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Biomedical subjects

R R MacGregor

Publications and source records attributed to R R MacGregor.

At least 37 records · Page 2Linked to original sources
PubMed1998

Prophylaxis with weekly versus daily fluconazole for fungal infections in patients with AIDS.

We compared the efficacy of a 400-mg once-weekly dosage versus a 200-mg daily dosage of fluconazole for the prevention of deep fungal infections in a multicenter, randomized, double-blind trial of 636 human immunodeficiency virus-infected patients to determine if a less intensive fluconazole regimen could prevent these serious but relatively infrequent complications of AIDS. In the intent-to-treat analysis, a deep fungal infection developed in 17 subjects (5.5%) randomly assigned to daily fluconazole treatment and in 24 (7.7%) given weekly fluconazole during 74 weeks of follow-up (risk difference, 2.2%; 95% confidence interval [CI], -1.7% to 6.1%). Thrush occurred twice as frequently in the weekly versus daily fluconazole recipients (hazard ratio, 0.59; 95% CI, 0.40-0.89), and in a subset of patients evaluated, fluconazole resistance was infrequent. Fluconazole administered once weekly is effective in reducing deep fungal infections in patients with AIDS, but this dosage is less effective than the 200-mg-daily dosage in preventing thrush.

AIDS-Related Opportunistic Infections↗
PubMed1998

First human trial of a DNA-based vaccine for treatment of human immunodeficiency virus type 1 infection: safety and host response.

A DNA-based vaccine containing human immunodeficiency virus type 1 (HIV-1) env and rev genes was tested for safety and host immune response in 15 asymptomatic HIV-infected patients who were not using antiviral drugs and who had CD4+ lymphocyte counts of > or = 500 per microliter of blood. Successive groups received three doses of vaccine (30, 100, or 300 microg) at 10-week intervals in a dose-escalation trial. Vaccine administration induced no local or systemic reactions, and no laboratory abnormalities were detected. Specifically, no patient developed anti-DNA antibody or muscle enzyme elevations. No consistent change occurred in CD4 or CD8 lymphocyte counts or in plasma HIV concentration. Antibody against gp120 increased in individual patients in the 100- and 300-/microg groups. Some increases were noted in cytotoxic T lymphocyte activity against gp160-bearing targets and in lymphocyte proliferative activity. The safety and potential immunogenicity of an HIV-directed DNA-based vaccine was demonstrated, a finding that should encourage further studies.

AIDS Vaccines↗
PubMed1998

HIV-1 DNA based vaccine induces a CD8 mediated cross-clade CTL response.

Novel approaches for the generation of more effective vaccines for HIV-1 are of significant importance. In this report we analyse the immunogenicity and efficacy of a DNA vaccination approach in a chimpanzee model system. Three chimpanzees were vaccinated with DNA constructs which express the env, rev, gag and pol proteins. These animals developed specific cellular responses to these proteins, although the nature of the responses varied among the animals. We demonstrated that DNA vaccination led to a CD8 mediated killing of targets expressing the homologous clade B envelope as well as targets expressing heterologous clade E envelope. In addition seronegative individuals have been inoculated with a DNA construct which expresses the env, rev proteins. These studies serve as an important benchmark for the use of DNA vaccine technology for the production of protective immune responses.

AIDS Vaccines↗
PubMed1997

Secretion of cardiac plasminogen activator during hypoxia-induced right ventricular hypertrophy.

In the circulation, fibrinolytic activity is determined to a large degree by the relative levels of tissue plasminogen activator (tPA) and its major inhibitor (PAI-1). Vascular beds in different organs secrete tPA and PAI-1 into the circulation, and the total secretory rate of each protein is balanced by its half-life in the bloodstream. We are testing the hypothesis that in the heart, ventricular hypertrophy will alter the rates of formation of tPA and/or PAI-1 and the rates of their release into the cardiac vasculature. In this study, we have examined the effects of continuous hypoxia on PA activity in extracts of rat heart ventricles, on the activity secreted into the cardiac vasculature of perfused hearts, and on the levels of mRNAs for tPA and PAI-1. Rats were subjected to hypobaric hypoxia at 0.5 atm for 1-21 days. The treatment caused polycythemia within 1-3 days, and right ventricular hypertrophy by 3 days. PA activity in extracts of both right and left ventricles was significantly elevated after 3 days of hypoxia, continued to increase for 4 additional days, and remained elevated for 3 weeks. The actions of inhibitors of urokinase and tPA indicated that the PA activity in heart extracts was exclusively tPA. Fibrin zymography confirmed that result. The mRNAs for tPA and for PAI-1 were elevated after 1 day of hypoxia and then returned to near control levels on days 2 and 3. After 7 days, hearts from hypoxic rats secreted more tPA activity into perfusates than did hearts from controls. The difference in secretory rates was proportional to the differences in the levels of tPA in the corresponding heart extracts.

Animals↗
PubMed1997

Thapsigargin shifts the Ca set point of parathyroid cells to lower extracellular [Ca].

The hypothesis that cytosolic calcium concentration ([Ca2+cyt]) is the primary regulator of parathyroid hormone (PTH) secretion is supported by a number of studies that show an inverse relationship between them. One agent shown to inhibit PTH secretion is thapsigargin, a sesquiterpene lactone that raises [Ca2+cyt] by inhibiting the Ca-ATPase that pumps Ca2+ from the cytosol into the lumen of the endoplasmic reticulum. Thapsigargin may act on the parathyroid cell other than to inhibit the Ca-ATPase, however, in ways that might also affect PTH secretion. We have tested its effects on functional parameters, such as protein synthesis, the exocytic machinery, and the ability of parathyroid cells to respond to different concentrations of extracellular Ca2+ ([Ca2+ex]). In particular, we have determined whether the inhibition of PTH secretion by thapsigargin is independent of or is modulated by changes in [Ca2+ex]. The results revealed no effects of thapsigargin on protein synthesis or the exocytic mechanisms within 2 h of treatment, and showed that [Ca2+ex] can modulate PTH secretion in the presence of thapsigargin. Its inhibition of PTH secretion, therefore, appears to rest on its ability to shift [Ca2+cyt] to higher levels, but the possibility that it interacts with the Ca receptor has not been eliminated. The results support the hypothesis that the primary regulator of steady-state PTH secretion is [Ca2+cyt].

Animals↗
PubMed1997

CCR5 genotypes in sexually active couples discordant for human immunodeficiency virus type 1 infection status.

Persons who are homozygous for the delta32 polymorphism of the CCR5 chemokine receptor gene are highly protected against human immunodeficiency virus type 1 (HIV-1) infection. Previous studies described 54 HIV-1-discordant couples in whom no virus transmission occurred despite extensive sexual contact. The possible role of the delta32 polymorphism in the lack of HIV-1 transmission between these partners was studied. No participants were homozygous for the delta32 allele, but the proportion that was heterozygous was higher among HIV-1-seronegative than HIV-1-seropositive partners (28% vs. 11%, P = .05). This association was seen in heterosexual couples (P = .03) but not in homosexual couples (P = .74). Among white persons, who are most likely to carry the delta32 allele, 38.9% of HIV-1-uninfected and 5.6% of HIV-1-infected heterosexual partners were heterozygous (P = .04). These data are consistent with a possible association between the heterozygous delta32 genotype in heterosexual sex partners and partial protection against HIV-1 infection, and they emphasize the importance of analyzing different risk groups in studies of host factors that influence infection.

Alleles↗
PubMed1997

Oral administration of antibiotics: a rational alternative to the parenteral route.

Much early experience with antibiotic therapy involved oral administration of sulfonamides, penicillins, tetracyclines, and chloramphenicol. Newer acid-labile, less-soluble agents created the need for intravenous (i.v.) administration, and i.v. technology (hyporeactive catheter polymers, infusion pumps, etc.) improved to where i.v. administration became normative for the treatment of serious infections. Recently, this preference is being reconsidered in light of agents that are highly effective orally, growing appreciation that i.v. treatment has serious complications, and economic pressures to provide the best care at the lowest cost. This article presents a brief history of administration routes and reviews the rationale for considering oral treatment for serious infections, including consideration of pharmacokinetics and minimum inhibitory concentrations. Published reports supporting the efficacy of orally administered antibiotics either as sole treatment or following an initial parenteral course are reviewed in detail, and examples of programs that educate physicians about the rationale, acceptibility, and benefits of oral administration are given.

Administration, Oral↗
PubMed1996

Brain monoamine oxidase A inhibition in cigarette smokers.

Several studies have documented a strong association between smoking and depression. Because cigarette smoke has been reported to inhibit monoamine oxidase (MAO) A in vitro and in animals and because MAO A inhibitors are effective antidepressants, we tested the hypothesis that MAO A would be reduced in the brain of cigarette smokers. We compared brain MAO A in 15 nonsmokers and 16 current smokers with [11C]clorgyline and positron emission tomography (PET). Four of the nonsmokers were also treated with the antidepressant MAO inhibitor drug, tranylcypromine (10 mg/day for 3 days) after the baseline PET scan and then rescanned to assess the sensitivity of [11C]clorgyline binding to MAO inhibition. MAO A levels were quantified by using the model term lambda k3 which is a function of brain MAO A concentration. Smokers had significantly lower brain MAO A than nonsmokers in all brain regions examined (average reduction, 28%). The mean lambda k3 values for the whole brain were 0.18 +/- 0.04 and 0.13 +/- 0.03 ccbrain (mlplasma)-1 min-1 for nonsmokers and smokers, respectively; P < 0.0003). Tranyl-cypromine treatment reduced lambda k3 by an average of 58% for the different brain regions. Our results show that tobacco smoke exposure is associated with a marked reduction in brain MAO A, and this reduction is about half of that produced by a brief treatment with tranylcypromine. This suggests that MAO A inhibition needs to be considered as a potential contributing variable in the high rate of smoking in depression and in the development of more effective strategies for smoking cessation.

Adolescent↗
PubMed1996

Measuring age-related changes in dopamine D2 receptors with 11C-raclopride and 18F-N-methylspiroperidol.

This study investigates the rate of age-related dopamine D2 receptor loss as determined by positron emission tomography (PET) and 11C-raclopride and compares it with D2 loss previously estimated with 18F-N-methylspiroperidol (NMS). Dopamine D2 receptors were measured with 11C-raclopride in 24 healthy volunteers (24-73 years of age) using the ratio of the distribution volume in striatum to that in cerebellum (Bmax/Kd + 1). The results were compared with those obtained in 20 healthy male volunteers (20-49 years of age) in whom D2 receptors were measured with NMS using the ratio index (slope of the striatum-to-cerebellum ratio as a function of time). Findings of correlational analysis between age and dopamine D2 receptor availability were significant for both ligands. Estimates of dopamine D2 receptor loss per decade corresponded to 7.9% for the 11C-raclopride study and 7.8% for the NMS study. Both ligands documented significant age-related decreases in dopamine D2 receptors that occurred relatively early in life (40 years of age).

Adult↗
PubMed1996

Cocaine uptake is decreased in the brain of detoxified cocaine abusers.

Binding of [11C]cocaine in brain was measured with positron emission tomography in 12 detoxified cocaine abusers and in 20 controls to evaluate if there were changes in cocaine binding and in dopamine (DA) transporter availability associated with chronic cocaine use. Nine controls and 10 cocaine abusers had an additional scan with [18F]N-methylspiroperidol to measure dopamine D2 receptors. Cocaine abusers had significantly lower uptake of [11C]cocaine in brain (6.2 +/- 1% dose/cc tissues) than controls (7.7 +/- 2%). The distribution volumes (DV) for [11C]cocaine were reduced in basal ganglia (BG), cortex, thalamus, and cerebellum (CB) of cocaine abusers. However there were no differences in the ratio of the DV in BG to that in CB, which is an estimate of DA transporter availability. Values for DA D2 receptor availability were decreased in cocaine abusers and did not correlate with estimates of dopamine transporter availability. In summary, detoxified cocaine abusers showed decreased uptake of cocaine in brain but did not show changes in DA transporter availability.

Adult↗
PubMed1996

Opioid receptor imaging and displacement studies with [6-O-[11C] methyl]buprenorphine in baboon brain.

Buprenorphine (BPN) is a mixed opiate agonist-antagonist used as an analgesic and in the treatment of opiate addiction. We have used [6-O-[11C]methyl]buprenorphine ([11C]BPN) to measure the regional distribution in baboon brain, the test-retest stability of repeated studies in the same animal, the displacement of the labeled drug by naloxone in vivo, and the tissue distribution in mice. The regional distribution of radioactivity in baboon brain determined with PET was striatum > thalamus > cingulate gyrus > frontal cortex > parietal cortex > occipital cortex > cerebellum. This distribution corresponded to opiate receptor density and to previously published data (37). The tracer uptake in adult female baboons showed no significant variation in serial scans in the same baboon with no intervention in the same scanning session. HPLC analysis of baboon plasma showed the presence of labeled metabolites with 92% +/- 2.2% and 43% +/- 14.4% of the intact tracer remaining at 5 and 30 min, respectively. Naloxone, an opiate receptor antagonist, administered 30-40 min after tracer injection at a dose of 1.0 mg/kg i.v., reduced [11C]BPN binding in thalamus, striatum, cingulate gyrus, and frontal cortex to values 0.25 to 0.60 of that with no intervention. There were minimal (< 15%) effects on cerebellum. Naloxone treatment significantly reduced the slope of the Patlak plot in receptor-containing regions. These results demonstrate that [11C]BPN can be displaced by naloxone in vivo, and they affirm the feasibility of using this tracer and displacement methodology for short-term kinetics studies with PET. Mouse tissue distribution data were used to estimate the radiation dosimetry to humans. The critical organ was the small intestine, with a radiation dose estimate to humans of 117 nrad/mCi.

Animals↗
PubMed1996

Safety of dapsone as Pneumocystis carinii pneumonia prophylaxis in human immunodeficiency virus-infected patients with allergy to trimethoprim/sulfamethoxazole.

OBJECTIVE: To assess the safety of dapsone prophylaxis of Pneumocystis carinii pneumonia (PCP) in patients with prior intolerance to trimethoprim/sulfamethoxazole (TMP/SMX). METHODS: We conducted a retrospective study in the categorical human immunodeficiency virus out-patient program of a university hospital. Patients who had filled prescriptions for dapsone at our pharmacy between January 1991 and April 1994 were evaluated and 75 patients were found eligible for analysis. RESULTS: The overall incidence of adverse events (AE) in our study cohort was 39%. The most common AEs were anemia (23%) and rash (16%). However, after critical evaluation of each case, only 3 cases of anemia (4%) and 2 cases of rash (3%) were judged to be "likely related" to dapsone. Only 5/75 patients (7%) developed the same intolerance to dapsone as previously experienced on TMP/SMX, and none of these cases was viewed as "likely related" to dapsone. A dapsone regimen of 100 mg qd and a prior episode of PCP were associated with a higher incidence of AEs. Eight cases of PCP occurred in spite of dapsone prophylaxis for an incidence of 7 cases per 1,000 patient-months. Seven of the cases of PCP occurred in patients who were receiving secondary prophylaxis. CONCLUSIONS: Given the low incidence of AEs judged to be "likely related" to dapsone, this drug is a reasonable choice for PCP prophylaxis in patients with prior AEs to TMP/SMX.

Adult↗
PubMed1996

New treatments for new TB strains.

Since the discovery of penicillin in the 1930s and antituberculous agents a decade later, antimicrobial chemotherapy has advanced tremendously. New generations of older antibiotics and combinations of drugs have resulted in greater efficacy in the treatment of life-threatening infections. Yet multi-drug resistant tuberculosis remains a threat today, particularly in Pennsylvania.

Antitubercular Agents↗
PubMed1995

Evidence of active cytomegalovirus infection in clinically stable HIV-infected individuals with CD4+ lymphocyte counts below 100/microliters of blood: features and relation to risk of subsequent CMV retinitis.

To determine the frequency and significance of cytomegalovirus (CMV) viremia and viruria in HIV-positive subjects with low CD4+ lymphocyte counts but with no clinical indications for culture, we studied 100 consecutive clinically stable subjects with CD4+ cells < or = 100/microliters of blood who agreed to culture of blood and urine. Serum was tested for CMV antibody, p24 antigen, neopterin, and liver enzyme concentrations, and patients were offered funduscopic examination. Subjects' records were reviewed an average of 9.1 months after enrollment for evidence of subsequent CMV retinitis. Three of the original cohort proved ineligible because of CD4+ count > 100/microliters; CMV antibody was present in 96% of the remainder. Isolation of CMV from blood was uncommon (2 of 93 seropositive subjects) whereas viruria occurred in 51.6%; likelihood of having a positive urine culture was significantly related to the subject's absolute CD4+ lymphocyte count: 60% for those with CD4+ < or = 50/microliters, vs. 26.1% for those with CD4+ 51-100/microliters. Neither serum p24 antigen nor neopterin was predictive of CMV in urine or blood. No subjects submitting to ophthalmologic exam had unsuspected CMV retinitis. Subsequent development of retinitis correlated with CMV viruria on entry: 13.5% if urine-positive, 1.9% if negative (p = 0.029; Fisher exact test).

Adult↗
PubMed1995

Serotonin 5-HT2 receptor availability in chronic cocaine abusers.

Serotonin 5-HT2 receptor availability was evaluated in chronic cocaine abusers (n = 19) using positron emission tomography and F-18 N-methylspiperone and was compared to control subjects (n =19). 5-HT2 Receptor availability was measured in frontal, occipital, cingulate and orbitofrontal cortices using the ratio of the distribution volume in the region of interest to that in the cerebellum which is a function of Bmax/Kd. 5-HT2 Receptor availability was significantly higher in cingulate and orbitofrontal cortices than in other frontal regions or occipital cortex. The values were not different in normal subjects and cocaine abusers. These results did not show any changes in 5-HT2 receptor availability in cocaine abusers as compared to the control subjects.

Adolescent↗