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Biomedical subjects

P A Volberding

Publications and source records attributed to P A Volberding.

At least 55 records · Page 3Linked to original sources
PubMed1991

Pharmacokinetics of GLQ223 in rats, monkeys, and patients with AIDS or AIDS-related complex.

The pharmacokinetics of GLQ223 administered as a single short intravenous infusion to rats, monkeys, and patients with AIDS or AIDS-related complex (ARC) are presented. GLQ223 was given at a dose of 3,500 micrograms/kg of body weight to five Sprague-Dawley rats; a dose of 300 micrograms/kg was given to three cynomolgus monkeys; and doses of 1, 8, 16, 24, and 36 micrograms/kg were given to 10 patients with AIDS and 8 patients with ARC in an escalating dose design. Plasma clearance was 0.85 +/- 0.24 liter/h/kg in rats, 0.16 +/- 0.08 liter/h/kg in monkeys, and 0.13 +/- 0.07 liter/h/kg in patients with AIDS or ARC. The volume of distribution at steady state was 0.42 +/- 0.12, 0.21 +/- 0.20, and 0.18 +/- 0.50 liter/kg in rats, monkeys, and patients, respectively. The elimination half-life was 1.3 +/- 0.4, 3.7 +/- 1.5, and 3.2 +/- 1.0 h in rats, monkeys, and patients, respectively. The disposition of GLQ223 was not dose dependent within the dose range tested in patients with AIDS or ARC. Interspecies pharmacokinetic scaling resulted in a good linear correlation for plasma clearance and the volume of distribution at steady state plotted versus species body weight on a log-log scale, indicating the predictability of elimination and distribution of GLQ223 among species. Allometric equations derived may be useful for the prediction of doses and dosage regimens to be used in animal models.

AIDS-Related Complex↗
PubMed1991

Phase 1 study of recombinant human CD4-immunoglobulin G therapy of patients with AIDS and AIDS-related complex.

The safety and pharmacokinetics of recombinant CD4-immunoglobulin G (rCD4-IgG) were evaluated in a phase 1 study with dose escalation. A total of 16 patients, 6 with AIDS and 10 with AIDS-related complex, were evaluated at two university-affiliated hospital clinics. rCD4-IgG was administered once weekly for 12 weeks to four patients each at doses of 0.03, 0.1, 0.3, and 1.0 mg/kg of body weight. Dosing was intravenous for two patients in the 1.0-mg/kg dose group and intramuscular for the remaining patients. Dosing was intravenous for two patients in the 1.0-mg/kg dose group and intramuscular for the remaining patients. Pharmacokinetic, toxicity, and immunologic variables were monitored with all patients. Administration of rCD4-IgG was well tolerated, with no important clinical or immunologic toxicities noted. No subjects required dose reduction or discontinuation of therapy due to toxicity. No consistent changes were seen in human immunodeficiency virus antigen levels in serum or CD4 lymphocyte populations. The volume of distribution was small, and compared with that of rCD4, the half-life of the hybrid molecule was markedly prolonged following intramuscular or intravenous administration. The rate and extent of absorption following intramuscular dosing were variable. Intramuscular administration of rCD4-IgG appears to be inferior to intravenous dosing from a pharmacokinetic standpoint, with lower peak concentrations and variable absorption. After intravenous administration, peak concentrations of rCD4-IgG in serum (20 to 24 micrograms/ml) that have shown antiviral activity in vitro against more sensitive clinical isolates of human immunodeficiency virus were achieved. The peak concentrations in serum after intramuscular administration were below these levels. Treatment with rCD4-IgG was well tolerated at the doses administered to patients in this study but did not result in significant changes in CD4 lymphocyte counts or p24 antigen levels in serum.

AIDS-Related Complex↗
PubMed1991

Drug level monitoring in a double-blind multicenter trial: false-positive zidovudine measurements in AIDS clinical trials group protocol 019.

Twenty-three different laboratories using four different assay methods reported zidovudine (ZDV; azidothymidine) measurements in a double-blind trial of ZDV for asymptomatic human immunodeficiency virus-infected patients (AIDS Clinical Trials Group Protocol 019). The risk of false-positive ZDV measurements was defined with coded specimens containing no ZDV in a quality control testing program. This testing identified six problem laboratories which reported ZDV levels of greater than or equal to 100 ng/ml for specimens with no ZDV; all of these laboratories used high-performance liquid chromatography. These six laboratories reported a disproportionately high fraction of positive assays for subjects randomized to the placebo group (31% for these 6 laboratories versus 4% for the other 17 laboratories; P less than 0.0001). The high number of false-positive ZDV results reported by these six laboratories suggested that many of the positive results that they reported for patient specimens were also false-positive results. This hypothesis was examined by retesting specimens from patients in the placebo group that had been reported as positive by these laboratories. Ninety percent (19 of 21) of these specimens were negative on retesting at the reference laboratory. These results confirm the hypothesis; they demonstrate the need for quality control testing to avoid the misinterpretation of multicenter trials because of incorrect laboratory data.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Clinical and virologic effects of recombinant human granulocyte-macrophage colony-stimulating factor in patients receiving chemotherapy for human immunodeficiency virus-associated non-Hodgkin's lymphoma: results of a randomized trial.

Thirty patients with human immunodeficiency virus (HIV)-associated non-Hodgkin's lymphoma (NHL) receiving chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) were randomized to receive either subcutaneous recombinant human granulocyte-macrophage colony-stimulating factor (rGM-CSF) or no additional therapy. Recombinant rGM-CSF (at a dose of 10-20 micrograms/kg/d) was given on days 1 to 10 (early rGM-CSF) to the first five patients, but was changed to days 4 to 13 (delayed rGM-CSF) of each chemotherapy cycle in subsequent patients. Compared with the control group (N = 10), the delayed rGM-CSF group (N = 11) had higher mean nadirs of the absolute neutrophil count (0.36 v 0.89 x 10(9)/L; P = .009), shorter mean durations of neutropenia (4.9 v 1.3 days; P = .02), fewer chemotherapy cycles complicated by neutropenia and fever (67% v 27%; P = .001), fewer days hospitalized for fever and neutropenia (4.9 v 1.8; P = .004), fewer reductions in chemotherapy dosages, and less frequent delays in chemotherapy administration. No significant differences were observed between patients in the control group and those in the early rGM-CSF group (N = 5). Median levels of serum HIV-1 p24 antigen decreased to 18% and 17% of baseline values in control (N = 4) and rGM-CSF groups (N = 6), respectively, 1 week following administration of the first cycle of chemotherapy. In the third week after chemotherapy, median antigen levels remained below baseline in the control group, but rose to 243% of baseline values in the rGM-CSF group (P = .01), suggesting stimulation of HIV replication. The effect of this change in HIV activity on clinical outcome of treated patients could not be determined, and therefore the clinical significance of this finding remains unclear. Complete response rates of 67%, 70%, and 60% were observed in the control, delayed rGM-CSF, and early rGM-CSF groups, respectively, with corresponding survival times of 9.0, 11.4, and 8.0 months.

Adult↗
PubMed1991

Cryotherapy for cutaneous Kaposi's sarcoma (KS) associated with acquired immune deficiency syndrome (AIDS): a phase II trial.

To assess the response and toxicity of liquid nitrogen cryotherapy for cutaneous lesions of Kaposi's sarcoma (KS) associated with AIDS, we evaluated 20 subjects with biopsy-proven KS in a phase II clinical trial. Subjects had two to four cutaneous KS indicator lesions treated with liquid nitrogen cyrotherapy. Treatment was repeated at 3 week intervals, allowing adequate healing time. On average, subjects received three treatments per lesion with a mean follow-up time of 11 weeks (range of 6-25 weeks). One treatment consisted of two freeze-thaw cycles, with thaw times ranging from 11 to 60 s per cycle. A complete response was observed in 80% of treated KS lesions and lasted a minimum of 6 weeks following the completion of therapy. Greater than 50% cosmetic improvement of KS was observed. Histopathology of treated lesions correlated poorly with cosmetic improvement. Response was not predicted by tolerance to zidovudine therapy, CD4+ cell count, presence of B symptoms, or previous chemotherapy. Subjects without prior history of opportunistic infection (OI) were more likely to have a better response than those with a prior history of OI. Subjects tolerated cryotherapy well. Blistering occurred frequently, but local pain was limited and relieved by acetaminophen. Secondary infection did not occur. Based on this study, we recommend cryotherapy to subjects with cutaneous KS lesions. Liquid nitrogen cryotherapy is easily applied as a primary therapy, and may also have a role in the treatment of cutaneous KS lesions that respond slowly or show incomplete cosmetic improvement with systemic therapies.

Acquired Immunodeficiency Syndrome↗
PubMed1991

HIV antigen variability in ARC/AIDS.

To define the natural variability of human immunodeficiency virus p24 antigen (HIV Ag) over time in untreated HIV-infected patients, we analyzed the percentage change of serum HIV Ag in 40 antigenemic ARC/AIDS subjects receiving placebo in a 24 week clinical trial. When grouped by month of observation, no differences in HIV Ag change were seen among all five 1 month observation periods (p greater than 0.4). After all 105 monthly changes (median of 3 per subject) were pooled, the mean monthly HIV Ag change was 0% change (standard deviation: 77% increase, 44% decrease). Furthermore, HIV Ag changes did not differ among all lengths of observation (from 1 to 5 months using all possible pairwise combinations of HIV Ag levels, p greater than 0.4). CD4 T-cell changes over the whole study did not correlate with HIV Ag changes over the same period. Knowledge of this broad HIV Ag variability should be useful in calculating sample size and in choosing categorical responses unlikely to occur spontaneously in clinical trials of antiviral agents where HIV Ag changes are used as surrogate markers of efficacy.

AIDS-Related Complex↗
PubMed1991

Treatment of AIDS-related Kaposi's sarcoma.

Kaposi's sarcoma (KS) is the most common malignancy seen in association with AIDS. Important epidemiologic trends in the occurrence of AIDS-associated Kaposi's sarcoma (AIDS-KS) have been identified, and the molecular processes associated with the development of KS are being studied intensively. It is hoped that these studies will ultimately lead to an understanding of the etiology of the disease and to a rational approach to therapy. Treatment with conventional chemotherapy, radiation therapy, biologic therapy, and various local treatment modalities is effective for palliation of clinical problems associated with AIDS-KS, although the toxicities of these approaches may be problematic. Therapy for AIDS-KS must be individualized, with appropriate consideration given to the patient's overall clinical and immunologic status.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Aerosolized pentamidine for prophylaxis against Pneumocystis carinii pneumonia. The San Francisco community prophylaxis trial.

BACKGROUND AND METHODS: Pneumocystis carinii pneumonia (PCP) is the most frequent life-threatening opportunistic infection associated with human immunodeficiency virus (HIV) infection. To assess the possible value of aerosolized-pentamidine prophylaxis in different doses, a controlled clinical trial was begun in 1987 with 408 subjects at 12 treatment centers. The participants were randomly assigned to receive 30 mg of pentamidine every two weeks, 150 mg every two weeks, or 300 mg every four weeks. RESULTS: Eighteen months after randomization, the subjects in the 300-mg arm had had 8 confirmed episodes of PCP while receiving treatment, as compared with 22 in the 30-mg arm (P = 0.0008). The 150-mg arm had intermediate results but ones not significantly different from those of the 300-mg arm. Participants with previous episodes of PCP and CD4-cell counts less than 200 per cubic millimeter were at the highest risk for PCP. CONCLUSIONS: Aerosolized pentamidine was effective for prophylaxis against PCP in patients infected with HIV, according to the dose and schedule of administration. It and zidovudine were well tolerated together and had independent prophylactic benefits.

Adult↗
PubMed1990

Zidovudine in asymptomatic human immunodeficiency virus infection. A controlled trial in persons with fewer than 500 CD4-positive cells per cubic millimeter. The AIDS Clinical Trials Group of the National Institute of Allergy and Infectious Diseases.

Zidovudine (AZT) is a potent inhibitor of the replication of the human immunodeficiency virus (HIV), and it has been shown to improve survival in advanced HIV disease. We conducted a randomized, double-blind trial in adults with asymptomatic HIV infection who had CD4+ cell counts of fewer than 500 per cubic millimeter on entry into the study. The subjects (92 percent male) were randomly assigned to one of three treatment groups: placebo (428 subjects); zidovudine, 500 mg per day (453); or zidovudine, 1500 mg per day (457). After a mean follow-up of 55 weeks (range, 19 to 107), 33 of the subjects assigned to placebo had the acquired immunodeficiency syndrome (AIDS), as compared with 11 of those assigned to receive 500 mg of zidovudine (P = 0.002; relative risk, 2.8; 95 percent confidence interval, 1.4 to 5.6) and 14 of those assigned to receive 1500 mg of zidovudine (P = 0.05; relative risk, 1.9; 95 percent confidence interval, 1.0 to 3.5). In the three treatment groups, the rates of progression (per 100 person-years) to either AIDS or advanced AIDS-related complex were 7.6, 3.6, and 4.3, respectively. As compared with those assigned to placebo, the subjects in the zidovudine groups had significant increases in the number of CD4+ cells and significant declines in p24 antigen levels. In the 1500-mg zidovudine group, severe hematologic toxicity (anemia or neutropenia) was more frequent than in the other groups (P less than 0.0001). In the 500-mg zidovudine group, nausea was the only toxicity that was significantly more frequent (in 3.3 percent) than in the placebo group (P = 0.001). We conclude that zidovudine is safe and effective in persons with asymptomatic HIV infection and fewer than 500 CD4+ cells per cubic millimeter. Additional study will be required to determine whether such treatment will ultimately improve survival for persons infected with HIV.

AIDS-Related Complex↗
PubMed1990

Red cell transfusion therapy for anemia in patients with AIDS and ARC: incidence, associated factors, and outcome.

The records of the San Francisco General Hospital (SFGH) Blood Bank were reviewed, and 263 likely AIDS and AIDS-related complex (ARC) patients were identified, who received 1545 units of packed red cells (PBRCs) between July 1, 1987, and June 30, 1988. A probability sample of 80 of these patients was selected randomly for detailed chart review. Of this sample, 78 (98%) were confirmed to have AIDS (86%) or ARC (14%). On the basis of the yearly census of the SFGH AIDS clinic, a transfusion incidence of 0.89 PRBC units per patient per year for patients with AIDS and 0.27 PRBC units per patient per year for those with ARC was estimated. Whereas 26 percent of the 177 transfusions studied in detail involved more than one associated (possibly causative) factor, antimicrobial drug therapy, zidovudine therapy, and disseminated Mycobacterium avium complex (MAC) infection were the sole associated factors in 20, 14, and 12 percent of the transfusions, respectively. To assess the role of MAC, the 263 transfused patients were compared with the 574 patients whose blood was submitted to the SFGH Mycobacteriology Laboratory during the same period. Patients whose blood yielded MAC had a relative risk of 5.2 for transfusion-requiring anemia. In 80 percent of cases, the patient returned home after transfusion. Most PRBC transfusions administered to AIDS or ARC patients were optimal therapy.

AIDS-Related Complex↗
PubMed1990

The safety and pharmacokinetics of GLQ223 in subjects with AIDS and AIDS-related complex: a phase I study.

A phase I dose-escalation study was performed to evaluate the safety and pharmacokinetics of a single intravenous infusion of GLQ223 in subjects with AIDS and AIDS-related complex (ARC). The active ingredient in GLQ223 is trichosanthin. Trichosanthin, imported from China, is the active drug in community-initiated treatment programs for patients with HIV infection. Eighteen subjects were enrolled, 10 with AIDS and eight with ARC. All subjects were monitored for tolerance and toxicity. Immunological and virological parameters were also followed. GLQ223 administration was not associated with notable toxicity with the exception of one subject who experienced a severe neurological adverse reaction. No consistent or sustained changes in CD4+ lymphocyte populations or HIV antigen levels were observed. Serum concentrations of GLQ223 that were comparable to concentrations shown to have antiviral activity in vitro were achieved transiently but may not have been maintained for a sufficient duration to exert antiretroviral effects. Further studies are indicated to determine pharmacodynamic properties of GLQ223, its optimal dosing schedule, and whether GLQ223 or related molecules will be useful in the treatment of HIV infection.

AIDS-Related Complex↗
PubMed1989

The HIV epidemic: medical and social challenges.

The sudden appearance, rapid spread, and devastating clinical impact of HIV infection in Africa, Europe and North America has created a medical problem unprecedented in the modern era. HIV is sexually transmitted, afflicts sexual and racial minorities in developed countries, and appears likely to be fatal and incurable in a majority of infected people. Its epidemiology (transmission and natural history) and clinical manifestations have been well described, but treatment of HIV remains minimally effective, creating only a short respite from progressive deterioration. In the absence of effective vaccination, HIV will continue to spread, abetted by a long period of asymptomatic carriage during which carriers are infectious. It has spread internationally to most undeveloped countries aided by fear and ignorance. The problem will resist simple technological solutions and adversely impact the lives of tens of millions of people in these areas over the next several decades. In developed countries HIV will strain medical resources and kill several million people before the end of the century. Despite the tremendous problems created by the AIDS epidemic, it has driven a remarkable expansion of virologic and immunologic understanding which promises to ultimately lead to control of not only AIDS, but a variety of other serious diseases. The following reviews of pivotal issues in AIDS research document this progress.

Acquired Immunodeficiency Syndrome↗
PubMed1989

Prolonged zidovudine therapy in patients with AIDS and advanced AIDS-related complex. AZT Collaborative Working Group.

We examined the long-term safety and efficacy of zidovudine therapy in 229 subjects with acquired immunodeficiency syndrome (AIDS) and AIDS-related complex who previously participated in a placebo-controlled study of zidovudine. One hundred two placebo recipients (delayed treatment group) and 127 zidovudine recipients (original treatment group) were followed up while receiving zidovudine therapy for a mean of 21 months. Survival rates for the original treatment group were 84.5% and 57.6% at 12 and 21 months, respectively; for the delayed treatment group, 78.8% and 64.6% at 12 and 21 months, respectively, and 78.8% and 47.5% at 12 and 21 months, respectively, for 77 subjects with AIDS and 93.0% and 71.8%, respectively, for 50 subjects with AIDS-related complex in the original treatment group. Adverse reactions decreased over time and newly observed toxic reactions were unusual. The clinical course of these subjects suggests continued survival benefits with long-term zidovudine therapy.

AIDS-Related Complex↗
PubMed1989

AIDS-associated non-Hodgkin's lymphoma in San Francisco.

The characteristics of acquired immunodeficiency syndrome-associated non-Hodgkin's lymphoma in 84 patients diagnosed and treated at San Francisco General Hospital are presented herein. While the majority were high-grade B-cell lymphomas, one cutaneous T-cell and one peripheral T-cell lymphoma were observed. In addition, three other tumors were suspicious for T-cell lymphoma. Sixty-seven percent of patients had stage IV disease, often at unusual sites. Epstein-Barr virus DNA sequences were identified in only five of 15 tumors by dot-blot analysis. Patients were treated with a variety of standard chemotherapeutic regimens, with radiation therapy alone, or with a novel chemotherapy protocol (COMET-A). No significant differences in complete response rates were observed. The most important predictor of survival was the total number of CD4-positive lymphocytes. Other predictors of survival included history of a diagnosis of acquired immunodeficiency syndrome, Karnofsky performance score, and the presence of extranodal disease. Survival was shorter among patients who received higher doses of cyclophosphamide (greater than 1 g/m2), including those treated with the COMET-A regimen. Implications for therapeutic decision making are discussed.

Acquired Immunodeficiency Syndrome↗
PubMed1989

Serum beta 2-microglobulin decreases in patients with AIDS or ARC treated with azidothymidine.

Abnormally elevated serum beta 2-microglobulin has been associated with progression of human immunodeficiency virus (HIV) disease and could reflect in vivo HIV activity. We prospectively studied the effect of azidothymidine therapy on serum beta 2-microglobulin concentration in 41 patients with AIDS or AIDS-related complex. Median beta 2-microglobulin concentration decreased from 4.02 mg/L before therapy to 3.73 mg/L at week 24 of therapy (P = .016). Individual changes in beta 2-microglobulin during azidothymidine therapy correlated with changes in serum HIV p24 antigen (Spearman, r = .42, P = .007). Also, in a randomized placebo-controlled study, median beta 2-microglobulin concentration decreased after 16 w of therapy in 5 azidothymidine-treated patients compared with levels in 7 placebo-treated controls (P = .05). Serum beta 2-microglobulin appears to be a sensitive marker for in vivo antiretroviral drug activity and may be a better marker than serum p24 antigen for early intervention trials involving antiretroviral agents.

AIDS-Related Complex↗
PubMed1989

Kaposi's sarcoma in AIDS.

Because Kaposi's sarcoma is a highly visible disease and one readily confirmed histologically, it continues to play an important role in the clinical spectrum of AIDS. At this time, it can not be confirmed whether AIDS-related Kaposi's sarcoma is caused by an initial viral infection, whether the development of an immune deficiency predisposes patients to develop this malignancy, or whether viral or other cofactors may be involved. Evaluation of therapies for AIDS-related Kaposi's sarcoma is made more difficult by the lack of natural history information. In addition, available drugs are often immunosuppressing and investigators have considerable concern in utilizing these therapies to treat Kaposi's sarcoma, a cancer that is intimately associated with immune deficiency. Extensive research continues on single-agent trials of cytotoxic agents as well as immune modulators and antiviral agents. Although considerable progress has been made in the treatment of AIDS-related Kaposi's sarcoma, therapeutic decision-making is extremely difficult. It is expected that additional trials and experimental agents will improve our ability to provide effective treatment.

Acquired Immunodeficiency Syndrome↗