Biomedical subjects

J D Connor

Publications and source records attributed to J D Connor.

At least 19 recordsLinked to original sources

PubMed1996

A phase-I study of the safety, pharmacokinetics, and antiviral activity of combination didanosine and ribavirin in patients with HIV-1 disease. AIDS Clinical Trials Group 231 Protocol Team.

A phase-I study was conducted to examine the safety, pharmacokinetics, and activity of combination 2',3'-dideoxyinosine (ddI) and ribavirin against human immunodeficiency virus type 1 (HIV-1)-positive individuals with CD4+ cell counts of < or = 500/microliter. Nineteen patients were enrolled into the study in which ddI monotherapy (200 mg p.o.b.i.d.) was administered for the first 4 weeks, followed by the coadministration of ribavirin (600 mg p.o.q.d.) and ddI (200 mg p.o.b.i.d.) for 8 or 20 additional weeks. The combination regimen was safe and well tolerated. Three patients did not complete 12 weeks of the study because of adverse events or voluntary withdrawal. The pharmacokinetic studies performed at weeks 4, 6, and 12 on specimens collected from the 15 individuals who completed 12 weeks of therapy revealed no pharmacokinetic interaction between ddI and ribavirin. A significant decline from baseline in HIV-1 titer as measured by quantitative HIV-1 culture was detected both during the ddI-monotherapy phase (week 4, p < 0.001) and during the combination-therapy ddI + ribavirin phase (week 12, p < 0.001); the median drop observed was 0.90 log10 at week 4 and 0.92 log10 at week 12. While the addition of ribavirin did not result in further reductions in viremia in the following weeks on study treatment, 13 (81%) of the 16 patients had at least a -0.5 log10 change in viral titer at week 12. The median decline in plasma viral RNA was 0.68 log10 at week 4(p < 0.001) and 0.67 log10 at week 12 (p = 0.005). CD4+ cell counts increased above baseline significantly during the ddI-monotherapy phase of the study (p = 0.0038). The median increase was +26 cells/mm3 at week 4 and +11 cells/mm3 at week 12; for patients who remained on treatment through 24 weeks, the median CD4+ cell count increase was +10 cells/mm3. The L74V ddI resistance-conferring HIV-I reverse-transcriptase mutation emerged in 53% of the patients. Patients with non-syncytium-inducing HIV variants demonstrated greater responses to treatment with larger decreases in virus load and greater increases in CD4+ cell count. Our results reveal that the combination of ddI and ribavirin in HIV-positive patients is safe, well tolerated, without adverse pharmacologic interaction, and associated with significant and sustained declines in virus load over 12 weeks of therapy.

Adult↗

PubMed1996

Simple reversed-phase high-performance liquid chromatography quantitation of ganciclovir in human serum and urine.

A fast, simple, and cost-effective HPLC method for the quantitation of the antiviral drug ganciclovir is described. The serum samples are extracted with perchloric acid and neutralized with potassium phosphate buffer, and urine samples are diluted with distilled water. A reversed-phase column with isocratic elution by 15 mM potassium phosphate buffer (pH 2.5) containing 0.25% acetonitrile is used to separate ganciclovir; quantitation is by UV absorbance at 254 nm. Total turnaround time is 22 min; more than 3000 samples can be run on a single column without loss of peak quality. The limit of quantitation is 0.05 micrograms/ml. Recoveries varied from 91 to 107% with coefficients of variation ranging from 0.387 to 7.95%.

Antiviral Agents↗

PubMed1996

Liposome-encapsulated (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine for long-acting therapy of viral retinitis.

The effect of liposome-encapsulated (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC; cidofovir) was evaluated as prophylaxis in a rabbit model of experimentally induced retinitis caused by preretinal inoculation of herpes simplex virus type 1 (HSV-1). Cidofovir (100 micrograms) in liposomes (0.1 mL) was injected intravitreally 10-120 days before retinal inoculation with HSV-1. Twenty-two of 26 eyes pretreated with liposome-encapsulated cidofovir 10-60 days before HSV-1 inoculation were protected from experimentally induced retinitis, and 2 of 5 eyes pretreated 120 days before inoculation were protected. Intravitreal levels of cidofovir were low (0.7 microgram/mL) but detectable 120 days after injection. One 100-micrograms intravitreal injection of liposome-encapsulated cidofovir appears to have a remarkably potent and prolonged (up to 4 months) antiviral effect in this experimental model of HSV-1 retinitis. Since HPMPC is even more potent against cytomegalovirus than HSV-1, liposome-encapsulated cidofovir may prove to be effective local therapy for AIDS patients with cytomegalovirus retinitis.

Animals↗

PubMed1996

Clinical and laboratory characteristics of a large cohort of symptomatic, human immunodeficiency virus-infected infants and children. AIDS Clinical Trials Group Protocol 152 Study Team.

BACKGROUND: A large cohort of antiretroviral therapy-naive, symptomatic, HIV-infected children were enrolled into a controlled therapeutic trial (AIDS Clinical Trials Group Protocol 152), providing an opportunity to describe their clinical and laboratory characteristics and determine age-related distinctions. METHODS: Study entry evaluations for 838 of 839 enrolled children were analyzed. Weight, head circumference (if < 30 months of age), neuroradiologic imaging of the head, developmental or cognitive status and neurologic examination were assessed. Laboratory studies included hemoglobin, absolute neutrophil count, CD4 cell count, serum amylase, alanine aminotransaminase, p24 antigen and HIV blood culture. Data were categorized by age (3 to < 12 months, 12 to < 30 months, 30 months to 6 years and > or = 6 years). RESULTS: Younger children had significantly higher rates of abnormalities before antiretroviral therapy, especially factors relating to growth and neurologic or cognitive function. Lower CD4+ cell counts and percentages as well as a positive serum p24 antigen correlated with lower weight-for-age Z scores and developmental indices. CONCLUSIONS: These data provide a description of the clinical characteristics of HIV-infected US children at the time antiretroviral therapy is initiated for HIV-related symptoms. The high rate of abnormalities of growth, development and cognitive ability that were observed in children < 30 months of age demonstrates that treatment strategies should be developed for earlier intervention.

AIDS-Related Opportunistic Infections↗

PubMed1996

Health care worker exposure to aerosolized ribavirin: biological and air monitoring.

Aerosolized ribavirin is administered frequently to treat severe respiratory syncytial virus infections. The drug's potential reproductive effects in occupationally exposed workers remains a concern among health care workers. In this evaluation, we measured urinary ribavirin concentrations in occupationally exposed health care workers. Ribavirin was detected in 16 of 26 (62%) post-work-shift urine samples that had been provided by nurses, and in five of 22 (23%) post-work-shift urine samples that had been provided by respiratory therapists (range, < 0.01 to 0.22 mumol/L). We also measured airborne ribavirin concentrations in the personal breathing zones of nurses. Ventilators and other administration units that were enclosed by an aerosol containment tent produced significantly lower airborne ribavirin exposures than administration units without a containment tent did (range, < 2.5 to 78 micrograms/m3). On the basis of this and other evaluations of airborne ribavirin concentrations, we recommend using aerosol containment systems with all types of ribavirin administration units except mechanical ventilators.

Adult↗

PubMed1995

Pharmacokinetic, safety, and antiviral profiles of oral ganciclovir in persons infected with human immunodeficiency virus: a phase I/II study. AIDS Clinical Trials Group, and Cytomegalovirus Cooperative Study Group.

A phase I/II study evaluated the pharmacokinetics, tolerability, and antiviral activity of oral ganciclovir in persons infected with human immunodeficiency virus (HIV). Oral bioavailability ranged from 2.6% to 7.3%. The mean maximum serum concentration achieved at 1000 mg every 8 h was 1.11 micrograms/mL, and mean trough level was 0.54 microgram/mL. The time to maximum serum drug concentration was 1.0-2.9 h, with a serum half-life of 3.0-7.3 h, suggesting prolonged oral absorption. Serious adverse events were uncommon. Decreased cytomegalovirus (CMV) shedding was observed from all sites. The median days (by dosage) to retinitis progression assessed by retinal examination after initiation of oral ganciclovir were 62 (1000 mg every 8 h), 148 (500 mg every 3 h), 75 (750 mg every 3 h), 148 (1000 mg every 3 h), and 139 (2000 mg every 8 h). Thus, oral ganciclovir has pharmacokinetic, toxicity, and antiviral profiles that may prove beneficial for both maintenance therapy of CMV retinitis and prevention of CMV disease in HIV-infected persons.

Administration, Oral↗

PubMed1995

Intravitreous and plasma concentrations of ganciclovir and foscarnet after intravenous therapy in patients with AIDS and cytomegalovirus retinitis.

This study evaluated intravitreous and plasma ganciclovir and foscarnet concentrations after intravenous administration in AIDS patients with cytomegalovirus (CMV) retinitis and retinal detachment. Undiluted vitreous samples were prospectively obtained from 60 eyes (52 patients) at the time of pars plana vitrectomy. Thirty-three plasma samples (from 27 patients in the initial group of 52) were obtained simultaneously during surgery on 33 eyes. High-pressure liquid chromatography showed the mean vitreous ganciclovir concentrations in patients on induction and maintenance therapy were, respectively, 4.74 +/- 1.49 microM (n = 24) and 3.29 +/- 1.84 microM (n = 30; P = .005). Simultaneous plasma ganciclovir concentrations were less than the vitreous concentrations in 78% of the patients. The mean intravitreous foscarnet concentrations in patients receiving induction dosages were 189 +/- 177 microM (n = 5) versus 163 +/- 167 microM (n = 4; P > .20) for those receiving maintenance therapy. The foscarnet vitreous plasma concentration ratio averaged 1.43. Current drugs and doses for CMV retinitis result in borderline or progressively subtherapeutic concentrations.

Acquired Immunodeficiency Syndrome↗

PubMed1995

Effect of partial retinal destruction and gliosis on the intravitreal pharmacokinetics of HPMPC.

PURPOSE: Intravitreal HPMPC ([S]-1-[3-hydroxy-2 phosphonylmethoxypropyl cytosine) has a long antiviral effect in patients with cytomegalovirus retinitis. The authors evaluated the pharmacokinetics of intravitreal injections of HPMPC to understand major route of HPMPC elimination in a pigmented rabbit that had undergone scatter laser photocoagulation over half of the retinal surface. METHODS: The authors treated the inferior half of the retina, receiving an average of 605 grade 3 or 4 (gray-white or white) diode laser burns in a scatter fashion in the left eyes of 13 rabbits. After 4 weeks, 13 rabbits received intravitreal injection of HPMPC (100 micrograms in 0.1 mL) in both eyes. Forty-eight hours after injection, unfixed vitreous samples were obtained for high-pressure liquid chromatography analysis. Two rabbits were used for light microscopic examination of diode laser photocoagulated retina with the perfusion fixation. RESULTS: The HPMPC concentration in the vitreous was 5.93 +/- 1.75 micrograms/mL in the laser-treated group and 4.76 +/- 1.2 micrograms/mL in the control group 48 hours after intravitreal HPMPC injection. The difference was statistically different (P = 0.037). CONCLUSIONS: Results showed a higher concentration of intravitreal HPMPC in the eye that had approximately 25% of the retina destroyed by the laser photocoagulation. The higher concentration is likely the result of reduced elimination and a concomitant increase in half-life. This suggests that HPMPC may be eliminated via the retinal route. Eyes with more extensive retinal involvement with human cytomegalovirus may have an even longer duration of action of intravitreal HPMPC. This may lead to modification of dosing regimens.

Animals↗

PubMed1995

Therapy of pediatric AIDS.

Therapy of pediatric AIDS utilizes antiretroviral compounds; antibiotic, antifungal, and antiparasitic agents; and both active and passive immunization in a multifactorial approach. Currently, newly diagnosed pediatric AIDS cases are acquired predominantly through vertical transmission from HIV-infected mothers. Pediatric AIDS research is focused on strategies to prevent vertical transmission of HIV infection as well as therapy against opportunistic and progressive HIV disease. Zidovudine remains first-choice therapy for HIV infection and can reduce the rate of vertical transmission of HIV. Didanosine is also approved to treat HIV infection in pediatric AIDS. Other reverse transcriptase inhibitors are under investigation as alternative or combination therapies because of HIV resistance to zidovudine and didanosine. Alternative therapies for opportunistic infections are being investigated. Passive immunity with intravenous immunoglobulin is being reevaluated to determine efficacy in combination with other therapies. Finally, vaccination against usual childhood diseases with standard immunization schedules produces limited immunity, and alternative vaccination protocols warrant further investigation.

AIDS-Related Opportunistic Infections↗

PubMed1995

Population differences in ganciclovir clearance as determined by nonlinear mixed-effects modelling.

We examined the pharmacokinetics of ganciclovir in different populations of cytomegalovirus (CMV)-infected patients through the use of nonlinear mixed-effects modelling. As expected, patient weight and estimated creatinine clearance were shown to be important covariates in the serum ganciclovir clearance. Unexpectedly, major differences in ganciclovir clearance between different populations of patients were found. Human immunodeficiency virus (HIV)-infected patients with CMV retinitis cleared ganciclovir 41% faster than HIV-infected patients only shedding CMV into the urine. Solid-organ transplant patients had a serum clearance one-fourth that of HIV-infected patients, even with correction for creatinine clearance. These findings require prospective validation and may have important implications for ganciclovir dosing in different populations of CMV-infected patients.

AIDS-Related Opportunistic Infections↗

PubMed1994

The influence of endogenous and exogenous sex hormones in adolescents with attention to oral contraceptives and anabolic steroids.

The endogenous sex hormones produce dispositional changes in the developing child as well as imparting unique male and female dispositional patterns. Age-related changes have been observed for digoxin disposition and caffeine and theophylline metabolism. These age-related dispositional changes have led to age-dependent dosing recommendations. Studies with caffeine and antipyrine indicate that this change in drug disposition occurs over a short period of time, is seen earlier in girls than in boys, and is related to pubertal (Tanner) stage and the "growth spurt". Significant changes in endogenous sex hormone concentrations occur during the menstrual cycle and during pregnancy, leading to alterations in drug binding, distribution, and clearance. Oral contraceptives (OCs) inhibit the metabolism of certain drugs resulting in toxicity or lack of efficacy. Rifampin induces the OC metabolism, resulting in decreased clinical effectiveness. Most studies did not examine these kinetic and dynamic interactions between adult and adolescent users. It is estimated that there are over 45 anabolic steroid compounds available for abuse by athletes, and their use is increasing among male and female adolescents. Although the adolescent is at increased risk of developing adverse effects from these agents, a systematic evaluation of the long-term effects of anabolic steroid abuse has not been undertaken in this population. Further research is needed regarding the influence of endogenous and exogenous hormones on adolescent drug kinetics and dynamics. Because of their frequency of use among adolescents, OCs and anabolic steroids require particular emphasis.

Adolescent↗

PubMed1994

Diagnosis of enteroviral central nervous system infection by polymerase chain reaction during a large community outbreak.

Enteroviruses are common causes of localized and systemic infection in patients of all ages and are the most frequent cause of epidemic aseptic meningitis in the United States. We have developed a polymerase chain reaction (PCR) assay of cerebrospinal fluid (CSF) for rapid diagnosis of enteroviral meningitis. This assay was applied to 257 CSF specimens during a large community outbreak of enterovirus disease; 109 (97%) of 112 enterovirus culture-positive CSF samples contained enterovirus RNA. In addition 35 (66%) of 53 samples from patients with suspected central nervous system disease with negative or no CSF viral cultures were positive by enterovirus PCR. The enterovirus PCR detected 13 different enterovirus serotypes. PCR results are available within 24 hours compared with a mean of 6.8 days for enterovirus culture. The clinical characteristics of 141 patients with enterovirus central nervous system disease are presented. This study demonstrates the usefulness of enterovirus PCR for the rapid diagnosis of enterovirus central nervous system disease and the potential for PCR tests to shorten hospitalization.

Base Sequence↗

PubMed1993

Influence of ZnCl2 pretreatment on behavioral and histological responses to kainic acid in rats.

Kainic acid evokes behavioral convulsions and causes lesions in hippocampal pyramidal cell layers in rats. The effects of ZnCl2 pretreatments on these events were examined. Rats were given ZnCl2 (35 mg/kg, subcutaneously (s.c.)) 15 min prior to kainic acid administration (12 mg/kg, intraperitoneally (i.p.)). Another group of animals was given an additional dose of ZnCl2 (35 mg/kg, i.p.) 24 h prior to the s.c. ZnCl2 and i.p. kainic acid. All rats that received kainic acid, whether saline controls or ZnCl2 pretreated, experienced wet dog shakes (WDS) and convulsions. No significant differences were seen between groups in number or latency of WDS or convulsions. Two days after behavioral data were collected, the brains were perfused and the extent of lesioning among hippocampal CA1 and CA3 pyramidal cells was quantified. A single dose of ZnCl2 had either no effect or a slight protective effect on cell lesioning induced by kainic acid. However, lesioning was more pronounced in animals treated twice with zinc. It is concluded that zinc, co-administered with kainic acid, augments kainate cytotoxicity when the dose and timing of zinc exposure are within a critical period.

Animals↗

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↗

PubMed1993

Pathophysiology and treatment of clinically resistant cytomegalovirus retinitis.

PURPOSE: To determine the incidence, pathophysiology, clinical outcome, and survival in patients with clinically resistant retinitis. METHODS: Cytomegalovirus (CMV) retinitis was prospectively studied in 100 patients with acquired immune deficiency syndrome (AIDS). In 11 of these patients, clinically resistant retinitis developed, defined as new activity or progression, despite at least 8 consecutive weeks of induction doses of either foscarnet or ganciclovir. Fundus photography, pharmacokinetics, CMV cultures and sensitivities, and survival analyses were studied. The therapeutic interventions attempted after clinically resistant retinitis was identified included continuing a high dose (induction level) of the same antiviral drug, changing the antiviral drug, and combining antiviral therapy with foscarnet and ganciclovir. RESULTS: Clinically resistant retinitis occurred in 11 (11%) of 100 patients with CMV retinitis and appeared to be a manifestation of acquired CMV antiviral drug resistance. Drug metabolism and pharmacokinetics in these patients were normal. The use of combination therapy with foscarnet and ganciclovir was effective in halting the progression of retinitis in three (75%) of four patients (6 of 7 eyes able to be evaluated) receiving combination therapy. CONCLUSION: Clinically resistant retinitis is a manifestation of infection by CMV that has acquired drug resistance. In these patients, combination antiviral drug treatment should be considered. It is likely that clinically resistant retinitis will become more frequent as patients with CMV retinitis and AIDS survive longer.

AIDS-Related Opportunistic Infections↗

PubMed1993

Intravitreal ganciclovir concentration after intravenous administration in AIDS patients with cytomegalovirus retinitis: implications for therapy.

To determine whether therapeutic intravitreal concentrations of ganciclovir are achieved after intravenous administration, vitreous samples were obtained intraoperatively from 23 eyes of 22 AIDS patients with retinal detachments associated with cytomegalovirus (CMV) retinitis. The mean intravitreal ganciclovir concentration of all samples was 0.93 +/- 0.39 microgram/mL (3.6 +/- 1.5 microM). This level is near the published trough serum concentrations obtained with every-12-h intravenous dosing and well below the peak. It is significantly below the concentration of ganciclovir required to achieve 50% of viral plaque formation for many human CMV strains. Only a small decrease in vitreous drug levels was observed as a function of time after last dose. Intravenous administration of ganciclovir results in near-steady-state subtherapeutic intravitreal ganciclovir concentrations for many CMV isolates. This may explain the difficulty of long-term complete suppression of CMV retinitis.

AIDS-Related Opportunistic Infections↗

PubMed1992

Differential effects of octreotide on motor responses to nicotine in rats.

We tested the hypothesis that brain somatostatin levels modify two motor behaviors evoked by ICV infusions of nicotine. Unrestrained, awake rats were given fixed-concentration infusions of nicotine until the prostration/immobility (PI) syndrome and convulsions were produced. Infusion duration ranged from 0.9 to 1.2 min for the PI syndrome and 2.5 to 4.9 min for the convulsions. Octreotide, a stable somatostatin analog (4.5 micrograms, ICV), significantly raised the threshold for nicotine convulsions 1.0 and 5.5 h after pretreatment but not at 24 or 48 h. Cysteamine, a somatostatin releaser and depletor (0.35-0.75 mg/rat, ICV), also caused a dose-dependent increase in seizure threshold. Similarities in the response to octreotide and cysteamine suggest that depression of nicotine convulsions by cysteamine may be mediated by release of endogenous somatostatin. Neither octreotide nor cysteamine altered the threshold for the PI syndrome. These results support the view that one motor behavior evoked by nicotine is subject to control by somatostatin whereas another is not.

Animals↗

PubMed1992

Autonomic mechanisms in heart rate variability after isoproterenol-induced myocardial damage in rats.

The effect of isoproterenol-induced myocardial damage on heart rate variability was examined in conscious, unrestrained, male, Sprague-Dawley rats. We used power spectrum analysis of beat-to-beat heart rate to study the levels and interaction of sympathetic and parasympathetic neural influences on the heart. One day after isoproterenol (80 mg/kg s.c.), mean heart rate was significantly elevated when compared to controls (isoproterenol 413.9 b.p.m. +/- 7.7 S.E.M.; saline 368.8 b.p.m. +/- 12.8 S.E.M.; P less than 0.05), even though the low frequency and respiratory components of the power spectrum were not different between the two groups. By contrast, a week after isoproterenol administration, heart rate was normal; however, variability in low frequency and respiratory areas of the power spectrum was significantly increased suggesting an abnormal sympathovagal balance. An imbalance in autonomic regulation of cardiac automaticity could account for the 27% incidence of arrhythmias in rats given isoproterenol. These results indicate that autonomic responses associated with isoproterenol-induced myocardial ischemia differ from those in human and in animal models of myocardial infarction.

Animals↗