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Biomedical subjects

O L Laskin

Publications and source records attributed to O L Laskin.

At least 19 recordsLinked to original sources
PubMed1994

Pharmacodynamics of MK-0963, a new 5 alpha-reductase inhibitor: effects on serum androgen concentrations.

The hormonal effects after a 10-day administration of a 4-azasteroid inhibitor of 5 alpha-reductase, MK-0963 (previously L-654,066), were evaluated in 35 healthy male volunteers in an increasing-dose, five-panel design. Marked suppression of serum dihydrotestosterone was observed after the once-daily administration at each active dose level (placebo, 0.1, 0.5, 1.0, 10, and 25 mg). Maximum dihydrotestosterone suppression occurred at doses greater than or equal to 10 mg. The mean percentage (+/- SE) decreases in dihydrotestosterone at 24 hours after the last dose in the groups treated with the 10 and 25 mg doses were 78% +/- 4.9% and 80% +/- 2.9%, respectively. The 25 mg dose maintained a dihydrotestosterone suppression of at least 70% for more than 6 days after the last dose. No consistent changes in serum testosterone were noted. This study shows that administration of multiple doses of MK-0963 results in a substantial suppression of serum dihydrotestosterone with no consistent influence on serum testosterone concentrations.

5-alpha Reductase Inhibitors↗
PubMed1993

A short-term clinical evaluation of L-697,661, a non-nucleoside inhibitor of HIV-1 reverse transcriptase. L-697,661 Working Group.

BACKGROUND: The non-nucleoside reverse transcriptase inhibitors are novel antiretroviral agents with selective activity in vitro against human immunodeficiency virus type 1 (HIV-1). They act through direct inhibition of reverse transcriptase and are not incorporated into DNA. METHODS: We evaluated a pyridinone non-nucleoside reverse transcriptase inhibitor, L-697,661, in separate six-week double-blind trials in patients with HIV-1 infection whose CD4 counts ranged from 200 to 500 cells per cubic millimeter (68 patients) or less than 200 cells per cubic millimeter (67 patients). Eligible patients were randomly assigned to receive L-697,661 orally in one of three doses (25 mg twice a day, 100 mg three times a day, or 500 mg twice a day) or zidovudine (100 mg five times a day). Clinical and laboratory assessments were performed weekly. Viral isolates were obtained from a subgroup of patients before and after treatment and were evaluated for in vitro sensitivity to L-697,661. RESULTS: Both L-697,661 and zidovudine were well tolerated. Transient increases in CD4 counts were noted in the patients with fewer than 200 CD4 cells per cubic millimeter who received the two higher doses of L-697,661, but not in those who received the lowest dose or zidovudine. Patients who received L-697,661 had rapid, dose-related decreases in plasma p24 antigen levels. However, this response virtually disappeared after six weeks in some patients receiving L-697,661, coincidently with the emergence of resistant viruses. This change in susceptibility was more frequent among patients receiving the higher doses of L-697,661 and was associated with amino acid substitutions at positions 103 and 181 in the HIV-1 reverse transcriptase gene. CONCLUSIONS: L-697,661 is safe and well tolerated and has significant dose-related activity against HIV-1. However, resistant strains of the virus emerge rapidly and may limit the effectiveness of non-nucleoside reverse transcriptase inhibitors as monotherapy for HIV-1 infection.

Adult↗
PubMed1993

Effect of oral acyclovir on pain resolution in herpes zoster: a reanalysis.

The most frequent complication of herpes zoster is postherpetic neuralgia, usually defined as chronic pain in the area of the exanthem that persists for at least a month after the skin lesions have healed. Several clinical studies of acyclovir showed a reduction in severity and duration of acute pain, but provided no definitive data for chronic pain. In order to determine if acyclovir therapy could reduce chronic pain, we reanalyzed data from the largest U.S. placebo-controlled treatment trial of 187 immunocompetent persons with herpes zoster. By considering pain as a continuum, we found that the median duration of pain in acyclovir recipients was 20 days vs. 62 days for their placebo counterparts (P = 0.02). Thus, acyclovir has been shown to reduce chronic zoster-associated pain. We also noted that the absence of pain at the onset of cutaneous herpes zoster did not preclude its later development.

Acyclovir↗
PubMed1992

Pharmacodynamics and tolerability of L-654,066, a steroid 5 alpha-reductase inhibitor, in men.

A four-period, two-panel single rising-dose study (0.1 to 100 mg) was conducted in healthy men to investigate the pharmacodynamics and tolerability of L-654,066, a steroid 5 alpha-reductase inhibitor. Within each panel, six subjects received L-654,066 and two subjects received placebo at each dose level; the placebo subjects changed between periods so that each subject received placebo once. Testosterone and dihydrotestosterone were measured in serum at 0, 4, 24, and 48 hours after each treatment. L-654,066 was associated with a significant reduction in serum dihydrotestosterone concentrations, which was maximal at 48 hours after dose. Forty-eight hours after treatment, mean percentage of inhibition was 24% and 39% for the 0.1 and 0.5 mg doses, respectively, and ranged from 50% to 65% at doses from 1 to 25 mg and from 70% to 75% at doses from 50 to 100 mg. Testosterone serum levels did not show any significant difference between the various treatments, including placebo.

5-alpha Reductase Inhibitors↗
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

Disseminated ecthymatous herpes varicella-zoster virus infection in patients with acquired immunodeficiency syndrome.

Herpesvirus infections are among the most common and debilitating opportunistic infections in patients with acquired immunodeficiency syndrome (AIDS), and they may have atypical clinical features. We describe the cases of three patients with AIDS in whom atypical persistent ulcerative skin lesions developed as a result of varicella-zoster virus infection. Two patients had disseminated infection without a vesicular stage; one patient had underlying asteatotic eczema. All responded well to acyclovir. One patient was treated with azidothymidine, and typical dermatomal herpes zoster subsequently developed. The profound loss of helper T cell function in AIDS may lead to multiple abnormalities in local immune response to cutaneous herpesvirus infections and may be responsible for the atypical morphology and a prolonged course.

Acquired Immunodeficiency Syndrome↗
PubMed1988

Therapy of herpes zoster with oral acyclovir.

Oral acyclovir therapy for herpes zoster has been studied in double-blind, placebo-controlled trials of two dosages, 400 mg and 800 mg five times per day for 10 days. Compared with placebo recipients, recipients of the high-dosage acyclovir experienced a significantly shortened period of viral shedding, significantly accelerated time to 50 percent scabbing, significantly accelerated time to 50 percent healing, and after two days of therapy, significantly less frequent formation of new lesions. The duration and severity of acute pain were less in acyclovir recipients, with differences in pain severity achieving statistical significance (p = 0.03) between Days 3 and 10 and correlating with the treatment differences in new lesion formation. In studies of the 400 mg five times per day dose schedule, differences between acyclovir and placebo recipients were not significant. In a six-month follow-up of recipients in the higher dosage study, the acyclovir recipients experienced less post-zoster pain than placebo recipients; differences in the prevalence of pain were most significant for the presence of a persistent pain in the first three months of follow-up. Oral acyclovir at these dosages appears to be free of adverse reactions. In summary, oral acyclovir at a dosage of 800 mg five times per day for 10 days for treatment of acute herpes zoster is superior to 400 mg five times per day and favorably alters the course of the disease.

Acyclovir↗
PubMed1987

The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial.

We conducted a double-blind, placebo-controlled trial of the efficacy of oral azidothymidine (AZT) in 282 patients with the acquired immunodeficiency syndrome (AIDS) manifested by Pneumocystis carinii pneumonia alone, or with advanced AIDS-related complex. The subjects were stratified according to numbers of T cells with CD4 surface markers and were randomly assigned to receive either 250 mg of AZT or placebo by mouth every four hours for a total of 24 weeks. One hundred forty-five subjects received AZT, and 137 received placebo. When the study was terminated, 27 subjects had completed 24 weeks of the study, 152 had completed 16 weeks, and the remainder had completed at least 8 weeks. Nineteen placebo recipients and 1 AZT recipient died during the study (P less than 0.001). Opportunistic infections developed in 45 subjects receiving placebo, as compared with 24 receiving AZT. The base-line Karnofsky performance score and weight increased significantly among AZT recipients (P less than 0.001). A statistically significant increase in the number of CD4 cells was noted in subjects receiving AZT (P less than 0.001). After 12 weeks, the number of CD4 cells declined to pretreatment values among AZT recipients with AIDS but not amonG AZT recipients with AIDS-related complex. Skin-test anergy was partially reversed in 29 percent of subjects receiving AZT, as compared with 9 percent of those receiving placebo (P less than 0.001). These data demonstrate that AZT administration can decrease mortality and the frequency of opportunistic infections in a selected group of subjects with AIDS or AIDS-related complex, at least over the 8 to 24 weeks of observation in this study.

AIDS-Related Complex↗
PubMed1987

The toxicity of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial.

We conducted a double-blind, placebo-controlled trial of oral azidothymidine (AZT) in 282 patients with the acquired immunodeficiency syndrome (AIDS) or AIDS-related complex. Although significant clinical benefit was documented (N Engl J Med 1987; 317:185-91), serious adverse reactions, particularly bone marrow suppression, were observed. Nausea, myalgia, insomnia, and severe headaches were reported more frequently by recipients of AZT; macrocytosis developed within weeks in most of the AZT group. Anemia with hemoglobin levels below 7.5 g per deciliter developed in 24 percent of AZT recipients and 4 percent of placebo recipients (P less than 0.001). Twenty-one percent of AZT recipients and 4 percent of placebo recipients required multiple red-cell transfusions (P less than 0.001). Neutropenia (less than 500 cells per cubic millimeter) occurred in 16 percent of AZT recipients, as compared with 2 percent of placebo recipients (P less than 0.001). Subjects who entered the study with low CD4 lymphocyte counts, low serum vitamin B12 levels, anemia, or low neutrophil counts were more likely to have hematologic toxic effects. Concurrent use of acetaminophen was also associated with a higher frequency of hematologic toxicity. Although a subset of patients tolerated AZT for an extended period with few toxic effects, the drug should be administered with caution because of its toxicity and the limited experience with it to date.

AIDS-Related Complex↗
PubMed1987

Concomitant herpes simplex virus type 1 and cytomegalovirus ventriculoencephalitis in acquired immunodeficiency syndrome.

Three patients with the acquired immunodeficiency syndrome (AIDS) had combined infections of the central nervous system, with both herpes simplex virus (HSV) and cytomegalovirus (CMV). All three had a diffuse ventriculoencephalitis documented at postmortem examination. The presence of HSV type 1 and CMV was confirmed microscopically with immunohistochemistry. The clinical importance of these three patients is that they establish the presence of concomitant HSV and CMV encephalitis in acquired immunodeficiency syndrome, and suggests the possibility of therapeutic intervention with antiviral drugs that have activity against HSV and/or CMV.

Acquired Immunodeficiency Syndrome↗
PubMed1987

Ganciclovir for the treatment and suppression of serious infections caused by cytomegalovirus.

Ganciclovir is a congener of acyclovir with in vitro activity against cytomegalovirus. Ninety-seven patients with the acquired immune deficiency syndrome (AIDS) and a serious cytomegalovirus infection received ganciclovir, 3.0 to 15 mg/kg per day. Viremia cleared during drug therapy in 88 percent of patients. Viral shedding from urine and throat ceased or became inapparent during treatment in 78 percent and 68 percent of patients, respectively. Among patients with cytomegalovirus retinitis, 87 percent of evaluable patients had improvement in (30 of 60) or stabilization (22 of 60) of their disease. However, when the drug was discontinued, progression or recurrence of disease always occurred. Long-term suppressive therapy with ganciclovir, 5.0 mg/kg five to seven times weekly, prevented the recurrence of cytomegalovirus disease (p less than 0.001). The drug was eliminated by renal excretion, and in patients without renal impairment (creatinine clearance rates of more than 60 ml/minute/1.73 m2), ganciclovir has a mean half-life of 4.2 hours. Significant neutropenia and leukopenia occurred in 55 percent and 32 percent of patients, respectively.

Acquired Immunodeficiency Syndrome↗
PubMed1987

Changes in cerebrospinal fluid cells, IgG and IgA during herpes simplex virus encephalitis in rabbits.

Rabbits were infected with herpes simplex-type 1 virus either by corneal scarification or intrathecal inoculation. Encephalitis was induced predictably by either route but was most severe after intrathecal inoculation. Serial examination of the cerebrospinal fluid (CSF) demonstrated abnormalities reflecting two distinct phases of the immune response to this central nervous system infection. The acute phase was manifested by a mononuclear pleocytosis and transudation of serum proteins into the CSF. The recovery phase was manifested by increased amounts of IgG, IgA and antibody specific for herpes simplex virus in the CSF. These studies demonstrate that IgA is a significant component of the local immune response to viral encephalitis in the rabbit as well as in mice and man.

Albumins↗
PubMed1987

Ribavirin pharmacodynamics in high-risk patients for acquired immunodeficiency syndrome.

Ribavirin was administered orally in escalating doses for 2 or 4 weeks to 15 symptom-free, human immunodeficiency virus seropositive homosexual men with generalized lymphadenopathy. Reverse transcriptase activity was inhibited during therapy when steady-state plasma concentrations were greater than 6 mumol/L. These concentrations were achieved with 1200 or 2400 mg/day for 2 weeks or a loading dose of 2400 mg/day for 3 days followed by 600 mg/day for 4 weeks. Drug accumulation occurred at all doses. The elimination half-life appeared to be approximately 2 weeks. Reversible adverse reactions, principally resulting in central nervous system symptoms and anemia, correlated with dose and duration of therapy. Immunologic enhancement of T-lymphocyte-mediated mitogen-induced responses was observed in the majority of patients who had reduction in reverse transcriptase activity. However, specific T4+ lymphocyte-mediated antigen-induced responses increased to within the normal range in only three patients. Significant enhancement appeared to correlate with the severity of baseline antigen-induced functional impairment. These data indicate that oral ribavirin can be given for at least 1 month with acceptable toxicity at doses that appear to inhibit human immunodeficiency virus replication.

Acquired Immunodeficiency Syndrome↗
PubMed1987

Ribavirin disposition in high-risk patients for acquired immunodeficiency syndrome.

Ribavirin is a broad-spectrum antiviral drug that has in vitro activity against human immunodeficiency virus. To determine the kinetics of ribavirin, 17 symptom-free homosexual men with lymphadenopathy were studied. Single doses of ribavirin, 600, 1200, or 2400 mg, were given orally or intravenously. The plasma ribavirin concentration-time profiles were well fitted by a three-compartment open model. Ribavirin followed linear kinetics over the dose range studied. The mean 1-hour postinfusion concentrations after intravenous ribavirin, 600, 1200, and 2400 mg, were 8.0, 19.7, and 37.1 mumol/L, respectively. The mean +/- SD plasma beta-phase half-life, terminal-phase (gamma) half-life, and volume of distribution at steady state were 2.0 +/- 1.1 hours, 35.5 +/- 14.0 hours, and 647 +/- 258 L, respectively. The mean ribavirin renal clearance and total body clearance were 99 +/- 30 and 283 +/- 37 ml/min, respectively. After an oral dose of 600, 1200, and 2400 mg, the mean peak plasma ribavirin concentrations (which occurred 1.5 hours after administration) were 5.1, 9.9, and 12.6 mumol/L, respectively. The mean absorption half-life and bioavailability of ribavirin were 0.5 hour and 45%. Ribavirin had no plasma protein binding and the drug accumulated within red blood cells. In conclusion, ribavirin is incompletely absorbed from the gastrointestinal tract, its renal excretion accounts for approximately one third of the drug's elimination, and drug accumulation (greater than threefold) will result with repetitive dosing at the 6- to 8-hour dosing interval currently used.

AIDS-Related Complex↗
PubMed1986

Antiviral therapy for cytomegalovirus retinitis in AIDS with dihydroxy propoxymethyl guanine.

Six patients (all male, five homosexual and one bisexual, 23 to 48 years old) with the acquired immune deficiency syndrome (AIDS) who had cytomegalovirus retinitis were treated with a new antiviral drug as a part of a prospective open-labeled trial for serious cytomegalovirus infections. The drug, 9-[2-hydroxy-1-(hydroxymethyl)ethoxymethyl] guanine (referred to as dihydroxy propoxymethyl guanine), a new acyclic nucleoside antiviral agent similar in structure to acyclovir, produced positive results. These patients treated with dihydroxy propoxymethyl guanine (2.5 mg/kg of body weight every eight hours) showed regression and often disappearance of the lesions of cytomegalovirus retinitis during and for several weeks after therapy, usually with concomitant resolution of viral shedding. The cytomegalovirus retinitis recurred in four patients (the other two were lost to follow-up), but retreatment usually led to remission. Adverse drug toxicity (reversible granulocytopenia) occurred in two patients.

Acquired Immunodeficiency Syndrome↗
PubMed1986

Herpes zoster and zosteriform herpes simplex virus infections in immunocompetent adults.

Among 111 immunocompetent patients referred to a general hospital setting with the clinical diagnosis of herpes zoster, viral cultures were obtained from 47 patients. Six of these patients (13 percent) had herpes simplex virus isolated, with four of the six infections involving the facial distribution, and the other two involving the T4 (breast) distribution. Excluding those in whom herpes simplex virus was isolated, the mean age (+/- SD) of the remaining 105 patients was 50 +/- 19 years. Thirty-two percent of the patients were at least 65 years old; however, 39 percent were younger than 40 years of age. Thus, herpes zoster frequently occurs in young, immunocompetent adults. Also, since zosteriform rashes may be caused by herpes simplex virus, viral cultures of lesions are useful to differentiate infections caused by herpes simplex virus from those due to varicella-zoster virus. The need to distinguish between these two viruses may be important with the advent of antiviral drugs and for use of the proper epidemiologic isolation procedures.

Adolescent↗