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Biomedical subjects

Gene D Morse

Publications and source records attributed to Gene D Morse.

At least 19 recordsLinked to original sources
PubMed2025

Immunomodulatory Nanoparticles Induce Autophagy in Macrophages and Reduce Mycobacterium tuberculosis Burden in the Lungs of Mice.

Tuberculosis (TB) is the leading cause of death from infectious disease. Macrophages are the primary immune responders and become the primary host cells for the causative agent Mycobacterium tuberculosis. Following the uptake of M. tuberculosis, the inherent antimicrobial action of macrophages is dampened, enabling the bacterium to reside within these cells and multiply. Rising resistance of M. tuberculosis to antibiotics has led to the investigation of novel approaches for the treatment of TB. Here, we report a host-directed approach, employing biomimetic Curdlan poly(lactic-co-glycolic acid) (C-PLGA) nanoparticles (NPs), and examine autophagy induction in infected macrophages, eradication of M. tuberculosis and immune modulation in a mouse model. We demonstrate that the NPs induce autophagy in M. tuberculosis-infected macrophages. Treatment of H37Rv infected C57BL/6 mice with these NPs reduced M. tuberculosis burden in the lungs of mice and modulated cytokines and chemokines and this work demonstrates that these immunomodulatory NPs are a potential treatment approach for TB.

Animals↗
PubMed2006

Pharmacokinetic interactions between buprenorphine and antiretroviral medications.

Buprenorphine is used for the treatment of opioid dependence. As the number of persons receiving buprenorphine treatment and antiretroviral therapy continues to grow, so too does the existence and clinical impact of drug interactions between buprenorphine and medications for treating human immunodeficiency virus (HIV) infection. Awareness that such interactions exist may deter some patients and physicians from initiating potentially lifesaving therapy or lead to complications among patients whose treatment is already under way. Complications include nonadherence to antiretroviral therapy and the development of viral resistance. Illicit drug use is a frequent consequence of adverse drug effects experienced by injection drug users. The occurrence of unrecognized drug interactions can lead to unsuccessful therapy for HIV infection and the treatment of substance dependence. The present review is organized to provide a working background of buprenorphine pharmacology. Review of the current state of knowledge regarding specific interactions between buprenorphine and antiretrovirals is followed by a review of the clinical applicability of these interactions.

Animals↗
PubMed2006

Interactions between buprenorphine and antiretrovirals. I. The nonnucleoside reverse-transcriptase inhibitors efavirenz and delavirdine.

This study examined drug interactions between buprenorphine, an opioid partial agonist medication used in the treatment of opioid dependence, and the nonnucleoside reverse-transcriptase inhibitors (NNRTIs) efavirenz (EFV) and delavirdine (DLV). Opioid-dependent, buprenorphine/naloxone-maintained, human immunodeficiency virus (HIV)-negative volunteers (n=10 per NNRTI) participated in 24-h sessions to determine pharmacokinetics of buprenorphine and of buprenorphine with either EFV or DLV after administration of standard doses of either antiretroviral for 15 or 7 days, respectively. Opiate withdrawal symptoms, cognitive effects, and adverse events were determined before and after antiretroviral administration in opioid-dependent participants. The pharmacokinetics of NNRTIs in healthy control participants were used to determine the effect of buprenorphine on NNRTIs. EFV decreased the buprenorphine area under the concentration-time curve (P<.001). DLV increased buprenorphine concentrations (P<.001). Clinically significant consequences of these interactions were not observed. Buprenorphine did not alter antiretroviral pharmacokinetics. Adjustments of doses of either buprenorphine or EFV or DLV are not likely to be necessary when these drugs are administered for the treatment of opiate dependence and HIV disease.

Adult↗
PubMed2006

Interactions between buprenorphine and antiretrovirals. II. The protease inhibitors nelfinavir, lopinavir/ritonavir, and ritonavir.

We examined drug interactions between buprenorphine, an opioid partial agonist available by prescription for treatment of opioid dependence, and the protease inhibitors (PIs) nelfinavir (NFV), ritonavir (RTV), and lopinavir/ritonavir (LPV/R). Opioid-dependent, buprenorphine/naloxone-maintained, human immunodeficiency virus (HIV)-negative volunteers (n=10 per PI) participated in 24-h pharmacokinetic studies, before and after administration of each PI. Symptoms of opiate withdrawal and excess were determined before and after PI administration. PI pharmacokinetics were determined and compared between opiate-dependent participants and healthy control participants (n=15 per PI). Administration of RTV, but not of NFV or LPV/R, resulted in a significant increase in the buprenorphine area under the concentration-time curve (AUC). Symptoms of opiate excess, however, were not observed. Buprenorphine had no significant effects on PI AUC. Adjustments of doses of either buprenorphine or NFV, LPV/R, or RTV are not likely to be necessary when these drugs are administered for the treatment of opioid dependence and HIV disease.

Adult↗
PubMed2006

Clinical pharmacodynamics of HIV-1 protease inhibitors: use of inhibitory quotients to optimise pharmacotherapy.

The introduction of HIV-1 protease inhibitors and non-nucleoside reverse transcriptase inhibitors in 1996 began an era described as that of highly active antiretroviral therapy. In addition, the more recent development and availability of HIV-1 genotypic and phenotypic resistance tests and advances in pharmacological assays that support therapeutic drug monitoring (TDM) have created tools that may help clinicians to provide more individualised treatment with HIV-1 protease inhibitors. All current treatment guidelines provide fixed doses of protease inhibitors with vague recommendations for the use of TDM in selected clinical situations. In patients with resistance to protease inhibitors, the combined use of resistance tests with TDM provide a mechanism for individualising the clinical pharmacodynamics of protease inhibitors. Current therapeutic approaches seek to include the monitoring of protease-inhibitor concentrations as part of a TDM programme with phenotypic assays to calculate an inhibitory quotient, virtual inhibitory quotient, or normalised inhibitory quotient, whereas genotypic tests are used with TDM to calculate a genotypic inhibitory quotient. Current investigation is focused on examining the predictive value of this approach for clinical monitoring.

HIV Infections↗
PubMed2006

Determination of tipranavir in human plasma by reverse phase liquid chromatography with UV detection using photodiode array.

Tipranavir has recently received accelerated approval from the FDA. The initial clinical use of tipranavir will be for patients with prior virologic failure with the presence of key HIV-1 protease inhibitor mutations. In Phase III trials patients with greater virologic response also had higher trough tipranavir concentrations (BI product information 2005). In addition, hepatotoxicity was concentration-related with a higher incidence in those patients exceeding a trough plasma concentration of 48.2 microg/mL (80 microM). Therefore, tipranavir may be an HIV-1 protease inhibitor for which therapeutic drug monitoring (TDM) may be helpful in optimizing outcomes. To quantitate tipranavir concentrations in human plasma, a method using reversed phase high performance liquid chromatography (RP-HPLC) was validated. Detection was effected using a photodiode-array detector, scanning at a wavelength of 254 nm. This method allows for detection of tipranavir to a lower limit of quantitation of 0.390 microg/mL with an interday variation in control value ranging from 2.9 to 4.6%. The method is being used in a clinical therapeutic drug monitoring program that is ongoing in our laboratory.

Calibration↗
PubMed2006

Multilocus genetic interactions and response to efavirenz-containing regimens: an adult AIDS clinical trials group study.

OBJECTIVE: For the HIV-1 reverse transcriptase inhibitor efavirenz, variant drug transporter gene ABCB1 may predict virologic response but not plasma efavirenz exposure. Conversely, variant drug metabolizing enzyme gene CYP2B6 predicts greater plasma efavirenz exposure but not virologic response. We examined whether long-term responses to efavirenz, and/or plasma efavirenz exposure, are better predicted by multilocus genetic interactions than by individual polymorphisms. MATERIALS AND METHODS: We studied antiretroviral-naïve study participants randomized to receive efavirenz (with or without nelfinavir) plus two nucleoside analogues in study ACTG 384, and who had DNA available for analysis. Participants were followed up for up to 3 years. Nine single nucleotide polymorphisms in ABCB1, CYP2B6, CYP3A4, CYP3A5 and CYP2C19 were identified. Gene-gene interactions were identified using multifactor dimensionality reduction. RESULTS: Among 340 efavirenz recipients, higher efavirenz AUC24 h values were associated with a single locus model involving CYP2B6 516G>T (73% accuracy; P<0.001). This was also the best model among blacks (69% accuracy; P<0.001), whereas among whites the best model involved a gene-gene interaction between CYP2B6 516G>T and ABCB1 2677G>T (82% accuracy, P<0.001). Among 155 participants who received efavirenz without nelfinavir, virologic failure was associated with a two-locus interaction between ABCB1 2677G>T and CYP2B6 516G>T (65% accuracy, P<0.001). Toxicity failure was best predicted by an interaction between ABCB1 2677G>T and ABCB1 3435C>T (71% accuracy, P<0.001). CONCLUSIONS: Multilocus genetic interactions between variant drug metabolism and transporter genes may predict efavirenz pharmacokinetics and treatment responses. This finding may have implications for better individualizing antiretroviral therapy.

Acquired Immunodeficiency Syndrome↗
PubMed2006

Quality assurance program for pharmacokinetic assay of antiretrovirals: ACTG proficiency testing for pediatric and adult pharmacology support laboratories, 2003 to 2004: a requirement for therapeutic drug monitoring.

Proficiency testing (PT) is a mandated requirement for clinical laboratories doing therapeutic drug monitoring and is an invaluable tool to help laboratories identify and correct problems in analytical procedures. The AIDS Clinical Trial Group Pharmacology Quality Assurance Committee implemented a new antiretroviral PT program for all currently available antiretroviral drugs in 2001. The PT program was designed for the AIDS Clinical Trial Group Pharmacology Specialty Laboratories actively involved in assaying these drugs in clinical trial samples so as to comply with the Clinical Laboratory Improvement Amendments. Results from the first 3 rounds of PT have been analyzed and reported and provided support for formalizing the guidelines of the PT testing program. The PT program has expanded with the addition of nucleoside reverse transcription inhibitors (NRTIs) and atazanavir. This report includes results from rounds 4 to 7 over 2 additional years of standard operations. Additionally we include results from NRTIs for all rounds and atazanavir for a single round. There were 9 participating laboratories. Eight used high-performance liquid chromatography as the primary method of detection and 2/8 also reported LC-MS-MS results. One laboratory used LC-MS-MS as their primary detection method. All laboratories measured protease inhibitors, most measured at least 1 non-nucleoside reverse transcription inhibitor and 5 had NRTI capabilities. Results were normally distributed and the acceptance range of +/-20% best corresponded to a 95% confidence interval. Overall score for 9 participating laboratories was 96% correct out of 1826 challenges over 4 rounds. Laboratories scored 95, 98 and 97% correct for protease inhibitors, non-nucleoside reverse transcription inhibitorss and NRTIs, respectively. Three laboratories reporting LC-MS-MS results had 92% correct (347/378) challenges for all drugs. The percentage of correct results is about the same as previously reported. There is a continued need for a PT program to help participating laboratories maintain essential quality assurance and quality control.

Anti-HIV Agents↗
PubMed2006

Inhibition of atazanavir oral absorption by lansoprazole gastric acid suppression in healthy volunteers.

STUDY OBJECTIVE: To determine whether the pharmacokinetics of atazanavir, a protease inhibitor used to treat human immunodeficiency virus (HIV) infection, are altered by its coadministration with lansoprazole, a proton pump inhibitor. DESIGN: Single-dose, open-label, complete-crossover study. SETTING: Clinical research center. SUBJECTS: Ten healthy adult volunteers. MEASUREMENTS AND MAIN RESULTS: In phase A, subjects received a single oral dose of atazanavir 400 mg alone. In phase B, the same subjects received oral lansoprazole 60 mg, and after 24 hours they were given a second dose of oral lansoprazole 60 mg with atazanavir 400 mg. Eleven blood samples were collected from each subject over a 24-hour period for determination of atazanavir plasma concentrations by a validated high-performance liquid chromatography assay. Pharmacokinetic analysis was performed by standard noncompartmental methods. Nine subjects completed the study, and no significant adverse events were reported. Absorption of atazanavir was significantly reduced when it was coadministered with lansoprazole, as evidenced by a 94% decline in mean area under the concentration-time curve during the 24 hours after administration (AUC(0-24)) (p<0.01). The mean +/- SD AUC(0-24) for phase A was 16.3 +/- 9.0 microM x hour versus 0.95 +/- 1.8 microM x hour for phase B (p<0.01). The mean +/- SD maximum concentration of atazanavir was 3.2 +/- 1.7 microM for phase A and 0.13 +/- 0.19 microM for phase B (p<0.01). CONCLUSION: Acid suppression markedly reduced the bioavailability of atazanavir in this group of healthy volunteers. Based on these results, atazanavir should not be coadministered with lansoprazole or other proton pump inhibitors.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed2005

Pharmacogenetics of long-term responses to antiretroviral regimens containing Efavirenz and/or Nelfinavir: an Adult Aids Clinical Trials Group Study.

BACKGROUND: Efavirenz and nelfinavir are metabolized by cytochrome P-450 (CYP) 2B6 and CYP2C19, respectively, with some involvement by CYP3A. Nelfinavir is a substrate for P-glycoprotein, which is encoded by MDR1. The present study examined associations between genetic variants and long-term responses to treatment. METHODS: Adult AIDS Clinical Trials Group study 384 randomized antiretroviral-naive subjects to receive efavirenz and/or nelfinavir plus 2 nucleoside analogues, with follow-up lasting up to 3 years. Population pharmacokinetics were estimated from a nonlinear mixed-effects model. Polymorphisms in CYP2B6, CYP2C19, CYP3A4, CYP3A5, and MDR1 were characterized. RESULTS: The 504 participants in the genetic study included 340 efavirenz recipients and 348 nelfinavir recipients (184 of the 504 participants received both efavirenz and nelfinavir). Of the participants, 49% were white, 31% were black, and 19% were Hispanic. Plasma exposure to efavirenz and nelfinavir in each population was significantly associated with the polymorphisms CYP2B6 516G-->T and CYP2C19 681G-->A, respectively. Among efavirenz recipients, the MDR1 position 3435 TT genotype was associated with decreased likelihood of virologic failure and decreased emergence of efavirenz-resistant virus but not with plasma efavirenz exposure. Among nelfinavir recipients, a trend toward decreased virologic failure was associated with the polymorphism CYP2C19 681G-->A. CONCLUSIONS: Genetic variants predict plasma exposure to efavirenz and nelfinavir, and they may predict virologic failure and/or emergence of drug-resistant virus. These associations with treatment responses must be validated in other studies.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2005

Amprenavir and efavirenz pharmacokinetics before and after the addition of nelfinavir, indinavir, ritonavir, or saquinavir in seronegative individuals.

Adult AIDS Clinical Trials Group 5043 examined pharmacokinetic (PK) interactions between amprenavir (APV) and efavirenz (EFV) both by themselves and when nelfinavir (NFV), indinavir (IDV), ritonavir (RTV), or saquinavir (SQV) is added. A PK study was conducted after the administration of single doses of APV (day 0). Subjects (n = 56) received 600 mg of EFV every 24 h (q24h) for 10 days and restarted APV with EFV for days 11 to 13 with a PK study on day 14. A second protease inhibitor (PI) (NFV, 1,250 mg, q12h; IDV, 1,200 mg, q12h; RTV, 100 mg, q12h; or SQV, 1,600 mg, q12h) was added to APV and EFV on day 15, and a PK study was conducted on day 21. Controls continued APV and EFV without a second PI. Among subjects, the APV areas under the curve (AUCs) on days 0, 14, and 21 were compared using the Wilcoxon signed-rank test. Ninety-percent confidence intervals around the geometric mean ratios (GMR) were calculated. APV AUCs were 46% to 61% lower (median percentage of AUC) with EFV (day 14 versus day 0; P values of <0.05). In the NFV, IDV, and RTV groups, day 21 APV AUCs with EFV were higher than AUCs for EFV alone. Ninety-percent confidence intervals around the GMR were 3.5 to 5.3 for NFV (P < 0.001), 2.8 to 4.5 for IDV (P < 0.001), and 7.8 to 11.5 for RTV (P = 0.004). Saquinavir modestly increased the APV AUCs (GMR, 1.0 to 1.4; P = 0.106). Control group AUCs were lower on day 21 compared to those on day 14 (GMR, 0.7 to 1.0; P = 0.042). African-American non-Hispanics had higher day 14 efavirenz AUCs than white non-Hispanics. We conclude that EFV lowered APV AUCs, but nelfinavir, indinavir, or ritonavir compensated for EFV induction.

Adolescent↗
PubMed2005

Pharmacokinetics of nelfinavir and efavirenz in antiretroviral-naive, human immunodeficiency virus-infected subjects when administered alone or in combination with nucleoside analog reverse transcriptase inhibitors.

Pharmacokinetic studies were conducted with human immunodeficiency virus-infected patients receiving efavirenz, nelfinavir, or both agents at weeks 4 and 32. Reductions of 25% and 45% were observed in the mean nelfinavir area under the concentration-time curve and minimum concentration of the drug in serum, and there was a 31% more rapid half-life for patients receiving both drugs compared to patients receiving nelfinavir alone. There were no significant differences in efavirenz pharmacokinetics.

Alkynes↗
PubMed2005

Pharmacokinetic drug interactions with non-nucleoside reverse transcriptase inhibitors.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are a diverse group of compounds that inhibit HIV Type 1 reverse transcriptase. Although possessing a common mechanism of action, the approved NNRTIs, delavirdine, efavirenz and nevirapine, differ in structural and pharmacokinetic characteristics. Each of the NNRTIs undergoes biotransformation by the cytochrome P450 (CYP) enzyme system, thus making them prone to clinically significant drug interactions when combined with other antiretrovirals. In addition, they interact with other concurrent medications and complementary/alternative medicines, acting as either inducers or inhibitors of drug-metabolising CYP enzymes. These drug interactions become an important consideration in the clinical use of these agents when designing combination regimens, as recommended by current guidelines. This review provides an updated summary of pharmacokinetic interactions with NNRTIs.

Animals↗
PubMed2005

Population pharmacokinetics of delavirdine and N-delavirdine in HIV-infected individuals.

OBJECTIVE: Delavirdine is a non-nucleoside reverse transcriptase inhibitor used in combination regimens for the treatment of HIV-1 infection. Our objective was to characterise the population pharmacokinetics of delavirdine in HIV-infected patients who participated in the adult AIDS Clinical Trials Group (ACTG) 260 and 261 studies. METHODS: ACTG 261 was a randomised, double-blind study of delavirdine 400mg three times daily, in various combination regimens; ACTG 260 was a concentration-targeted monotherapy study. Two hundred and thirty-four patients, and 1254 and 1251 plasma concentrations for delavirdine and N-delavirdine, respectively, were available for population pharmacokinetic analysis. The pharmacokinetic model (and initial parameters), based on previous studies, included two compartments for delavirdine (peripheral and central) and parallel clearance pathways (nonlinear conversion to N-delavirdine and first order clearance from the body). The model was one compartment for N-delavirdine with first order clearance. Diurnal variation of delavirdine and N-delavirdine oral clearance was modelled as a cosine function, with amplitude variation a fitted parameter. Pharmacokinetic parameter estimates were derived from iterative two-stage analysis; observed delavirdine and N-delavirdine concentrations fit with weighting by the inverse observation variance. Covariates were analysed by multiple general linear modelling. RESULTS: The mean (percent coefficient of variation [%CV]) CD4 count was 315 (109) cells/mm(3), weight 76.9 (14.7) kg, age 37 (8.5) years, and 15% of the population were women. Mean (%CV) population pharmacokinetic parameter estimates for delavirdine were: volume of distribution at steady state 67.6 (100) L, intrinsic oral clearance 19.8 (64) L/h, concentration at half the maximum velocity of metabolism (V(max)) 6.3 (69) micromol/L and first order oral clearance 0.57 (86) L/h. For N-delavirdine, the mean (%CV) apparent volume of distribution was 24.7 (75) L and apparent clearance 29.7 (42) L/h. The mean V(max) was 1376 (68) mg/day. The final model for average intrinsic clearance of delavirdine included race, sex, weight and age as significant covariates (p < 0.05); however, these covariates do not explain a significant proportion of the overall variability in the population. CONCLUSIONS: Delavirdine disposition exhibits nonlinear pharmacokinetics and large interpatient variability, and is significantly altered by time of day (impacting potential therapeutic drug monitoring and future pharmacokinetic study designs). Although race and sex appear to influence delavirdine pharmacokinetics, men and women and patients of different races should receive similar mg/kg dosage regimens. The presence of large interpatient variability supports the further investigation of the utility of therapeutic drug monitoring for delavirdine, if target drug concentrations can be better defined.

Adolescent↗
PubMed2004

Drug interactions with antiretrovirals.

The recent development of new antiretroviral drugs, along with the evolution in clinical practice guidelines that include the recommendation of the use of three- to four-drug combination regimens for achieving optimal suppression of viral replication, has focused clinicians on the relevance of drug-drug interactions in the chronic care of HIV-infected individuals. However, the routine clinical management of drug interactions is complicated by our expanding knowledge of the physiologic mechanisms underlying pharmacokinetic interactions, particularly as they relate to drug transport and tissue distribution (eg, P-glycoprotein) and biotransformation (hepatic cytochrome p450 mono-oxygenase induction and inhibition). This review provides an updated summary of key drug interactions that have been reported since its initial publication.

Anti-Retroviral Agents↗
PubMed2004

Quality assurance program for clinical measurement of antiretrovirals: AIDS clinical trials group proficiency testing program for pediatric and adult pharmacology laboratories.

Clinical trials designed to compare antiretroviral regimens, investigate therapeutic drug monitoring, or measure pharmacometrics often include protease inhibitors (PIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), and nucleoside reverse transcriptase inhibitors, requiring the measurement of these antiretrovirals in plasma. Within the adult and pediatric AIDS Clinical Trials Group (ACTG), a network of Pharmacology Support Laboratories (PSLs) is a component of the group laboratory infrastructure and conducts these types of pharmacologic assays. The adult ACTG has developed a comprehensive quality assurance program for the conduct of clinical pharmacology protocols, one component of which is the antiretroviral proficiency testing (PT) program that has been implemented between the adult and pediatric pharmacology laboratories of the ACTG. PT testing samples were prepared and distributed in July 2001, February 2002, and July 2002. High, medium, and low concentrations of PIs (indinavir, saquinavir, amprenavir, lopinavir, ritonavir, and nelfinavir) and NNRTIs (nevirapine and efavirenz) were added to drug-free EDTA plasma and distributed, on dry ice, to eight ACTG PSLs. One testing laboratory used liquid chromatography-tandem mass spectrometry, and seven used high-performance liquid chromatography-UV analysis. A result was considered acceptable if it was within 20% deviation of the assigned concentration. For all concentrations of PIs evaluated, 96% of samples tested (430 of 448 measurements) met the acceptance criteria. For both NNRTIs, 100% of samples tested (140 of 140 measurements) met the acceptance criteria. In conclusion, the PT program results presented demonstrate excellent interlaboratory agreement for all antiretrovirals tested and provide support for the merger of plasma concentration data among laboratories for large clinical trials.

Acquired Immunodeficiency Syndrome↗