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Biomedical subjects

D Richman

Publications and source records attributed to D Richman.

At least 37 records · Page 2Linked to original sources
PubMed1995

The tolerability and pharmacokinetics of N-butyl-deoxynojirimycin in patients with advanced HIV disease (ACTG 100). The AIDS Clinical Trials Group (ACTG) of the National Institute of Allergy and Infectious Diseases.

Twenty-nine patients were enrolled in a phase I dose-escalating tolerance trial of N-butyl-deoxynojirimycin, an alpha-glucosidase I inhibitor that inhibits human immunodeficiency virus (HIV)-1 replication by altering glycosylation of gp120. Dosing was begun at 8 mg/kg/day and subsequent doses were 16, 32, 48, and 64 mg/kg/day. The maximum tolerated dose was not achieved because of slow accrual and because the study was stopped after the finding of cataracts in initial long-range rat toxicology studies. These cataracts were later shown to be transient and not found in other animals. The most common side effects were gastrointestinal, with diarrhea and flatulence occurring in most subjects, which seemed to partially improve on a modified diet that excluded complex carbohydrates. Grade III elevations in liver function tests were seen in two patients. Grade III leukopenia and neutropenia were seen in seven patients, but were only severe enough in two to require discontinuation. No significant trends in CD4 cell counts or HIV-1 p24 levels were noted.

1-Deoxynojirimycin↗
PubMed1995

Tat-independent replication of human immunodeficiency viruses.

The replication of human immunodeficiency retroviruses involves a complex series of events that is regulated at both transcriptional and posttranscriptional levels. The tat gene product is a potent trans-activator of viral transcription and therefore an attractive target for the development of antiviral drugs. Tat-defective HIV-1 proviral DNA clones have been shown previously to be replication defective. In this study, we report that tat-defective HIV-1 and HIV-2 viral DNA transfected into U937 cells can direct efficient viral replication in the presence of transcriptional stimulators such as TNF-alpha and PMA. In MT-4 cells, tat-defective HIV-1 can replicate without any stimulation. The viruses recovered from MT-4 cells remained tat defective defined by their inability to infect T cell lines (e.g., Molt 4/8) although replication could be rescued with cytokines. Limited replication was observed in primary mononuclear cells. Furthermore, we showed that Ro 24-7429, a potent tat antagonist and antiviral compound, failed to suppress HIV-1 replication in TNF-alpha-stimulated T cells. These results have important implications for targeting tat as a therapeutic strategy for AIDS.

Benzodiazepines↗
PubMed1995

Use of component analyses to identify active variables in treatment packages for children with feeding disorders.

We evaluated the separate components in treatment packages for food refusal of 4 young children. First, treatment packages were implemented until food acceptance improved. Next, a component analysis was conducted within a multielement or reversal design to identify the active components that facilitated food acceptance. The results indicated that escape extinction was always identified as an active variable when assessed; however, other variables, including positive reinforcement and noncontingent play, were also identified as active variables for 2 of the children. The results suggest that the component analysis was useful for identifying variables that affected food acceptance.

Child, Preschool↗
PubMed1993

Amino acid substitutions in HIV-1 reverse transcriptase with corresponding residues from HIV-2. Effect on kinetic constants and inhibition by non-nucleoside analogs.

Nevirapine is a highly potent and specific inhibitor of human immunodeficiency virus type 1 (HIV-1) polymerase, but is inactive against HIV-2 and other polymerase. Previous studies demonstrated that residues 176-190 of HIV-1 reverse transcriptase (RT) can confer nevirapine sensitivity to HIV-2 RT. To better characterize the role of this sequence in HIV-1 RT, we have progressively substituted residues 176-190 of HIV-2 RT for those of HIV-1 RT and monitored the impact on the kinetic properties; inhibitory activity of nevirapine (11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[2,3-b:2',3'-e] [1,4]diazepin-6-one), E-BPU (5-ethyl-1-benzyloxymethyl-6-(phenylthio)-uracil), and TIBO-R82150 ((+)-S-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo[4,5,1-j k] [1,4]benzodiazepin-2(1H)-thione); and inhibitor-induced fluorescence changes of the mutant enzymes. The study revealed that in addition to Try-181 and Tyr-188, a new amino acid residue (Gly-190) plays an important role in determining susceptibility to nevirapine and E-BPU, but not to TIBO-R82150. These data argue that these non-nucleoside inhibitors fit differently, even though they share a common binding pocket. Nevirapine was seen to exert inhibitory activity by altering the interaction of the enzyme with the template-primer. Kinetic parameters were modulated by the template (DNA versus RNA) as well as by some of the mutations.

Amino Acid Sequence↗
PubMed1993

2',3'-dideoxycytidine (ddC) toxic neuropathy: a study of 52 patients.

We administered the antiviral agent 2',3'-dideoxycytidine (ddC) to HIV-infected patients with either ARC or AIDS as part of the AIDS Clinical Treatment Group protocol 012 and serially evaluated them with neuropathic symptom questionnaires, neurologic examinations, nerve conduction studies, and quantitative sensory testing (QST). All patients treated with high-dose ddC (0.06 and 0.03 mg/kg every 4 hours) developed a painful, predominantly sensory peripheral neuropathy, with a mean onset of 7.7 weeks, which reached severe intensity over several days. Abnormalities of vibration QST threshold preceded clinical symptoms. Treatment with 0.01 mg/kg every 4 hours produced a similar neuropathy, although of milder severity, later onset (mean, 9.3 weeks), and slower progression. In these patients, the onset of clinical symptoms and QST abnormalities were coincident. Only two of six patients treated with 0.005 mg/kg every 4 hours developed clinical or laboratory evidence of neuropathy; in both cases it was very mild and delayed in onset (26 weeks). All patients treated with high-dose ddC reported progression of symptoms (coasting) for 2 to 3 weeks following discontinuation of therapy. This study documents a painful sensory neuropathy resulting from treatment with ddC. With high-dose treatment, only the rapidity of onset and progression differentiated it from the distal, predominantly sensory neuropathy of AIDS.

HIV Infections↗
PubMed1991

Human immunodeficiency virus type 1 mutants resistant to nonnucleoside inhibitors of reverse transcriptase arise in tissue culture.

We have recently described a nonnucleoside compound that specifically inhibits the reverse transcriptase of human immunodeficiency virus type 1 (HIV-1), the causative agent of AIDS. This compound, nevirapine (BI-RG-587), interacts with highly conserved tyrosine residues at positions 181 and 188 in the reverse transcriptase to inhibit the recombinant enzyme and virus replication in cell culture with 50% inhibitory concentrations in the 40 nM range. HIV-1 variants resistant to nevirapine emerged with passage in cell culture in the presence of drug. This resistant phenotype was stable with continued passage in the absence of drug. These mutants had a substitution of cysteine for the tyrosine at position 181. Introduction of this mutation into the recombinant enzyme increased the inhibitory concentration of nevirapine 100-fold. Substitution of cysteine for tyrosine at residue 181 into the wild-type viral genome conferred a similar reduction in susceptibility to nevirapine. Mutants were also resistant to a tetrahydroimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-one and -thione derivative and two 6-phenylthiouracil derivatives but retained their sensitivity to the other reverse transcriptase inhibitors, 3'-azido-3'-deoxythymidine and foscarnet.

Amino Acid Sequence↗
PubMed1991

Effect of parainfluenza infection on gas exchange and FRC response to anesthesia in sheep.

We examined the interaction of viral pneumonitis with the respiratory effects of halothane/N2O anesthesia in six tracheostomized sheep. Ventilation-perfusion (VA/Q) distribution, pulmonary artery pressure (PAP), metabolic rate (VO2), and functional residual capacity (FRC) measurements were compared in awake and anesthetized animals before and 1 week after inoculation by tracheal instillation of ovine parainfluenza type-3 (PI-3) virus. Awake shunt (VA/Q less than 0.005) was 0.6 +/- 0.4% (+/- standard deviation [SD]) before, versus 3.9 +/- 2.0% after PI-3 infection (P less than 0.05). Awake arterial O2 tension (PaO2) was 139.9 +/- 14.0 mmHg before and 114.5 +/- 8.7 mmHg after infection (P less than 0.05). Mean PAP increased from 6.0 +/- 1.9 mmHg before to 11.5 +/- 1.6 mmHg after infection (P less than 0.05). Anesthesia shunt increased to 5.7 +/- 2.3% before and 11.2 +/- 3.4% after PI-3 (P less than 0.05 for the change from awake, and P less than 0.05 for a PI-3 anesthesia shunt difference). PAP was not significantly different from awake, either before or after infection. Anesthesia also produced an average 14.8 +/- 3.8% FRC reduction before and 17.4 +/- 6.4% reduction after infection (P less than 0.05 for FRC reduction with anesthesia, not significantly different for PI-3). Three of the six sheep developed shunt at higher FRCs after infection, both awake and during anesthesia; however, the average slope of the shunt/FRC response to anesthesia was unchanged, suggesting that this was not a neurogenic form of auto-PEEP. We therefore conclude that viral infection significantly enhanced the pulmonary effects of anesthesia.

Anesthesia, Inhalation↗
PubMed1991

BI-RG-587 is active against zidovudine-resistant human immunodeficiency virus type 1 and synergistic with zidovudine.

A series of dipyridodiazepinones have been shown to be potent inhibitors of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase. The lead compound, BI-RG-587, had a 50% inhibitory concentration of 84 nM against HIV-1 reverse transcriptase activity. This compound reduced plaque formation of HIV-1 in HeLa cells expressing the CD4 receptor by 50% at 15 nM. BI-RG-587 at comparable concentrations inhibited the production of p24 antigen following the acute infection of CEM T-lymphoblastoid cells or primary human monocyte-derived macrophages with HIV-1. No inhibitory effects against HIV-2 or against three picornaviruses were detected. Zidovudine (3'-azido-3'-deoxythymidine [AZT])-susceptible and AZT-resistant isolates of HIV-1 were equally susceptible to BI-RG-587. AZT and BI-RG-587 exhibited synergistic inhibition of HIV-1BRU at all concentrations examined.

Antigens, Viral↗
PubMed1991

Long-term safety and efficacy of zidovudine in patients with advanced human immunodeficiency virus disease. Zidovudine Epidemiology Study Group.

An epidemiologic study was initiated in 1987 to evaluate the long-term safety and efficacy of zidovudine in patients with advanced human immunodeficiency virus disease. Data from 886 patients with the acquired immunodeficiency syndrome (AIDS) or AIDS-related complex and CD4+ lymphocyte count less than 0.25 x 10(9)/L are reported. Eighteen-month survival was 67% for the cohort. Pretreatment factors associated with increased survival time included index diagnosis of AIDS-related complex, hematocrit of 0.35 or greater, CD4+ lymphocyte count of 0.15 x 10(9)/L or greater, high functional status, and time from diagnosis of AIDS to treatment of less than 60 days. By proportional hazards analysis, development of serious anemia was the most significant factor associated with early death. Receiving zidovudine for a high proportion of time significantly improved chances of survival even if anemia developed. Serious leukopenia occurring in 37% and serious anemia occurring in 32% of patients. Nonhematologic adverse events were uncommon and no previously unreported adverse events were seen.

Adult↗
PubMed1990

Falls efficacy as a measure of fear of falling.

We developed the Falls Efficacy Scale (FES), an instrument to measure fear of falling, based on the operational definition of this fear as "low perceived self-efficacy at avoiding falls during essential, nonhazardous activities of daily living." The reliability and validity of the FES were assessed in two samples of community-living elderly persons. The FES showed good test-retest reliability (Pearson's correlation 0.71). Subjects who reported avoiding activities because of fear of falling had higher FES scores, representing lower self-efficacy or confidence, than subjects not reporting fear of falling. The independent predictors of FES score were usual walking pace (a measure of physical ability), anxiety, and depression. The FES appears to be a reliable and valid method for measuring fear of falling. This instrument may be useful in assessing the independent contribution of fear of falling to functional decline among elderly people.

Accidental Falls↗
PubMed1989

T cell recognition of HIV synthetic peptides in a natural infection.

Because T cell responses are critical for defense against viral infections, a series of synthetic peptides derived from the predicted sequence for HIV-1 proteins gp41, pg120, gag, and viral polymerase were used to test the T cell proliferative response of HIV-1 seropositive individuals. Of HIV-1-infected donors from various clinical categories 90% (27/30) had sensitized cells that proliferated in response to at least one of 21 HIV peptides tested. Cells from HIV seronegative controls did not proliferate (0/9) in response to these HIV peptides. Individuals with fewer clinical manifestations of HIV-1 disease responded to a greater number of peptides (average for asymptomatic seropositives = 8.1 peptides; AIDS patients averaged 2.0). The number of peptides recognized also correlated with absolute number of CD4+ cells, but not with delayed cutaneous hypersensitivity to a (non-HIV) battery of Ag. However, clinical stage at no time correlated with the response to any particular peptide. Response patterns differed considerably among individuals, and some peptides stimulated proliferation in many (48%) HIV-infected donors (peptides gp41-2 and pol-3), whereas another peptide elicited no T cell response in any donor tested (peptide gp120-8). We have also begun to investigate the basis for individual heterogeneity of T lymphocyte proliferative responses of HIV-infected donors to the 21 HIV synthetic peptides. Peptide structure and HLA class II determinants both influenced patterns of lymphocyte responses. Reactivity correlated with peptide size, the presence of alpha and beta secondary structure and lack of reverse turn potential. Hydropathy and charge had no predictive value. Peptides derived from HIV sequences that vary highly among strains tended to be recognized less frequently. HIV-infected lymphocyte donors were HLA typed to examine the influence of the MHC on T lymphocyte proliferation. Analysis of the frequencies of individuals reacting to specific peptides, when compared to the allele frequencies in the population at large, indicated association of some responses to DR alleles. More DR association was observed with peptides that showed "moderate" reactivity than with those that were "highly" reactive. We suggest that highly reactive peptides are capable of forming a structure closer to an "ideal" T cell epitope that can associate with many DR alleles. In contrast, "moderately" reactive determinants have less favorable structures for interaction, are more limited in their ability to interact and therefore show more restriction to specific class II alleles.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1989

Circulating p24 antigen levels and responses to dideoxycytidine in human immunodeficiency virus (HIV) infections. A phase I and II study.

STUDY OBJECTIVE: To determine the safety and efficacy of dideoxycytidine in patients with the acquired immunodeficiency syndrome (AIDS) or advanced AIDS-related complex. DESIGN: A partially randomized phase I and II outpatient, dose-ranging study. SETTING: Four university medical centers involving government-supported referral AIDS Clinical Trial Units. PATIENTS: Sixty-one patients with AIDS or advanced AIDS-related complex and 100 pg/mL or more serum p24 antigen titers. INTERVENTIONS: Dideoxycytidine was administered orally at 0.06, 0.03, 0.01, or 0.005 mg/kg body weight every 4 hours for 3 to 6 months depending on tolerance and benefit. MEASUREMENTS AND MAIN RESULTS: In patients receiving 0.06 and 0.03 mg/kg, diffuse erythematous rash, fever, and aphthous stomatitis occurred in the first weeks of therapy, but resolved later. Hematopoietic suppression was rare. Peripheral sensory neuropathy occurred in patients receiving 0.06 mg/kg and 0.03 mg/kg and improved after discontinuation of therapy. Serum p24 antigen fell significantly (P less than 0.01) from baseline entry values in most of these patients. The CD4 lymphocytes rose transiently at the 0.03 mg/kg dosage. At the 0.005 mg/kg dosage, skin rash, fever, and aphthous stomatitis were mild or absent. Peripheral neuropathy, which occurred in all patients receiving 0.01 mg/kg was less severe than at higher dosages. At the 0.005 mg/kg dosage, peripheral neuropathy was occasionally seen. Significant suppression of serum p24 antigen was seen in most patients with AIDS-related complex receiving 0.01 mg/kg and less frequently in patients receiving 0.005 mg/kg. CONCLUSIONS: Less toxic regimens of dideoxycytidine merit clinical assessment for advanced anti-human immunodeficiency virus-1 (HIV) infection. Several studies alternating dideoxycytidine and zidovudine are in progress.

AIDS-Related Complex↗
PubMed1988

Rapid and reversible modulation of T4 (CD4) on monocytoid cells by phorbol myristate acetate: effect on HIV susceptibility.

The effect of phorbol myristate acetate (PMA) on T4 (CD4) expression by monocytoid cells was studied. Greater than 99% of untreated U937 and HL-60 cells expressed surface T4 as measured with a fluorescence-activated cell sorter. The percentage of T4 positive cells decreased to less than 20% after incubation with PMA (10(-8) M). A decrease was observed within 15 min of PMA exposure, was maximal within 1 hr, and persisted for at least 3 days in the continuous presence of PMA. The susceptibility of untreated and PMA-treated U937 cells to human immunodeficiency virus (HIV) was also studied. Pretreatment of cells with PMA for 18 hr decreased the production of viral RNA and p24 antigen 24 hr after infection. The dose of PMA resulted in a parallel reduction of both T4 expression and infection by HIV. When PMA was washed from cultures and replaced with fresh medium for 48 hr, then T4 expression and the production viral RNA and p24 antigen following infection were restored. These data suggest that pharmacologic manipulation of surface T4 expression may have a potential role in the prevention or treatment of HIV infection.

Acquired Immunodeficiency Syndrome↗
PubMed1988

Acquired immunodeficiency syndrome. Magnetic resonance patterns of brain involvement with pathologic correlation.

Magnetic resonance brain scans of 30 patients with either acquired immunodeficiency syndrome (AIDS) or AIDS-related complex were reviewed. Twenty patients had focally abnormal neurological examination results at the time of scanning. Pathological diagnosis was available in nine. Four patterns of abnormality were observed on T2-weighted images. Multiple discrete high-signal foci (pattern A) were found in patients with toxoplasmosis and progressive multifocal leukoencephalopathy. Large, bilateral patchy to confluent high-signal areas within the white matter (pattern B) represented a white matter encephalitis secondary to cytomegalovirus or human immunodeficiency virus. Generalized enlargement of the cortical sulci and ventricles (pattern C) probably reflected atrophic changes from the chronic human immunodeficiency virus infection and prolonged debilitating illness. Solitary high-signal-intensity lesions (pattern D) suggested a nonviral opportunistic infection. Differential diagnosis of brain abnormalities in patients with AIDS can be assisted by recognition of these characteristic patterns.

Acquired Immunodeficiency Syndrome↗