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Biomedical subjects

J D Connor

Publications and source records attributed to J D Connor.

At least 37 records · Page 2Linked to original sources
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↗
PubMed1992

A pneumococcal clinical isolate with high-level resistance to cefotaxime and ceftriaxone.

A beta-lactam-resistant serotype 23F Streptococcus pneumoniae clinical isolate from the cerebrospinal fluid of a pediatric patient from California is unusual in that the MICs of cefotaxime and ceftriaxone (2.5 micrograms/ml each) are higher than that of benzylpenicillin (0.3 micrograms/ml); the isolate also has patterns of penicillin-binding proteins and of cell wall peptides which are atypical compared with those of previously examined penicillin-resistant pneumococci.

Cefotaxime↗
PubMed1992

Distinguishing between respiratory syncytial virus subgroups by protein profile analysis.

We subgrouped 75 strains of respiratory syncytial virus by a protein profile method (PPM) which relies on different mobilities of the phosphoprotein in one-dimensional polyacrylamide gel electrophoresis and does not require monoclonal antibodies. When compared with enzyme immunoassay, PPM correctly subgrouped 54 of 56 subgroup A and all 19 subgroup B strains.

Antigens, Viral↗
PubMed1992

Lack of retinal toxicity of the anticytomegalovirus drug (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl) cytosine.

The drug (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl) cytosine (HPMPC) is an antiherpesvirus group compound with a higher potency and longer duration of action against human cytomegalovirus (CMV) than ganciclovir or foscarnet. Twenty eyes of ten New Zealand white rabbits received 0.1-ml injections of either normal saline or HPMPC at doses of 10, 50, 100, 300, or 1000 micrograms. The animals were killed on days 14 and 28. Toxicity was assessed by indirect ophthalmoscopy, electroretinography (ERG), and light and electron microscopy. Both a- and b-wave ERG findings and indirect ophthalmoscopic appearance of retinas in all groups were normal. Light and electron microscopy of perfusion-fixed retinal tissue revealed no morphologic changes at doses of 100 micrograms or lower. The pharmacokinetics of eight rabbits injected intravitreally with 100 micrograms of HPMPC showed a 24.4-hr half-life for the drug. These results indicate that HPMPC is not toxic to the rabbit retina at 500-1000-fold the dose that is effective in suppressing CMV infections. Doses of 100 micrograms also were injected into the vitreous of monkey eyes. Intravitreal injections of HPMPC may be efficacious in inhibiting CMV retinitis for longer dosing intervals than can be used with other anti-CMV compounds.

Animals↗
PubMed1991

Pharmacokinetics of acyclovir in the term human pregnancy and neonate.

Concern about neonatal herpes often leads to cesarean delivery of infants in women with a history of genital herpes. The antiviral drug acyclovir has been used effectively to suppress genital herpes simplex virus recurrences in nonpregnant adults. Its administration to pregnant women with recurrent genital herpes may reduce herpes simplex virus recurrences and thus may decrease the cesarean section rate among this population. To study the pharmacokinetics, safety, and patient tolerance of suppressive oral acyclovir, either 200 mg (n = 7) or 400 mg (n = 8) was administered orally every 8 hours to pregnant women with a history of recurrent herpes simplex virus, from 38 weeks' gestation until delivery. The mean +/- SD plasma levels for the 200 and 400 mg groups, respectively, were: first dose peak, 1.7 +/- 0.6 and 2.3 +/- 1.0 mumol/L; steady-state trough, 0.7 +/- 0.3 and 0.8 +/- 0.6 mumol/L; steady-state peak, 1.9 +/- 1.0 and 3.3 +/- 1.0 mumol/L. In late gestation maternal acyclovir pharmacokinetics were similar to those of nonpregnant adults from other studies. Acyclovir was concentrated in the amniotic fluid; however, there was no accumulation in the fetus (mean maternal/infant plasma ratio at delivery was 1.3). Acyclovir was well tolerated, and no toxicity was seen in the mothers or infants. The administration of acyclovir, 400 mg every 8 hours, appears appropriate for use in an efficacy and safety study regarding suppression of herpes simplex virus recurrences during the last weeks of pregnancy.

Acyclovir↗