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Biomedical subjects

M A Jacobson

Publications and source records attributed to M A Jacobson.

At least 73 records · Page 4Linked to original sources
PubMed1994

Relationship between plasma concentrations of 3'-deoxy-3'-fluorothymidine (alovudine) and antiretroviral activity in two concentration-controlled trials.

Two concentration-controlled trials (CCTs) defined the relationship between plasma concentrations of 3'-deoxy-3'-fluorothymidine (alovudine) and changes in surrogate markers of antiretroviral activity. In an initial open-label CCT involving 14 subjects infected with human immunodeficiency virus (HIV), unacceptable hematologic toxicity occurred when the area under the concentration-time curve during a 12-h dosing interval (AUC12) was > or = 300 ng*h/mL. Consequently, 46 subjects were assigned to AUC12s of 50, 100, or 200 ng*h/mL for up to 16 weeks in a prospective, randomized, double-blind CCT. Alovudine caused a concentration-dependent reduction in p24 antigen and peripheral blood mononuclear cell HIV titers within 4 weeks of start of treatment. The AUC12 producing a 50% reduction in p24 (108 ng*h/mL) had a trough concentration identical to the reported IC50 of alovudine in HIV-infected H9 cells. It may be possible to predict the antiretroviral activity of certain nucleoside analogues as a function of plasma drug concentration.

Adult↗
PubMed1994

Phase II dose-ranging trial of foscarnet salvage therapy for cytomegalovirus retinitis in AIDS patients intolerant of or resistant to ganciclovir (ACTG protocol 093). AIDS Clinical Trials Group of the National Institute of Allergy and Infectious Diseases.

OBJECTIVE: To document response to foscarnet salvage therapy in patients with cytomegalovirus (CMV) retinitis who are intolerant of or resistant to ganciclovir. METHODS: Patients with AIDS and CMV retinitis who had documented hematologic intolerance or resistance to ganciclovir therapy received an induction course of foscarnet, 60 mg/kg every 8 h for 14 days, and subsequent chronic maintenance foscarnet therapy at a daily dose of 60, 90 or 120 mg/kg/day. The first 87 patients were randomly assigned to receive maintenance foscarnet at a dose of 60 or 90 mg/kg/day; all subsequent patients were assigned a maintenance dose of 120 mg/kg/day. RESULTS: A total of 156 evaluable patients were enrolled. Median time to retinitis progression and survival did not differ significantly among groups assigned to different maintenance foscarnet doses. Among patients with retinitis progression documented ophthalmologically occurring at < or = 2 week intervals, despite optimal doses of ganciclovir, time to progression on foscarnet therapy was a median 8 weeks at all doses studied. By dose assignment, there were no significant differences in serious drug-associated toxicity, although trends toward increased renal and hypocalcemic adverse events were observed at higher maintenance doses. CONCLUSION: In patients intolerant of ganciclovir, salvage foscarnet therapy resulted in a longer time to retinitis progression than reported previously in historic controls who terminated ganciclovir therapy. In patients who exhibited clinical resistance to ganciclovir, foscarnet appeared to have efficacy in controlling retinitis. No significant differences in either efficacy or toxicity were observed in the range of foscarnet maintenance doses studied.

AIDS-Related Opportunistic Infections↗
PubMed1994

Pharmacodynamic relationship of pharmacokinetic parameters of maintenance doses of foscarnet and clinical outcome of cytomegalovirus retinitis.

The pharmacodynamic relationship between a range of foscarnet exposure measurements obtained from studying nine patients receiving ongoing maintenance therapy for cytomegalovirus retinitis and a range of efficacy values (days to retinitis progression) obtained by independent examination of serial retinal photographs from the same nine patients was analyzed. In the resulting proportional hazards models, the foscarnet area under the concentration-time curve approached statistical significance (P = 0.11) as a predictor of decreased risk of retinitis progression.

Acquired Immunodeficiency Syndrome↗
PubMed1994

Phase I trial of valaciclovir, the L-valyl ester of acyclovir, in patients with advanced human immunodeficiency virus disease.

Valaciclovir, the L-valyl ester of acyclovir, is rapidly and extensively converted in humans to acyclovir after oral administration by first-pass metabolism. A phase I study was conducted in two cohorts of volunteers with advanced human immunodeficiency virus (HIV) disease (absolute CD4 lymphocyte count of < 150 cells per microliters) who received oral valaciclovir at dosages of 1,000 or 2,000 mg four times daily for 30 days. All patients were clinically stable without any changes in underlying HIV-related medications for > or = 6 weeks prior to entry in study; these medications were continued throughout the study. Multiple-dose administration of valaciclovir showed a generally favorable safety profile. Nausea, vomiting, diarrhea, and abdominal pain each were reported in < or = 31% of the patients; of these symptoms, only one episode of diarrhea was considered causally related to valaciclovir exposure. Four patients developed neutropenia (two at each dose level) which was not clinically significant. There were no renal or neurologic adverse events. Valaciclovir was rapidly absorbed and converted to acyclovir, with plasma valaciclovir levels generally undetectable or levels of < or = 0.4 microgram/ml. After 3 h postdosing, valaciclovir was not detectable in plasma. Acyclovir was measurable in plasma as early as 15 min following valaciclovir dosing, and plasma concentrations of acyclovir greatly exceeded those of valaciclovir. The mean values for the maximum concentration of drug in plasma, time to maximum concentration of drug in plasma, area under the concentration-time curve from 0 h to infinity, and apparent half-life of acyclovir obtained after single- and multiple-dose valaciclovir administration in HIV-infected patients were similar to those reported in normal healthy volunteers. The time to maximum concentration in serum and half-life of acyclovir after valaciclovir administration were approximately 2 and 3 h, respectively, which were similar to those reported after oral administration of acyclovir itself. The mean trough and peak acyclovir concentrations and the daily area under the concentration-time curve acyclovir values at steady state were 2.5 and 8.4 micrograms/ml and 120 h micrograms/ml, respectively, after a dosage of 2,000 mg of valaciclovir four times daily. These values were approximately fivefold greater than those achieved with high dosages of oral acyclovir (800 mg, five times daily) and were not affected by continued use of medications necessary for management of advanced HIV disease. Thus, 2,000 mg of valaciclovir given orally four times daily should be evaluated for its potential efficacy in suppressing cytomegalovirus and other herpes group virus infections not optimally managed with current oral acyclovir therapy.

Acyclovir↗
PubMed1994

Central venous catheter infections in AIDS patients receiving treatment for cytomegalovirus disease.

Central venous catheters (CVC) are commonly used to deliver daily intravenous medications to patients with AIDS, and CVC-associated bacterial infections have been a cause of substantial morbidity in such patients. Although previous studies have reported rates of CVC-associated infections in AIDS patients, none has compared rates by type of intravenous drug regimen used or by whether CVCs were percutaneously placed or tunneled under the skin. The charts of all AIDS patients diagnosed with cytomegalovirus (CMV) end-organ disease at San Francisco General Hospital between 1985 and 1990 were reviewed for evidence of CVC use and CVC-associated infection. Infection rates and time to infection were analyzed for serious CVC-associated infections (requiring catheter removal or hospitalization for intravenous antibiotic therapy) by type of anti-CMV therapy administered (ganciclovir versus foscarnet) and by type of CVC (tunneled versus percutaneous placement). Fifty-four patients had 72 CVCs in use for 11,622 days of intravenous anti-CMV therapy. There were 36 CVC-associated infections of which 23 were categorized as serious (rate, 0.20/100 catheter days). In patients receiving either ganciclovir or foscarnet therapy, we found no significant difference in serious infection rates or in infection-free survival time (216 vs. 282 days, p = 0.7). However, serious CVC infection-free time was significantly longer in patients with tunneled than with percutaneous CVCs (419 vs. 195 days, p = 0.018). The use of ganciclovir compared to foscarnet in the treatment of AIDS-related CMV disease was not associated with a greater risk of serious catheter-related infection.(ABSTRACT TRUNCATED AT 250 WORDS)

AIDS-Related Opportunistic Infections↗
PubMed1993

Molecular cloning and characterization of the human A3 adenosine receptor.

The human A3 adenosine receptor was cloned from a striatal cDNA library using a probe derived from the homologous rat sequence. The cDNA encodes a protein of 318 amino acids and exhibits 72% and 85% overall identity with the rat and sheep A3 adenosine receptor sequences, respectively. Specific and saturable binding of the adenosine receptor agonist N6-(4-amino-3-[125I]iodobenzyl)adenosine [125I]ABA was measured on the human A3 receptor stably expressed in Chinese hamster ovary cells with a Kd = 10 nM. The potency order for adenosine receptor agonists was N-ethylcarboxamidoadenosine (NECA) > or = (R)-N6-phenyl-2-propyladenosine [(R)-PIA] > N6-cyclopentyladenosine (CPA) > (S)-N6-phenyl-2-propyladenosine [(S)-PIA]. The human receptor was blocked by xanthine antagonists, most potently by 3-(3-iodo-4-aminobenzyl)-8-(4-oxyacetate)phenyl-1-propylxanthine (I-ABOPX) with a potency order of I-ABOPX > 1,3-dipropyl-8-(4-acrylate)phenylxanthine > or = xanthine amino congener >> 1,3-dipropyl-8-cyclopentylxanthine. Adenosine, NECA, (R)- and (S)-PIA, and CPA inhibited forskolin-stimulated cAMP accumulation by 30-40% in stably transfected cells; I-ABA is a partial agonist. When measured in the presence of antagonists, the dose-response curves of NECA-induced inhibition of forskolin-stimulated cAMP accumulation were right-shifted. Antagonist potencies determined by Schild analyses correlated well with those established by competition for radioligand binding. The A3 adenosine receptor transcript is widespread and, in contrast to the A1, A2a, and A2b transcripts, the most abundant expression is found in the lung and liver. The tissue distribution of A3 mRNA is more similar to the widespread profile found in sheep than to the restricted profile found in the rat. This raises the possibility that numerous physiological effects of adenosine may be mediated by A3 adenosine receptors.

Adenosine↗
PubMed1993

Valaciclovir (BW256U87): the L-valyl ester of acyclovir.

Valaciclovir (BW256U87) is an L-valyl ester of acyclovir, which is extensively and almost completely converted to acyclovir. In healthy human volunteers, single valaciclovir doses of 100-1000 mg resulted in dose-proportional increases in acyclovir area under the curve (AUC). The 1,000 mg dose produced an acyclovir peak plasma concentration (Cmax) of 5-6 micrograms/ml, AUC6 of 19 hr. micrograms/ml, time to maximum plasma concentration (Tmax) of 1-2 hr, and half-life (T1/2) of 2.8 hr. Plasma valaciclovir peak levels were < 0.3 micrograms/ml, and the prodrug was undetectable after 3 hr. Multiple valaciclovir doses of 250-2,000 mg given four times daily for 10 days resulted in dose-proportional increases in acyclovir Cmax. There were less than proportional increases in the AUCs. No serious or unexpected adverse events or laboratory abnormalities were reported. In volunteers with advanced human immunodeficiency virus (HIV) disease (absolute CD4 lymphocyte count < 150 cells/microliters), acyclovir and valaciclovir pharmacokinetic results were nearly identical to those in healthy volunteers. At the 2 g dose administered four times daily, steady-state acyclovir Cmax = 8.4 micrograms/ml, Tmax = 2.0 hr, AUC6 = 30.5 hr. micrograms/ml, and T1/2 = 3.3 hr. Nausea, vomiting, diarrhoea, and abdominal pain were commonly reported; however, only one adverse event (diarrhoea) was causally linked to valaciclovir exposure. There were no renal or neurologic adverse events. Valaciclovir is well absorbed and is rapidly converted to acyclovir, resulting in three- to fourfold higher acyclovir levels than can be achieved with oral acyclovir, even in patients with advanced HIV disease. The safety profile is generally favourable, with no evidence of nephrotoxicity or neurotoxicity.

Acyclovir↗
PubMed1993

Expression, purification and characterization of multigram amounts of a recombinant hybrid HV1-HV2 hirudin variant expressed in Saccharomyces cerevisiae.

Hirudin (HIR), derived from leeches, and tick anticoagulant peptide (TAP) are polypeptide protease inhibitors of thrombin and coagulation factor Xa (fXa), respectively, and they have both shown utility in vitro and in vivo as potent antithrombotic agents. A thorough side-by-side comparison of the in vivo efficacy of factor Xa inhibition compared to thrombin inhibition by TAP and HIR, respectively, required purification and characterization of multigram amounts of hirudin. Therefore, a recombinant Saccharomyces cerevisiae strain was developed using a plasmid containing the gene encoding the MF alpha 1 preproleader, a synthetic hybrid HV1-HV2 HIR gene, and a galactose-inducible promoter which directed the secretion of 44 mg/liter of recombinant HIR (rHIR) after induction. rHIR was purified by a process that consisted of two chromatographic steps and decolorization. Total yield for the purification process was 3.6 g, or 41%. This process gave 59-fold purification of rHIR that was judged to be > 96% pure with regard to polypeptide content by capillary zonal electrophoresis and reversed-phase high-performance liquid chromatography. Single, unique N- and C-termini were obtained by sequencing and were identical to those predicted from the deduced sequence of the cDNA. Determination of the dissociation constant, by thrombin:hirudin inhibition reaction, and anticoagulant activity, by the activated partial thromboplastin time, demonstrated that the hybrid rHIR HV1-HV2 protein discussed in this report was essentially equipotent with rHIR preparations HV1 and HV2 reported by others.

Amino Acid Sequence↗
PubMed1993

Tolerability of combined ganciclovir and didanosine for the treatment of cytomegalovirus disease associated with AIDS.

Ganciclovir is one of only two drugs licensed by the U.S. Food and Drug Administration for the treatment of opportunistic cytomegalovirus (CMV) disease. The combination of ganciclovir and zidovudine has been reported to be poorly tolerated because of dose-limiting hematologic toxicity; thus we retrospectively examined the tolerability of combination therapy with ganciclovir and didanosine in 32 patients with AIDS. These patients were receiving ganciclovir for CMV disease in addition to didanosine in the Videx U.S. Expanded Access Program. During the period of combined therapy, dose-limiting hematologic toxicity (absolute neutrophil count, < 500 cells/microL) developed in only 9.4% of patients and severe anemia (hemoglobin level, < 8.0 g/dL) in only 12.5%. Rates of dose-limiting intolerance to didanosine were similar to those previously reported in the Expanded Access Program. Overall, 15 of 32 patients in the current study tolerated therapeutic doses of didanosine in combination with ganciclovir; in contrast, only 5 of 29 patients tolerated zidovudine (600 mg/d) in combination with ganciclovir in the largest trial of therapy with this combination whose results have been published to date (P = .02, Fisher's exact test). Since recent data suggest that the administration of some form of antiretroviral therapy prolongs survival in patients with CMV retinitis, coadministration of didanosine with ganciclovir should be considered for such patients who do not tolerate other regimens with activity against both retroviruses and CMV.

AIDS-Related Opportunistic Infections↗
PubMed1993

Randomized, placebo-controlled trial of rifampin, ethambutol, and ciprofloxacin for AIDS patients with disseminated Mycobacterium avium complex infection.

Patients with AIDS and disseminated Mycobacterium avium complex (MAC) infection received rifampin (600 mg) plus ethambutol (25 mg/kg) plus ciprofloxacin (750 mg) or matching placebos daily for 8 weeks. Patients were monitored every 2 weeks clinically and by quantitating MAC colony-forming units (cfu) per milliliter of blood. Analysis of baseline characteristics revealed no significant differences between groups. After 8 weeks, MAC cfu had decreased by > or = 1 log/mL in 4 of 9 treated patients versus 0 of 10 placebo recipients while increasing by > or = 1 log/mL in 1 and 7, respectively (P = .006). While the average combined clinical response score declined in both groups, it tended to decrease less in treated patients (P = .36). On the other hand, dose-limiting toxicity (primarily nausea and adverse drug interactions) occurred in 9 of 12 treatment versus 1 of 12 placebo patients (P = .005). Combined rifampin [corrected]-ethambutol-ciprofloxacin therapy for disseminated MAC infection had significant microbiologic efficacy with some evidence of clinical efficacy but was associated with drug intolerance.

AIDS-Related Opportunistic Infections↗
PubMed1993

A dose-ranging study of daily maintenance intravenous foscarnet therapy for cytomegalovirus retinitis in AIDS.

Thirty-two patients with AIDS and previously untreated cytomegalovirus retinitis completed an induction course of foscarnet, 60 mg/kg every 8 h for 14 days, had retinitis stabilize, and were then randomly assigned to receive foscarnet maintenance as either a 90- or 120-mg/kg/day infusion administered over 2 h. Median survival was 157 and 336 days for the 90- and 120-mg/kg/day groups, respectively (P < .001). In an independent, masked analysis of retinal photographs, median time to progression of retinitis was 31 versus 95 days (P = .13). Daily intravenous foscarnet at a dose of 120 mg/kg (adjusted for renal function) resulted in significantly longer survival and tended to increase time to retinitis progression compared to the standard 90-mg/kg/day maintenance dose. Although a substantial increase in the risk of serious toxicity at the 120-mg/kg/day dose was not observed, the small sample size in this trial limited the power to detect differences that might be clinically important.

AIDS-Related Opportunistic Infections↗
PubMed1993

An open-label dose-escalation trial of oral dehydroepiandrosterone tolerance and pharmacokinetics in patients with HIV disease.

Dehydroepiandrosterone (DHEA) is a naturally occurring adrenal steroid reported to have immunomodulatory and antiviral activity in cellular and animal models as well as modest in vitro antiretroviral activity against human immunodeficiency virus (HIV). A phase I dose-escalation study was performed to evaluate the safety and pharmacokinetics of DHEA in subjects with symptomatic HIV disease and an absolute CD4 lymphocyte count between 250 and 600 cells/microliters. Thirty-one subjects were evaluated and monitored for safety and tolerance. The oral drug was administered three times daily in doses ranging from 750 mg/day to 2,250 mg/day for 16 weeks. Some immunological and virological parameters were monitored as well. The drug was well tolerated and no dose-limiting side effects were noted. Dose proportionality was evidenced neither by the serum DHEA nor by DHEA-S time-concentration curves for the three dosing groups. However, the study cohort appeared to consist of two subpopulations with markedly different bioavailability for a given DHEA dose. No sustained improvements in CD4 counts nor decreases in serum p24 antigen or beta-2 microglobulin levels were observed. However, serum neopterin levels decreased transiently by 23-40% at week 8 compared with baseline in all dosing groups. DHEA was well tolerated by patients with mild symptomatic HIV disease; evaluation of this agent for efficacy in HIV disease would require randomized, controlled trials.

Acquired Immunodeficiency Syndrome↗
PubMed1993

Pharmacoepidemiology of adverse drug reactions in hospitalized patients with human immunodeficiency virus disease.

To evaluate the incidence, characteristics, and risk factors of adverse drug reactions (ADRs) in patients with human immunodeficiency virus (HIV) disease, we conducted was a prospective observational study of inpatients with HIV disease. The study was conducted in a public teaching hospital affiliated with the University of California, San Francisco. We reviewed daily the hospital records of all eligible inpatients throughout their hospitalization for potential ADRs. Potential ADRs were independently evaluated by two of the authors with regard to the extent of their causal association(s) with implicated drug(s) using a previously validated algorithm. Type (A, augmented; B, bizarre) and severity (mild, moderate, severe) were also evaluated. Among 495 patient admissions involving 390 eligible patients, 173 potential ADRs were identified, of which 118 (68.2%) had a probable or definite causal relationship to the implicated drugs. These probable or definite ADRs occurred among 79 (20%) eligible patients; 82 ADRs (69.5%) were classified as augmented (type A) and 36 (30.5%) were classified as bizarre (type B) reactions. Skin rash was the most frequent (17%) ADR encountered. Of the medications causing ADRs, 70% were antimicrobial drugs. Significant independent risk factors for developing ADRs included advanced stage of HIV disease, intake of a greater number of medications, and longer hospital stay. A high percentage of patients with HIV disease developed ADRs. Skin rash was the single most common kind of ADR. Advanced stage of illness and prolonged drug exposure were the only risk factors for ADRs.

Adult↗
PubMed1992

Maintenance therapy for cytomegalovirus retinitis in patients with acquired immunodeficiency syndrome: foscarnet.

The use of ganciclovir in the treatment of cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome (AIDS) is limited by marrow toxicity and by the development of resistance to this agent in CMV strains capable of causing progressive disease. Foscarnet retains activity against ganciclovir-resistant CMV and has an adverse effect profile different from that of ganciclovir. Preliminary data from studies conducted under the AIDS Clinical Trials Group (ACTG) program indicate that intravenous foscarnet maintenance therapy at 60, 90, and 120 mg/kg/day in AIDS patients with CMV retinitis successfully completing foscarnet induction therapy is associated with median times to retinitis progression of 90, 95, and greater than 123 days, respectively. An ACTG trial of foscarnet in patients failing ganciclovir therapy has been initiated, as has a trial jointly sponsored by the National Eye Institute and the National Institute of Allergy and Infectious Diseases comparing the safety and efficacy of foscarnet and ganciclovir. Also underway is a trial evaluating the effects of combination and alternating regimens of these two agents.

Antiviral Agents↗
PubMed1992

Toxicity of clindamycin as prophylaxis for AIDS-associated toxoplasmic encephalitis. Community Programs for Clinical Research on AIDS.

A double-blind, placebo-controlled trial was set up to compare clindamycin and pyrimethamine as prophylaxis for toxoplasmic encephalitis (TE) in HIV-infected patients at risk of the disorder. Interim analysis showed that clindamycin-treated patients were 4.4 (95% confidence interval 1.3-15.2) times more likely to experience an adverse effect that necessitated withdrawal of the study drug than those who received placebo. Diarrhoea and rash were reported in 16 (31%) and 11 (21%), respectively, of 52 patients treated with clindamycin (300 mg twice daily) compared with 2 (6%; p = 0.06) and none (p = 0.01) of the 32 placebo-treated patients. The clindamycin arm of the trial was prematurely terminated, although recruitment to the pyrimethamine arm continues.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Effect of foscarnet therapy on human immunodeficiency virus p24 antigen levels in AIDS patients with cytomegalovirus retinitis.

Circulating human immunodeficiency virus (HIV) p24 antigen levels were measured in 22 AIDS patients who had detectable serum antigen at baseline after induction and maintenance therapy of foscarnet for cytomegalovirus retinitis in phase I/II multicenter trials. The HIV p24 antigen levels decreased from a baseline value of 199 +/- 236 (mean +/- SD) and 140 pg/mL (median) to 106 +/- 218 and 28 pg/mL after 14 days of foscarnet induction therapy (60 mg/kg every 8 h). During chronic foscarnet maintenance, there was a sustained decrease in mean HIV p24 antigen levels below pre-foscarnet therapy baseline concentrations for a median of 16 weeks after foscarnet induction. These results provide evidence for a sustained clinical antiretroviral effect of chronic foscarnet maintenance therapy, consistent with a recent report that foscarnet-treated AIDS patients live longer than ganciclovir-treated patients.

Acquired Immunodeficiency Syndrome↗