain because this fluid also is separated from the blood by a barrier to free diffusion, the blood-CSF barrier (BCB), which shares properties with the blood-brain barrier (BBB). These studies of nelfinavir CSF pharmacokinetics exploited the multiple CSF samples derived from individual study subjects who were enrolled in studies the primary objective of which was to compare viral kinetics in CSF and blood in response to antiviral therapy. METHODS: Six study subjects, four with and two without AIDS dementia complex, underwent multiple lumbar punctures (LP). Intervals of CSF sampling after drug dosing were varied (from 0.48 hours to 10.3 hours after nelfinavir administration) to quantitate nelfinavir concentrations throughout the steady-state dosing interval. In four study subjects, CSF sampling was accompanied by assessment of nelfinavir levels in plasma before and after LP, whereas in the other two subjects, a single plasma sample was obtained before or after the LP. In total, 25 CSF samples were analyzed. Nelfinavir concentrations in CSF and plasma were determined using an high-performance liquid chromatography (HPLC) method with a limit of quantitation of 25 and 50 ng/ml, respectively. RESULTS: Plasma concentrations before and after LP averaged 2420+/-1365 ng/ml and 2528+/-1132 ng/ml, respectively. Nelfinavir was not detected in any of the CSF samples and levels >25 ng/ml were not present in the CSF. Thus, standard therapy with nelfinavir does not result in CSF drug concentrations at or exceeding the IC95 level for most HIV-1 isolates. However, study subjects with high CSF viral loads experienced a marked reduction in the context of the combination-drug regimen including nelfinavir with two subjects showing a comparable CSF response with that in plasma. CONCLUSIONS: Nelfinavir does not appreciably penetrate into the CSF. The clinical importance of this observation is not certain, in that in four study subjects who initiated nelfinavir in combination with other antiretroviral therapy, a comparable degree of viral suppression was obtained in both the CSF and the blood when sampled 4 weeks or later after initiating therapy.

AIDS Dementia Complex↗
PubMed1996

Comparison of the analgesic effects of diflunisal and paracetamol in the treatment of postoperative dental pain.

The search for new effective analgesics without unwanted effects on the coagulation mechanism and a longer duration of activity has been intensified. One such development is diflunisal and the aim of this study was to compare the analgesic effect of diflunisal with that of paracetamol. A combined single dose (500-mg tablets), double-blind, randomized, controlled design in out-patients (n = 104) with moderate or severe pain caused by the surgical removal of impacted mandibular third molars was used in this study. Pain intensity and relief were assessed postoperatively for 8h using category-rating scales. The results showed a statistically significant difference in favour of diflunisal in each and every parameter used in determining the efficacy of the treatment.

Acetaminophen↗