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Robert Murphy

Publications and source records attributed to Robert Murphy.

9 recordsLinked to original sources
PubMed2006

An application of exposure modeling in exposure assessments for a university chemistry teaching laboratory.

Chemical exposures in a university teaching lab were assessed using a tiered approach to modeling. Zero ventilation and well mixed room models estimated air concentrations of ethyl ether, n-hexane, and methylene chloride during distillation and extraction exercises. A simple, zero ventilation model determined that health risks from the ethyl ether exercise were minimum. N-hexane and methylene chloride exposures were evaluated with higher tiered, well mixed room models. An assumption that all of the solvent evaporated during the lab resulted in estimated n-hexane concentrations well below the occupational exposure limit. Methylene chloride concentration estimates using this approach were only one-half the occupational exposure limit, so the model was refined using information on the actual amount of solvent that evaporated. This resulted in a concentration estimate approximately one-fifth of the occupational exposure limit. Air sampling was done to evaluate model performance. Measured concentrations were higher than modeled concentrations by up to a factor of two but were still below applicable occupational exposure limits. The exposure models selected were deemed useful in the assessment of exposure acceptability in these labs.

Air Pollution, Indoor↗
PubMed2005

Intrathecal mafosfamide: a preclinical pharmacology and phase I trial.

PURPOSE: Preclinical studies of mafosfamide, a preactivated cyclophosphamide analog, were performed to define a tolerable and potentially active target concentration for intrathecal (IT) administration. A phase I and pharmacokinetic study of IT mafosfamide was performed to determine a dose for subsequent phase II trials. PATIENTS AND METHODS: In vitro cytotoxicity studies were performed in MCF-7, Molt-4, and rhabdomyosarcoma cell lines. Feasibility and pharmacokinetic studies were performed in nonhuman primates. These preclinical studies were followed by a phase I trial in patients with neoplastic meningitis. There were five dose levels ranging from 1 mg to 6.5 mg. Serial CSF samples were obtained for pharmacokinetic studies in a subset of patients with Ommaya reservoirs. RESULTS: The cytotoxic target exposure for mafosfamide was 10 micromol/L. Preclinical studies demonstrated that this concentration could be easily achieved in ventricular CSF after intraventricular dosing. In the phase I clinical trial, headache was the dose-limiting toxicity. Headache was ameliorated at 5 mg by prolonging the infusion rate to 20 minutes, but dose-limiting headache occurred at 6.5 mg dose with prolonged infusion. Ventricular CSF mafosfamide concentrations at 5 mg exceeded target cytotoxic concentrations after an intraventricular dose, but lumbar CSF concentrations 2 hours after the dose were less than 10 micromol/L. Therefore, a strategy to alternate dosing between the intralumbar and intraventricular routes was tested. Seven of 30 registrants who were assessable for response had a partial response, and six had stable disease. CONCLUSION: The recommended phase II dose for IT mafosfamide, administered without concomitant analgesia, is 5 mg over 20 minutes.

Animals↗
PubMed2005

Integrated Modeling Program, Applied Chemical Theory (IMPACT).

We provide an overview of the IMPACT molecular mechanics program with an emphasis on recent developments and a description of its current functionality. With respect to core molecular mechanics technologies we include a status report for the fixed charge and polarizable force fields that can be used with the program and illustrate how the force fields, when used together with new atom typing and parameter assignment modules, have greatly expanded the coverage of organic compounds and medicinally relevant ligands. As we discuss in this review, explicit solvent simulations have been used to guide our design of implicit solvent models based on the generalized Born framework and a novel nonpolar estimator that have recently been incorporated into the program. With IMPACT it is possible to use several different advanced conformational sampling algorithms based on combining features of molecular dynamics and Monte Carlo simulations. The program includes two specialized molecular mechanics modules: Glide, a high-throughput docking program, and QSite, a mixed quantum mechanics/molecular mechanics module. These modules employ the IMPACT infrastructure as a starting point for the construction of the protein model and assignment of molecular mechanics parameters, but have then been developed to meet specialized objectives with respect to sampling and the energy function.

Computer Simulation↗
PubMed2004

Long-term efficacy and safety of atazanavir with stavudine and lamivudine in patients previously treated with nelfinavir or atazanavir.

The purpose of the study was to determine long-term efficacy, safety, and tolerability of atazanavir plus stavudine/lamivudine in 346 HIV-infected patients previously treated with atazanavir or nelfinavir. BMS AI424-044 is an ongoing, multicenter, international, open-label, rollover/switch study initiated in June 2001. Patients completing >or=48 weeks in trial BMS AI424-008 with a plasma HIV RNA viral load <10,000 copies/mL were eligible to continue on atazanavir (400 or 600 mg) or to switch from nelfinavir to atazanavir (400 mg) once daily. Antiviral efficacy, change in CD4 cell counts, and effect on lipid parameters were measured. After 24 weeks of atazanavir use in BMS AI424-044, 83%, 85%, and 87% of the atazanavir 400-mg, atazanavir 600-mg, and nelfinavir-to-atazanavir-switched patients, respectively, had HIV RNA levels <400 copies/mL compared with 76%, 76%, and 63%, respectively, at week 48 of BMS AI424-008. Atazanavir-treated patients showed minimal changes in lipid levels compared with baseline. Patients switched from nelfinavir to atazanavir showed significant mean percent decreases in total cholesterol (-16%), fasting low-density lipoprotein cholesterol (-21%), and fasting triglycerides (-28%) (P<0.0001) by week 12 of atazanavir treatment. No new safety issues were identified, and the overall incidence of treatment-emergent adverse events during BMS AI424-044 was comparable across treatment groups. Atazanavir was safe, tolerable, and effective during extended use and in patients switched from nelfinavir. Extended atazanavir use resulted in continued viral suppression and lipid changes that were not clinically relevant. In virologically suppressed nelfinavir-treated patients switched to atazanavir, virologic improvement continued, whereas nelfinavir-induced lipid elevations were reversed within 12 weeks, approaching pretreatment values.

Adult↗
PubMed2004

Evaluating therapeutic vaccines in patients infected with HIV.

Long-term survival of HIV infection can mean decades of treatment for a patient, with major side effects and costs that limit their efficacy and accessibility. Although antiretroviral therapy remains the only standard of care, alternative therapeutic strategies must be found to ensure efficient and safe clinical management of the disease in the long term. Therapeutic immunization against HIV might be a significant approach to enhancing immune control of the virus and limiting disease progression and thus the requirement for medication. Several anti-HIV vaccines are currently being evaluated in attempts to prolong periods of treatment interruption in HIV patients. The design and end-points of clinical trials, and the clinical settings in which these new strategies should be evaluated and will be of benefit, have yet to be defined and are the focus of this review.

AIDS Vaccines↗
PubMed2002

Use of filgrastim as adjuvant therapy in patients with AIDS-related cytomegalovirus retinitis.

BACKGROUND: Neutropenia in AIDS predisposes to bacterial infection. Granulocyte colony-stimulating factor (filgrastim) can reverse neutropenia. OBJECTIVE: To determine the effects of filgrastim on bacterial infections, hospitalization, and mortality in patients with cytomegalovirus retinitis and AIDS. METHODS: Using a person-time analysis, a retrospective cohort study of filgrastim adjuvant therapy in three multicenter clinical trials of anti-cytomegalovirus therapy during the period 1990-1997 measured filgrastim use, bacterial infections, and mortality. RESULTS: Of 719 patients, 379 patients used filgrastim for 31% of the follow-up time. There was an inverse relationship between the 389 confirmed bacterial infections, including 186 bacteremias, and absolute neutrophil counts. Before adjustment for CD4 T-cells counts and antibiotic/antiretroviral therapy, filgrastim was associated with reduced risk of catheter-related bacteremia [relative risk (RR), 0.52; P = 0.02] and repeat bacterial infection (RR, 0.41; P = < 0.01). After adjustment, the RR of catheter-related bacteremia with filgrastim use was decreased (RRadj, 0.69; P = 0.16) and the RR of repeat bacterial infection with filgrastim use was of marginal significance (RRadj, 0.57; P = 0.07), possibly due to the confounding effect of trimethoprim-sulfamethoxazole on all bacteremia (RRadj, 0.55; P = < 0.01). Unrelated to bacteremia, filgrastim use was associated with a 56% reduction in mortality (P < 0.01). CONCLUSIONS: There was a large survival benefit associated with filgrastim use in this study but the reasons for this benefit are unclear. Although a reduction in crude risk of some bacterial infections with filgrastim use was detected, after adjustment for potentially confounding factors these risks were smaller and no longer statistically significant.

AIDS-Related Opportunistic Infections↗
PubMed2002

HIV-1 genotype and phenotype correlate with virological response to abacavir, amprenavir and efavirenz in treatment-experienced patients.

OBJECTIVE: To assess the safety and efficacy of three new drugs in patients with antiretroviral failure and to correlate retrospectively baseline factors with virological response. DESIGN AND SETTING: Open-label, 48-week, single-arm, multi-center phase II trial conducted at nine US university or government clinics and private practices. PATIENTS AND INTERVENTIONS: Patients with HIV-1 RNA > or =500 copies/ml despite > or =20 weeks of treatment with at least one protease inhibitor received abacavir 300 mg twice a day, amprenavir 1200 mg twice a day and efavirenz 600 mg once a day. Other antiretrovirals were prohibited until week 16 except for substitutions for possible abacavir hypersensitivity. MAIN OUTCOME MEASURES: HIV RNA at weeks 16 and 48. RESULTS: A total of 101 highly treatment-experienced patients enrolled; 60 were naive to non-nucleoside analog reverse transcriptase inhibitors (NNRTI). HIV RNA < 400 copies/ml was attained in 25 out of 101 (25%) patients at 16 weeks (35% of NNRTI-naive and 10% of -experienced patients) and 23 (23%) patients at 48 weeks (33% of naive and 7% of experienced patients). CD4 cells increased by a median of 15 x 10(6) and 43 x 10(6) cells/l at weeks 16 and 48, respectively. Drug-related rash occurred in 50 out of 99 (51%) of patients, and 17 out of 99 (17%) permanently discontinued one or more drugs as a result. Lower baseline viral load, fewer NNRTI-related mutations, absence of decreased abacavir (> or =4-fold) and efavirenz (> or =10-fold) susceptibility, and greater number of drugs to which virus was susceptible were associated with virological response at week 16. CONCLUSIONS: Abacavir, amprenavir and efavirenz durably reduced HIV RNA and increased CD4 cell counts in a subset of treatment-experienced adults. Baseline viral load and some genotypic and phenotypic markers of resistance correlated with HIV RNA response.

Adult↗