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Biomedical subjects

H Friedman

Publications and source records attributed to H Friedman.

At least 217 records · Page 12Linked to original sources
PubMed1991

Delta-9-tetrahydrocannabinol augments murine retroviral induced immunosuppression and infection.

Delta-9-tetrahydrocannabinol (THC), the major psychoactive component in marijuana, and the murine retrovirus, Friend leukemia virus (FLV), have been demonstrated to depress cellular immune function, including lymphocyte blastogenic transformation and natural killer cell activity. The present study demonstrates tht the two agents can work in concert to depress these immune activities more severely than either agent administered by itself. When 7.5-10 micrograms/ml THC was added in vitro to spleen cells from mice infected 2-4 weeks earlier with FLV there was a noticeable decrease, beyond that seen with the drug or virus alone, for both lymphocyte blastogenesis and natural killer cell cytotoxicity. In addition, when both FLV and THC were administered to mice concurrently with infection by herpes simplex virus (HSV), mortality attributed to the retrovirus infection occurred significantly more rapidly than in the absence of the drug and HSV. The data indicate that THC acted in the presence of a HSV infection to enhance the FLV induced mortality. By extrapolation to the human condition, these results suggest that marijuana could serve as a cofactor, possibly in conjunction with opportunistic pathogens, in the progression of infection due to the human immunodeficiency virus from latency to overt acquired immunodeficiency syndrome.

Animals↗
PubMed1991

Extent and variability of the first-pass elimination of adinazolam mesylate in healthy male volunteers.

The pharmacokinetics of adinazolam and N-desmethyladinazolam (NDMAD) were studied in 14 healthy male volunteers who received 15 mg adinazolam mesylate orally as a solution and 5 mg adinazolam mesylate intravenously in a crossover design. Two weeks prior to the crossover study, each subject received 5 mg/kg indocyanine green (ICG) as an intravenous bolus injection to estimate liver blood flow. The absolute bioavailability (F), calculated as the dose-corrected ratio of oral to iv adinazolam area under the curve (AUC) values, was found to be 39%. NDMAD AUC values were similar following oral and iv administration, and adinazolam mean absorption time was approximately 0.77 hr. Thus, adinazolam is completely and rapidly absorbed after oral administration in man; the incomplete bioavailability is due to first-pass metabolism. Mean liver blood flow, adinazolam systemic clearance, blood/plasma ratio, and extraction ratio were 1189 ml/min, 498 ml/min, 0.70, and 0.57, respectively. The extraction ratio agrees with that calculated as 1-F (0.62), suggesting that the liver is primarily responsible for first-pass metabolism of adinazolam. The unbound fraction of adinazolam in plasma was 0.31 (range, 0.25-0.36); adinazolam free intrinsic clearance (a reflection of metabolic capacity) was 4285 ml/min (range, 2168-6312 ml/min). These results suggest that the majority of the variability in adinazolam plasma concentrations following oral administration is due to the variability in the metabolic capacity of the liver for adinazolam, rather than variability in plasma protein binding.

Adult↗
PubMed1991

Serum time curve characteristics of a fixed dose of beta-carotene in young and old men.

The present study was designed to evaluate age-related differences in serum beta-carotene time curve response characteristics when a beta-carotene dose was given in conjunction with 1500 kcal over the course of a day. On two consecutive days, seven old (73 +/- 4 years) and six young (24 +/- 1 years) men were each fed three 500-kcal meals of an isotonic liquid formula diet containing only trace amounts of beta-carotene. On the first day of testing, no supplemental beta-carotene was given (baseline day). A 15 mg dose of beta-carotene was fed with the morning meal on the second day (test dose day). Fasting blood and hourly blood samples were obtained for 8 consecutive hours on both days. Additional blood was drawn 24 and 48 hours after the test beta-carotene dose. There were no statistical differences in baseline beta-carotene concentrations between the two age groups tested, but, because of high individual variability, serum time curve characteristics were adjusted for fasting beta-carotene levels. After adjustment, the postdose serum beta-carotene response was two to three times greater (p less than or equal to 0.04) in young subjects, as evaluated by peak concentration, area under the curve, or ascending slope of the serum response curve. Examination of factors besides age group that may have accounted for these results suggests that the serum response of the elderly may be more a function of body composition and/or serum lipid patterns than of age per se. However, in the present US population, it may not be valid to control for these factors, which are both closely related to aging.

Adult↗
PubMed1991

Marijuana components suppress induction and cytolytic function of murine cytotoxic T cells in vitro and in vivo.

Killer lymphocytes play a major role in host defense against tumors and infectious diseases. Previously, we reported that delta-9-tetrahydrocannabinol (THC) and II-hydroxy-delta-9-tetrahydrocannabinol (II-hydroxy-THC) suppressed the cytolytic activity of cultured natural killer (NK) cells. Also, we showed that the drugs appeared to be affecting a stage in the killing process subsequent to the binding of the killer cell to the target cell. In the present report, we have extended these studies to an examination of the effect of cannabinoids on the activity of cytotoxic T lymphocytes (CTLs). The cytolytic activity of CTLs generated by cocultivation with either allospecific stimulators or TNP-modified-self stimulators were suppressed by both THC and II-hydroxy-THC treatment. Allospecific CTLs generated in vivo were also inhibited by an in vitro exposure to either THC or II-hydroxy-THC, and the sensitivity of these cells to drug effects appeared to be greater than the sensitivity of the in vitro generated CTLs. Suppression of cytolytic function by THC and II-hydroxy-THC was maximal after a 4-h drug treatment, suggesting that the drug effects were inducible and therefore required a finite period of time to develop maximally. As seen in previous studies involving NK cells, drug treatment of mature CTLs appears to have little effect on the binding capacity of these cells for the target. However, the maximal killing capacity of the cells and the frequency of CTLs were significantly reduced by drug treatment. In addition to suppressing the cytolytic activity of mature effector CTLs, we also show that drug treatment inhibits both the proliferation of lymphocytes responding to an allogeneic stimulus and the maturation of these lymphocytes to mature CTLs. Similarly, CTL activity developing in vivo could be inhibited by THC injection. These results suggest that CTLs are inhibited by cannabinoids by at least two mechanisms. First, the cytolytic activity of mature killers is suppressed at some point beyond the binding to the target cell. Second, the cannabinoids appear to suppress the normal development of these mature effector cells from less mature precursor cells.

Animals↗
PubMed1991

Age-related effects of chronic ethanol intake on vitamin A status in Fisher 344 rats.

The present study was designed to investigate the interaction of age and ethanol on vitamin A status in rats. Rats aged 2 and 19 mo were fed a liquid diet containing 36% of total energy as ethanol or pair-fed a diet containing isoenergetic carbohydrate in place of ethanol. After 3 wk older rats had lower serum retinol (P = 0.04) and higher vitamin A concentrations in liver (P = 0.0001), esophagus (P = 0.0001) and the proximal (P = 0.03) and distal (P = 0.0001) colon than younger animals. Hepatic microsomal cytochrome P-450, retinyl ester hydrolase (REH) and cellular retinol-binding protein (cRBP) were significantly reduced; acyl coenzyme A: retinol acyltransferase (ARAT) was increased; and alcohol (retinol) dehydrogenase (ADH) activity was unchanged with age. Ethanol ingestion increased serum retinol as well as esophageal and colonic vitamin A levels in both age groups. Hepatic cRBP decreased further in the older rats with ethanol feeding, but no change was noted in the percentage of hepatic vitamin A as retinol or retinyl esters. Ethanol ingestion decreased REH (P = 0.0001) and ARAT activities (P = 0.02) and increased cytochrome P-450 (P = 0.04) but had no effect on the activity of ADH in either age group. These data indicate that, regardless of age, chronic ethanol ingestion significantly alters the tissue distribution of vitamin A; however, ethanol reduced cRBP levels only in older rats.

Acyltransferases↗
PubMed1991

Legionella pneumophila growth in macrophages from susceptible mice is genetically controlled.

Growth of the intracellular opportunistic bacterium Legionella pneumophila in macrophages from A/J mice is a vigorous as growth in macrophages from susceptible guinea pigs and human monocytes, whereas growth is inhibited in macrophages from other mouse strains, such as nonpermissive BALB/c mice. Permissiveness versus nonpermissiveness of macrophages from A/J versus BALB/c mice appeared to be controlled by a genetic mechanism dependent upon a single gene or a closely clustered family of genes. Susceptibility versus resistance of macrophages from F1 offspring of these two strains of mice and macrophages from backcrossed mice prepared from F1 hybrids and the original parental strain showed a segregation of permissiveness for growth of Legionella in vitro, consistent with genetic control.

Animals↗
PubMed1990

Production of tumor necrosis factor (TNF-alpha) and lymphotoxin (TNF-beta) by murine pre-B and B cell lymphomas.

Media from murine pre-B and B lymphoma cell cultures, but not from myeloma cell cultures, was cytotoxic to WEHI 164 cells, causing these TNF-sensitive targets to release 51Cr. The cytotoxic activity in the culture medium reached maximum levels approximately 4 days after the cell culture was initiated. The constitutive production of the factors was not influenced by depletion of serum from the medium or by the addition of either phorbol ester or bacterial endotoxin. The factor has a Mr greater than 10 kDa, and its cytotoxicity was abolished by anti-serum against murine TNF. Northern blot analysis with the use of cDNA probes to murine tumor necrosis factor (TNF-alpha) and lymphotoxin (LT, TNF-beta) showed high levels of TNF-mRNA in the pre-B cell lines, lower levels in the mature B cell lines and no TNF-mRNA in the myeloma cell lines. LT mRNA was present in pre-B cell lines, at a much lower concentration in only one of the B cell lines, and was not present in three other B lymphomas or in the myelomas tested. The results show a positive correlation between the presence of TNF and/or LT mRNA and the 51Cr-releasing activity present in the cell culture medium. Our data indicate that TNF and LT can be produced by murine B cells and that the synthesis of these cytokines may be restricted to certain differentiation stages of the B cell lineage.

Animals↗
PubMed1990

A1, Cw7, B8, DR3 HLA antigen combination associated with rapid decline of T-helper lymphocytes in HIV-1 infection. A report from the Multicenter AIDS Cohort Study.

108 seropositive homosexual men were examined for associations between HLA phenotype and progression of human immunodeficiency virus type 1 (HIV-1) infection. Among men of predominantly European ethnic origin, 49 with very rapid 2-year declines in CD4+ lymphocyte counts showed significant differences in antigen frequencies from 59 men matched for ethnic background, study centre, and initial CD4+ cell count but with little or no decline in CD4+ cells. Relations of varying strength (odds ratios 6.1-10.3) were seen with several HLA antigens often linked in the A1-Cw7-B8-DR3 haplotype. The strongest relation was with the A1, Cw7, B8 combination (odds ratio 10.3). Associations between these antigen combinations and development of AIDS were weaker. The frequency of HLA A24 was also significantly higher in rapid than in slow decliners (odds ratio 4.3). These findings strengthen the suggested link between the product of a gene in the A1-Cw7-B8-DR3 haplotype and HIV-1-related disease.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Clinical pharmacology of predisintegrated ibuprofen 800 mg tablets: an endoscopic and pharmacokinetic study.

Thirty-five healthy adults were randomized to receive either: (1) ibuprofen 800 mg tablets; (2) ibuprofen 800 mg aqueous suspension; (3) ibuprofen 800 mg orange juice suspension; or (3) 325 mg aspirin tablets. All treatments were tid for 7 days. Pharmacokinetic sampling was conducted on days 1, 4 and 8. Gastroduodenoscopy was performed on days 1 and 8. Side effects and safety laboratory tests were monitored throughout the study. On day 8 the aspirin group showed significantly more gastric irritation than all of the ibuprofen groups (P less than .005). Both ibuprofen suspension groups showed more gastric irritation than the ibuprofen tablet group (P less than .1). The duodenal scores did not differ among the treatment groups. The aspirin group experienced a higher rate of tinnitus and abdominal pain. The rate and extent of absorption of the ibuprofen suspensions were significantly less than that of the tablets. These data suggest that the taking of ibuprofen as an extemporaneous suspension is therapeutically inferior to ibuprofen tablets and therefore should be discouraged.

Adult↗
PubMed1990

Human umbilical cord blood: a clinically useful source of transplantable hematopoietic stem/progenitor cells.

This is a review and discussion of studies leading to the first use of human umbilical cord blood, material usually discarded, for the provision of stem/progenitor cells for clinical hematopoietic reconstitution. This prospect arose as a result of extensive studies of the harvesting and cryopreservation of cord blood and of its numerical content of progenitor cells demonstrable in vitro. A male patient with Fanconi anemia (FA) was conditioned with a modified regimen of cyclophosphamide and irradiation that accommodates the abnormally high sensitivity to these agents that is characteristic of FA. Cryopreserved cord blood had been retrieved at birth from a female sibling known from prenatal testing to be unaffected by FA and to be human leukocyte antigen (HLA)-compatible with the prospective sibling recipient. After conditioning and therapeutic infusion of thawed cord blood, successful hematopoietic reconstitution was indicated by the general health of the patient, who had previously required supportive transfusions, by satisfactory hematological criteria and by counts of hematopoietic progenitor cells of various types in the bone marrow. Complete engraftment of the myeloid system with donor cells was evident from cytogenetics, ABO typing, study of DNA polymorphisms, and normal cellular resistance to cytotoxic agents that reveal the fragility of FA cells; the blood contained a residuum of host lymphocytes exhibiting chromosomal damage, but the trend has been towards eliminating these damaged cells. This implies that cord blood from a single individual should provide sufficient reconstituting cells for effective hematopoietic repopulation of an autologous or an HLA-compatible allogeneic recipient.

Blood Transfusion↗
PubMed1990

Immunoadjuvanticity of endotoxins and nontoxic derivatives for normal and leukemic immunocytes.

Studies with FLV infected mice, a model for retrovirus induced acquired immunodeficiency, showed that intact lipopolysaccharide rich extract from Serratia marcescens as well as the nontoxic polysaccharide derivative free of lipid A were equally adjuvantic in enhancing antibody formation to sheep erythrocytes, both in vivo and in vitro. The PS-rich endotoxin derivative had little or no toxic activity in leukemic animals as occurred with intact endotoxin. The adjuvanticity of both the nontoxic polysaccharide derivative as well as the intact endotoxin in enhancing antibody formation in FLV infected mice was evident also in vitro when spleen cells from infected animals were immunized with sheep erythrocytes simultaneously with the polysaccharide in comparison with the LPS. Supernatants from normal spleen cells treated in vitro either with the polysaccharide or the intact endotoxin showed immunoenhancing helper activity for both normal and FLV infected spleen cells and this enhancing activity was due to IL-1 induced by either bacterial product. Thus the immunoenhancing soluble mediator, i.e., IL-1, is induced equally by PS or LPS and has immunorestorative activity for FLV infected animals. The potential value of the nontoxic PS as an immunoadjuvant in retrovirus immunosuppressed lymphoid cells is evident. The results of these studies suggest that further investigations concerning the nature and mechanism involved in such adjuvancticity is warranted.

Adjuvants, Immunologic↗
PubMed1990

Auranofin-induced suppression of autoimmune antibody production and inflammation in genetically autoimmune-prone mice.

The gold compound auranofin and lobenzarit (CCA) were compared in regard to effects on development of an autoimmune-like disease in MRL/1 mice, which normally develop elevated levels of serum anti-DNA antibodies and rheumatoid factor as well as joint lesions similar to those seen in patients with rheumatoid arthritis. MRL/1 mice, which are genetically prone to development of autoimmune disease, were given auranofin or lobenzarit by gavage for 15 weeks, starting at 6 weeks of age. Mice were examined periodically for immunological abnormalities as well as histologic changes in articular joints. The auranofin-treated mice showed marked diminution in development of anti-DNA antibodies and serum rheumatoid factor as compared to control animals. Although higher than in the auranofin-treated animals, CCA-treated mice also had lower levels of serum autoantibodies than those seen in the control animals. Examination of limb joints for histopathologic changes indicated that the auranofin-treated animals developed only the slightest evidence of lesions as compared to control animals. CCA-treated mice also had a lessening of lesion development compared to control animals, but lesions were more developed than in auranofin-treated mice. This study indicates that auranofin is more effective than CCA in diminishing development of autoimmunity in MRL/1 mice.

Administration, Oral↗
PubMed1990

Age-related suppression of murine lymphoid cell blastogenesis by marijuana components.

Marijuana components modulate a variety of immune response parameters. The cannabinoids delta 9-tetrahydrocannabinol (THC) and 11-hydroxy-tetrahydrocannabinol (11 OH-THC) are known to depress the in vitro proliferative response of murine lymphoid cells to the mitogens concanavalin A (Con A) and phytohemagglutinin (PHA). In the present report the effects of THC and 11 OH-THC on adult thymus and spleen cells were compared to effects on lymphoid cells of those organs from juvenile mice at various ages. The results demonstrate differences in susceptibility to cannabinoid-induced suppression by lymphoid cells from different organs and different age mice. In adults, thymus cells were suppressed more readily than spleen cells. Splenocytes from mice under 2 weeks old were suppressed much more readily than those from older mice. Cell populations from organs with higher proportions of L3T4+/Lyt2- cells were more difficult to suppress. The possible mechanisms involved and directions for future work are discussed.

Age Factors↗
PubMed1990

Differential suppression of T-cell subpopulations by thc (delta-9-tetrahydrocannabinol).

THC (delta-9-tetrahydrocannabinol), the major psychoactive component of marijuana, has been shown to suppress various immune functions in vivo and in vitro. THC suppresses murine T-lymphocyte proliferation; however, the effects on T-cell subsets remain unclear. We have stimulated cultured murine splenocytes with the mitogens concanavalin A (Con A) or phytohemagglutinin (PHA) while exposing them to varying concentrations of THC. After three days, the cells were analyzed by the fluorescent activated cell sorter for the following T-cell markers--Thy1, L3T4 and Ly2. The Ly2 cells represent the suppressor/effector T-cells while L3T4 cells represent the helper T-cell subpopulations. The results show that the dose response suppressive effect of THC on T-cell proliferation reflects a preferential inhibition of Ly2 vs L3T4 cells. The effects of THC on other functional parameters are in the process of investigation.

Animals↗
PubMed1990

Clinical pharmacology of adinazolam and N-desmethyladinazolam mesylate after single oral doses of each compound in healthy volunteers.

The tolerance, pharmacokinetics, and pharmacodynamics of adinazolam and N-desmethyladinazolam (NDMAD) were assessed after single oral doses of 10, 30, and 50 mg adinazolam mesylate, NDMAD mesylate, and placebo. Within doses, six healthy male volunteers received these treatments in a double-blind crossover design. No clinically significant changes were observed in blood pressure, pulse, respiration, or clinical laboratory test results. Untoward effects were typical of benzodiazepines. Adinazolam and NDMAD kinetics were dose independent. Greater than 95% of the adinazolam dose was metabolized to NDMAD. Adinazolam and NDMAD mesylate produced dose-related increases in uric acid clearance and decreases in plasma uric acid. Both adinazolam and NDMAD mesylate administration resulted in dose-related sedation and decrements in psychomotor performance. Within doses, decrements produced by adinazolam and NDMAD were quantitatively similar. These results suggest that both adinazolam and NDMAD possess uricosuric activity and support the hypothesis that NDMAD primarily mediates benzodiazepine-like effects of adinazolam mesylate.

Administration, Oral↗
PubMed1990

Effects of beta-carotene repletion on beta-carotene absorption, lipid peroxidation, and neutrophil superoxide formation in young men.

The chemopreventive effects of beta-carotene are usually attributed to its antioxidant properties. To determine the effects of beta-carotene supplementation on different parameters of oxidative metabolism, 15 normal young male subjects (18-30 yrs) were placed on a carotenoid-free liquid diet for two weeks prior to entry into the study. Blood was then measured for five carotenoids, retinol, retinyl palmitate, retinol-binding protein, alpha-tocopherol, vitamin C, zinc, lipid peroxides, and neutrophil superoxide production. Absorption tests were performed with 15 mg of beta-carotene to determine absorption curves for each subject. Subjects were then divided into two groups and given either 15 (n = 7) or 120 (n = 8) mg of beta-carotene daily for four weeks along with the same carotenoid-free liquid diet. The absorption test and the blood measurements were repeated. After repletion with beta-carotene, serum lipid peroxide levels decreased in both groups (p less than 0.05), but no other changes were noted in either the neutrophil superoxide production or in the levels of any of the vitamins measured. In contrast to vitamin E, the superoxide scavenging ability of beta-carotene apparently does not contribute to its effects in lowering serum lipid peroxide levels.

Absorption↗
PubMed1990

Flowering Response of Pharbitis nil to Agents Affecting Cytoplasmic pH.

Permeant weak acids and auxins have been shown to reduce the cytosplasmic pH in several systems. Lactic, citric, formic, butyric, salicylic, parahydroxybenzoic, propionic acid, and sodium propionate inhibited the flowering response of Pharbitis nil seedlings when applied immediately before an inductive dark period. The acidic auxins IAA, indolebutyric, and alpha-naphtaleneacetic acid, as well as the nonacidic auxin alpha-naphtaleneaceteamid, also inhibited the flowering response. Inhibition was generally more pronounced with a 12-hour than with a 16-hour dark period. Salicylic acid and sodium propionate shifted the response curve of the dark period by about 2 hours. Salicyclic acid, sodium propionate, and indolebutyric acid were inhibitory when applied during the first few hours of the dark period. The permeant weak bases NH(4)Cl, procaine, and trisodium citrate enhanced the flowering response. NH(4)Cl reduced the length of the critical dark period. The inhibition of flowering by acids and auxins as well as the promotion of flowering by bases was obtained even when only the cotyledons had been treated. The inhibition of floral induction by auxins may not be dependent on their effect on the cytoplasmic pH.

Journal Article↗