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Biomedical subjects

H Friedman

Publications and source records attributed to H Friedman.

At least 253 records · Page 14Linked to original sources
PubMed1989

A large-sample study of diazepam pharmacokinetics.

Healthy male volunteers (n = 48) aged 18-44 years received a single 10-mg oral dose of diazepam. Plasma diazepam and desmethyldiazepam concentrations were measured at multiple points during the next 11 days. The distribution of peak plasma concentration (mean, 406 ng/ml) was not skewed and did not differ significantly from normal (Guassian). However, the distributions of elimination half-life (44.2 h), elimination rate constant (0.0219/h), clearance (26.6 ml/min), and volume of distribution (83 L) all were significantly skewed and deviated significantly fron normal. After logarithmic transformation, the distributions of elimination rate constant, elimination half-life, and volume of distribution were consistent with normal; however, this was not the case for time of peak plasma concentration. Thus, the pharmacokinetic characteristics of oral diazepam are highly variable even in a relatively homogeneous population. Parametric statistical testing procedures and pharmacokinetic forecasting schemes may be improved by more precise delineation of the underlying distributions for pharmacokinetic variables.

Adolescent↗
PubMed1989

Involvement of Calcium in the Photoperiodic Flower Induction Process of Pharbitis nil.

EGTA, a specific Ca(2+) chelator, inhibited the flowering response of Pharbitis nil when applied to the cotyledons immediately before the inductive dark period. Calcium sprayed 30 minutes after the EGTA blocked the effect of EGTA. The length of the critical dark period was increased both by EGTA and by LaCl(3). The calmodulin antagonists W-7 and chlorpromazine also reduced the flowering response. On the other hand, A23187, a calcium ionophore, increased the flowering response. Both EGTA and A23187 were effective at certain times of the photoperiod but had almost no effect when applied at other times. The results indicate that the level of endogenous Ca(2+) may be limiting for floral induction in Ph. nil. Ca(2+) seems to play a role during the early stages of the inductive dark period.

Journal Article↗
PubMed1989

Clearance of the antihistamine doxylamine. Reduced in elderly men but not in elderly women.

A single oral dose of doxylamine succinate 25 mg was administered to 21 young (20 to 43 years) and 22 elderly (60 to 87 years) volunteers. Multiple plasma doxylamine concentrations were determined during a 30-hour period after each dose. Elderly and young women did not differ significantly in peak plasma doxylamine concentration (Cmax) [116 vs 103 micrograms/L], time to Cmax (tmax) [2.4 vs 2.4 h], elimination half-life (12.2 vs 10.1 h), volume of distribution (179 vs 176 L) or clearance (191 vs 218 ml/min). Cmax (107 vs 108 micrograms/L) and tmax (2.1 vs 1.6 h) also did not differ between elderly and young men. However, elderly men had reduced doxylamine clearance (174 vs 240 ml/min, p less than 0.02; 2.5 vs 3.2 ml/min/kg, p less than 0.07) and prolonged half-life (15.5 vs 10.2 h, p less than 0.05). The reduced doxylamine clearance and prolonged half-life in elderly men, but not in elderly women, is similar to results for many other drugs which are transformed by oxidation.

Adult↗
PubMed1989

Induction of interleukin 1 by Legionella pneumophila in murine peritoneal macrophage cultures.

Legionella pneumophila-induced production of both membrane-associated and secreted interleukin 1 (mIL-1 and sIL-1, respectively) was examined utilizing peritoneal macrophages from BALB/c mice. The Legionella preparations for these studies included viable bacteria and formalin-killed whole cell preparations. Both of the preparations induced mIL-1 and sIL-1 in a dose-dependent fashion. However, the viable bacteria required about 1 log lower concentrations than the formalin-killed bacteria to induce the same level of IL-1 activity measured in the thymocyte proliferation assay. Kinetic studies showed that mIL-1 and sIL-1 were detectable within 4 hr after addition of either of the L. pneumophila preparations to the peritoneal macrophage cultures, with peak levels achieved within 24 hr. These results indicate that L. pneumophila is a potent inducer of both mIL-1 and sIL-1 in normal mouse peritoneal macrophage cultures.

Animals↗
PubMed1989

Unusual presentation of pulmonary edema in a hemodialysis patient.

Despite the technical advances made during the last several years, chronic dialysis still is plagued by continuing problems. Intermittent volume overload is one of the most common. The radiologic evidence of pulmonary edema can be confusing in the end-stage renal disease population. The following case illustrates a hemodialysis patient with pulmonary edema whose initial chest x-ray appeared more consistent with metastatic malignancy.

Diabetes Complications↗
PubMed1989

Beta-carotene serum response in young and elderly females.

This study was designed to investigate the effects of aging and food intake on the serum beta-carotene (BC) response curve in humans. Ten elderly (71 +/- 4 years) and 17 young (28 +/- 7 years) healthy females were given 15 mg BC with a semi-solid test meal devoid of BC and vitamin A. All the elderly and 10 young subjects (control A) received a test meal of 500 kcal while the remaining 7 young subjects (control B) were given 700 kcal. Subsequently, blood was drawn hourly for 8 h and again at 24 and 48 h. Serum carotenoids and retinoids were measured by HPLC and triglycerides (TG) and cholesterol by enzymatic methods. Small intestinal transit time was determined in the elderly and in control group A by a breath hydrogen test following ingestion of lactulose (12 g) with the test meal. The area under the absorption curve (AUC) of serum BC over the first 8 h was higher in the elderly subjects than in either control group A or B (P less than 0.001). The slopes of the BC and TG curves were significantly higher as compared to control A, but similar to control B. There was a positive correlation between the ascending slopes of the BC and TG absorption curves of all groups (P less than 0.001). The AUC of the retinyl ester serum response of the elderly group was greater than that of control A (P less than 0.001). The slope of this curve was steeper (P less than 0.01) in the elderly group as compared to control A, but was similar to control B. Intestinal transit time was similar in all groups. In young subjects, the larger test meal of control group B appeared to increase the rate of absorption of BC. These data indicate that the rate of intact BC absorption and its conversion to retinyl esters may be enhanced in old age as compared to younger subjects receiving the same amount of food. Age-related alterations of enterocytes and the intestinal lumen could account for this phenomenon.

Administration, Oral↗
PubMed1988

Tumor necrosis factor induction by Candida albicans from human natural killer cells and monocytes.

Other investigators have previously reported that TNF has been induced from macrophages by bacteria and, more recently, from NK cells by certain tumor cells. Sendai virus has also been reported to induce TNF from macrophages. We report here that an opportunistic fungi, Candida albicans, can also induce TNF, not only from human monocytes, but also from Percoll-fractionated large granular lymphocytes (LGL) which mediate NK function. Incubation of monocytes of LGL with C. albicans for 8 h was sufficient for detection of TNF release and peak induction was observed at 24 h. Induction of TNF from LGL did not require the participation of monocytes or T cells because treatment of the LGL with CD14 or CD15 to eliminate contaminating monocytes and CD3, CD4, or CD8 to eliminate contaminating T cells did not decrease the level of TNF produced from the treated LGL. Small T cells recovered from the denser fractions of the Percoll gradient had no ability to produce TNF, even when 10% monocytes were added to the T cells to provide accessory function. The phenotype of the TNF-producing LGL was CD2+, CD11+, CD16+, NKH1+, LEU7-. The TNF produced by both monocytes and LGL was neutralized by specific monoclonal and polyclonal anti-TNF but not by monoclonal antilymphotoxin. These results indicate that TNF production is a normal response of monocytes and LGL to stimulation by fungi such as C. albicans and that the release of TNF may be related to its ability to activate effector function to control Candida growth, which we have shown earlier for neutrophils with TNF.

Antibodies, Monoclonal↗
PubMed1988

Analysis of retinoids by direct exposure probe mass spectrometry.

Recently, our laboratory has investigated the depletion of Vitamin A and its metabolites in experimental animals. High Pressure Liquid Chromatography (HPLC) was used to measure retinal oxidase activity by monitoring the conversion of retinaldehyde (RALD) to retinoic acid (ROIC). In order to obtain more information about these compounds, a Direct Exposure Probe mass spectrometric method was developed to confirm the presence of ROIC and RALD in HPLC peaks. A rapid negative ion chemical ionization (NICI) method using ammonia as reagent gas was developed to detect the presence of ROIC and RALD with picogram sensitivity. The ROIC and RALD peaks were collected from HPLC, extracted with hexane, evaporated under nitrogen and reconstituted in ethanol before placing onto a rhenium filament with current programmed from 0-1.3 A at 50 mA/sec. The instrument employed was a Finnigan 4510 operated in the NICI mode and scanned from m/z 100-650 with a source temperature of 80 C. Other parameters were electron energy 140 eV and filament current at 0.25 mA. Prominent ions were generated at m/z 284 and m/z 300 for RALD and ROIC which were subsequently monitored in the selected ion monitoring mode. In summary, we have developed a rapid retinoid identification method (2.5 minutes) which is more sensitive (pg vs ng) than HPLC and does not require elaborate sample preparation or derivitization. This method can be used as an important adjunct to HPLC enzyme studies.

Chromatography, High Pressure Liquid↗
PubMed1988

Triazolam kinetics: interaction with cimetidine, propranolol, and the combination.

Nineteen healthy volunteers received a single 0.5-mg oral dose of triazolam on four occasions under the following conditions: (1) triazolam alone; (2) triazolam with cimetidine, 300 mg four times daily; (3) triazolam with propranolol, 40 mg four times daily; (4) triazolam with both cimetidine and propranolol. Triazolam kinetics were determined from multiple plasma concentrations measured during 24 hours after each dose. Compared with control, peak plasma triazolam concentration (Cmax) was significantly increased by cimetidine (5.4 versus 3.9 ng/mL), total area under the plasma concentration curve (AUC) increased (21.3 versus 16.1 ng/mL X hr), and oral clearance decreased (485 versus 668 mL/min). However triazolam half-life was not increased. During propranolol alone, triazolam Cmax (4.1 ng/mL), AUC (14.3 ng/mL X hr), and clearance (759 mL/min) did not differ significantly from control, whereas kinetic variables for triazolam with cimetidine plus propranolol were similar to those with cimetidine alone. Plasma free fraction for triazolam (17 to 18% unbound) did not differ significantly among the four treatment conditions. Mean steady-state plasma cimetidine concentrations during trials 2 and 4 were similar (1.04 versus .98 micrograms/mL), whereas plasma propranolol was significantly higher during cimetidine plus propranolol than with propranolol alone (47 versus 29 ng/ml, P less than .001). Thus cimetidine coadministration significantly inhibits triazolam clearance, causing increased triazolam AUC and Cmax, but without a prolongation in half-life. Propranolol itself does not impair triazolam clearance, nor does propranolol potentiate the inhibitory effect of cimetidine alone.

Adult↗
PubMed1988

Protective effects of tumor necrosis factor in experimental Legionella pneumophila infections of mice via activation of PMN function.

Tumor necrosis factor (TNF) was found in the lung lavage fluids of Legionella pneumophila-infected mice within 24 hr of intratracheal (i.t.) inoculation. Since this cytokine has been reported to activate polymorphonuclear leukocyte (PMN) function, the effect of TNF on the in vitro bactericidal capacity of PMN-enriched cultures was determined. Murine thioglycollate-elicited PMN which were treated with recombinant human TNF demonstrated augmented killing of L. pneumophila bacteria in vitro. Furthermore, treatment of PMN suspensions with cytokine-containing lung lavage fluid was found to enhance the bactericidal activity of PMN. The addition of anti-cachectin/TNF antibodies partially abrogated the stimulatory effects of the lavage fluid, suggesting that in vivo activation of PMN during the course of infection was likely, and that TNF was partially responsible for the enhanced bactericidal activity. In vivo treatment of animals with TNF resulted in significant protection of the animals from mortality. Furthermore, the rate of clearance of bacteria from the lung tissues of infected mice was increased in those animals treated with TNF, and correlated with the ability of this cytokine to protect the animals. These data suggest that the induction of TNF by Legionella bacteria during infection are involved in the non-specific host defense mechanisms, and that PMN activated by the TNF may be instrumental in clearing the organism from infected lung tissues, thereby protecting the animal.

Animals↗
PubMed1988

Legionella pneumophila immunity and immunomodulation: nature and mechanisms.

L. pneumophila is a facultative intracellular opportunistic pathogen ubiquitously present in the environment. Much is now known concerning the ecological niche of this organism as well as many other characteristics of these bacteria, including physiology and biochemistry. However, much less is known about immune mechanisms responsible for host resistance vs susceptibility. Not only outer membrane protein rich fractions but also LPS-rich components are potent immunogens, both in experimental animals such as susceptible guinea pigs and more resistant rodent species like rats and mice. Immunity to these organisms can be readily observed by a variety of serologic techniques. Antibody titers increase rapidly after exposure of individuals to these bacteria either by infection or immunization. However, such antibody does not appear to play an important role in host resistance. Serum antibody plus complement is not lytic for the bacteria in vitro. Furthermore, antibody appears to promote the phagocytosis of the bacteria by monocytes and/or macrophages in culture but such phagocytosis does not result in killing of the bacteria, merely an enhanced uptake and subsequent replication of the organisms. Studies on cellular immunity have focused attention on the role of T lymphocytes, monocytes and macrophages. In addition, cutaneous hypersensitivity is readily induced by infection or immunization of experimental animals with Legionella or antigenic components. In vitro correlates of hypersensitivity is also readily evident after infection or immunization. Although lymphoid cells from guinea pigs only show evidence of responsiveness to Legionella antigens by the lymphocyte blastogenic reaction after animals have been sensitized, peripheral blood monocytes from man as well as splenocytes from mice show evidence of responsiveness to Legionella even before known infection or sensitization. However, higher blastogenic responses become evident after sensitization or infection. In addition, interleukins, such as interleukin 1 and 2, as well as interferon and tumor necrotizing factor, appear in response to Legionella antigens and seem to play a role in resistance mechanisms. Cellular replication of Legionella in monocytes from man as well as macrophages from susceptible animals seems related to susceptibility or resistance to these organisms. Further analyses of the nature and mechanism of humoral vs cellular immune responses to Legionella antigens will provide valuable information about immunity and resistance to these intracellular pathogens in susceptible individuals.

Animals↗
PubMed1988

Kinetics, brain uptake, and receptor binding characteristics of flurazepam and its metabolites.

The benzodiazepine derivative flurazepam (FLZ) is widely used as a hypnotic, but the relative contributions of FLZ and its metabolites desalkylflurazepam (DA-FLZ), hydroxyethylflurazepam (ETOH-FLZ), and flurazepam aldehyde (CHO-FLZ) to overall clinical activity remain uncertain. A single 20 mg/kg dose of FLZ.HCl was administered to mice, with plasma and brain concentrations of FLZ and metabolites determined during 5 h after dosage. Brain and plasma concentrations of FLZ were maximal at 0.5 h after dosage, then declined rapidly in parallel, whereas those of DAFLZ were maximal at 2 h, then declined slowly. Concentrations of ETOH-FLZ, the most polar metabolite, were maximal at 0.5 h, and were undetectable after 3 h. Little CHO-FLZ was detected in either brain or plasma. A single 30-mg oral dose of FLZ.HCl was given to 18 human volunteers, with plasma levels determined over 9 days. FLZ was detected in plasma at low concentrations for no more than 3 h after dosage. ETOH-FLZ concentrations were higher and persisted for 8 h after dosage. CHO-FLZ reached intermediate peak levels and was present longer than FLZ or ETOH-FLZ. In contrast, DA-FLZ achieved the greatest peak concentrations, occurring at 10 h after dosage. Levels declined very slowly, with a mean half-life of 71.4 h, and were still detectable 9 days after FLZ dosage. Plasma free fractions (percent unbound) in mice were 40.3, 51.4, and 25.0% for FLZ, ETOH-FLZ and DA-FLZ, respectively; in humans, values were 17.2, 35.2, and 3.5%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

Non-toxic endotoxin polysaccharide induces soluble mediators which potentiate antibody production by murine retrovirus-suppressed splenocytes.

Mice infected with Friend leukemia virus show marked acquired immunodeficiency characterized by the impairment of immune function of spleen cells to various antigens, both in vivo and in vitro. The large mol. wt. endotoxin derived from Serratia marcescens, as well as a smaller non-toxic polysaccharide derivative, were found to augment the antibody responsiveness of spleen cells from normal as well as FLV-infected mice. In addition, serum from normal donor mice pretreated with BCG and injected either with endotoxin or the polysaccharide derivative potentiated the antibody response of spleen cells from both normal and FLV-infected mice. Similar enhancement was induced by "antibody response helper factor(s)" present in 3-5 day spleen culture supernatants from endotoxin or polysaccharide-treated spleen cells from normal mice. Enhancement of the antibody response of spleen cells from FLV-infected mice by the antibody helper activity was due to stimulation of B-lymphocytes and reversal of a defect in antibody helper factor(s) formation by macrophages. Similar antibody response enhancing activity was induced by both endotoxin and the non-toxic polysaccharide derivative in cultures of normal spleen cells, adherent spleen cell populations, peritoneal cells and the P388D1 macrophage cell line.

Animals↗
PubMed1988

Suppression by delta-9-tetrahydrocannabinol of interleukin 2-induced lymphocyte proliferation and lymphokine-activated killer cell activity.

The major psychoactive marijuana component, delta-9-tetrahydrocannabinol (THC), suppressed proliferation of murine spleen cells stimulated with recombinant human interleukin 2 (IL-2) and also suppressed the appearance of the lymphokine-activated killer (LAK) cell phenomenon in IL-2-treated spleen cell preparations. Cell function was depressed in a dose-dependent manner with as little as 2.5 micrograms/ml THC (8 microM). In addition, spleen cells previously stimulated in culture with IL-2 and then incubated with THC for 4 h prior to target cell addition, displayed suppressed cytolytic activity against both YAC-1 and EL-4 tumor targets. Killing of EL 4 cells was suppressed at lower drug doses than the killing of YAC-1 targets. These results suggest that THC can suppress several important functions of IL-2 including clonal expansion of lymphocytes, expansion of killer cell populations and stimulation of killer cell cytotoxic activity.

Animals↗
PubMed1988

Sex reversal in female Betta splendens as a function of testosterone manipulation and social influence.

In Experiment 1, female Betta given daily injections of testosterone (T) for 9 weeks acquired anatomical features characteristic of males as indicated by changes in fin length, body coloration, and gonadal morphology. These findings suggested that a potential for sex reversal exists in females of this species. In Experiment 2 we measured changes in aggressive behavior during testosterone-induced anatomical changes. Aggression decreased toward females and increased toward males as treatment with T progressed. The final displays of aggressive behavior and anatomical characteristics of fish injected with T resembled those of typical males. In Experiment 3, female Betta primed with T injections for 3 or 6 weeks and permitted to interact socially with females continued to display characteristics of sex reversal after T supplementation ceased. Sex reversal in isolated fish injected with T for 3 or 6 weeks was not sustained, and fish receiving only the control vehicle showed negligible change in both the isolated and community conditions. We discuss the results in terms of similarities with the sex change process found in isolated communities of coral reef fish.

Aggression↗
PubMed1988

Effect of zinc deficiency on hepatic enzymes regulating vitamin A status.

The elevation of hepatic vitamin A (VA) in zinc deficiency (ZD) is thought to be due, in part, to a reduced synthesis of plasma retinol-binding protein with a subsequent decrease in the release of retinol into the circulation. We hypothesized that the hepatic VA elevation may also be secondary to a change in the activity of enzymes that either regulate retinol degradation or affect the synthesis or hydrolysis of retinyl esters. To examine this question, 20 rats were divided into two groups and pair-fed for 3 wk. ZD rats received a ZD diet (zinc 2.3 mg/kg diet) and controls were fed a zinc-sufficient diet (zinc 50 mg/kg diet). The enzymes studied were retinyl ester hydrolase (REH) and microsomal acyl coenzyme A:retinol acyl transferase (ARAT), the principal enzymes regulating retinyl ester hydrolysis and synthesis. The activities of retinol (alcohol) dehydrogenase (ADH) and retinal oxidase (RO), enzymes regulating retinol degradation to polar metabolites, were also studied. ZD caused an increase in both total hepatic VA concentration and total hepatic VA content, but did not alter the ratio of retinol to retinyl esters. The specific activities of REH and ARAT were not affected by ZD. However, ZD caused a significant reduction in the activity of ADH, the enzyme that catalyzes the first step in retinol oxidation. In contrast, the activity of RO, the enzyme that regulates the irreversible oxidation of retinal to retinoic acid, was significantly increased in ZD rats. These findings indicate that the elevation in hepatic levels of VA in ZD rats may be, in part, secondary to decreased retinol degradation.

Acyl Coenzyme A↗