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Biomedical subjects

J D Berman

Publications and source records attributed to J D Berman.

At least 55 records · Page 3Linked to original sources
PubMed1991

Placebo controlled treatment of Ecuadorian cutaneous leishmaniasis.

Pentavalent antimony has been considered to be the standard treatment for leishmaniasis, but more recently, the orally administrable agent allopurinol ribonucleoside has been the subject of several clinical trials. In this study, these two agents were evaluated in patients with Ecuadorian cutaneous leishmaniasis. Patients were randomly assigned to the two treatment groups. The mean reduction in lesion size for the 28 patients treated with Pentostam (20 mg Sb/kg/day intramuscularly for 20 days) was 61%, 23%, and 11% after one, two, and three weeks, respectively. There was a wide range in the individual values, and some lesions markedly enlarged in the first week of therapy. An initially healed lesion was defined as one that had greater than 80% re-epithelialized by the 1.5-month post-treatment followup. All Pentostam patients demonstrated this degree of lesion resolution (100% initial healing rate), but one patient showed evidence of relapse at the three month followup resulting in a 96% complete healing rate for the 12 month observation period. Patients in the untreated control group demonstrated a strikingly high rate of healing with 9 of 12 patients having re-epithelialized all lesions after 1.5 months observation (75% initial healing rate). The mean reduction in lesion size for the untreated patients was 56%, 29%, and 25% after one, two, and three weeks, respectively. Twenty-one patients received allopurinol ribonucleoside (1,500 mg QID) plus probenecid (500 mg QID) for 28 days. Lesions in nine of these patients were healed at the time of the 1.5 month followup (41% healing rate).(ABSTRACT TRUNCATED AT 250 WORDS)

Allopurinol↗
PubMed1990

Efficacy and toxicity of sodium stibogluconate for mucosal leishmaniasis.

OBJECTIVE: To determine the efficacy and toxicity of the World Health Organization's (WHO) recommended treatment for mucosal leishmaniasis: antimony, 20 mg/kg body weight per day for 28 days. DESIGN: Open trial with 12-month follow-up. SETTING: Inpatient unit of a regional referral hospital in a developing country. PATIENTS: Twenty-nine consecutive eligible patients with culture-confirmed infection of the mucosa with Leishmania species who were otherwise healthy. Eight patients (28%) had mild to moderate disease (confined to the nasal mucosa). Twenty-one patients (72%) had severe disease (including the oropharynx as well as the nasal mucosa). INTERVENTION: Antimony, 20 mg/kg body weight intravenously every day for 28 days. Patients received antimony in the form of sodium stibogluconate. MEASUREMENTS AND MAIN RESULTS: Initial results of therapy were as follows: 63 of 72 lesions (88%) healed or markedly improved; all lesions were culture-negative for parasites; and 18 of 29 patients (62%) showed complete clinical and parasitologic cure of all lesions. By the 12-month follow-up examinations, however, 37 lesions had recurred, 8 new lesions had appeared, and only 8 patients (30%) showed clinical cure of all lesions. Of the 8 patients with mild to moderate disease, 6 were cured compared with only 2 of the 21 patients with severe disease. Side effects of this treatment regimen included T-wave inversion on electrocardiogram (4 patients), abnormal liver function tests (10 patients), and musculoskeletal pain (24 patients). No side effects occurred during week 1 of therapy. CONCLUSIONS: The only recommended treatment for mucosal leishmaniasis is ineffective in patients with severe disease. The acceptable toxicity of the regimen suggests that longer courses of therapy with antimony, or that trials with other antileishmanial agents alone or combined with antimony be evaluated as initial therapy for this disease.

Adult↗
PubMed1990

Efficacy of ketoconazole against Leishmania braziliensis panamensis cutaneous leishmaniasis.

PURPOSE, PATIENTS, AND METHODS: The classic agent for cutaneous leishmaniasis is pentavalent antimony. However, there are no reports of the efficacy of antimony versus placebo or of the efficacy of any alternative therapy versus either antimony or placebo. In the present report, the oral antifungal agent ketoconazole (600 mg/day for 28 days) was compared to a recommended regimen of intramuscular Pentostam (20 mg antimony/kg, with a maximum of 850 mg antimony/day, for 20 days) in a randomized study of the treatment of Panamanian cutaneous leishmaniasis due to Leishmania braziliensis panamensis. A separate group of patients with this disease was administered placebo. RESULTS: Ketoconazole clinically cured 16 of 21 (76%) patients. The lesions on nine patients healed by 1 month after therapy, and the lesions healed by 3 months after therapy on the other seven patients. Side effects were limited to a 27% incidence of mild, reversible hepatocellular enzyme elevation and an asymptomatic, reversible, approximately 70% decrease in serum testosterone in all patients. Pentostam cured 13 of 19 (68%) patients; the lesions on seven patients healed by the end of therapy, and the lesions on four other patients healed by 1 month after the end of therapy. Side effects were a 47% incidence of mild, reversible hepatocellular enzyme elevation and the morbidity due to 20 intramuscular injections in almost all patients. The placebo group of 11 patients had a 0% cure rate. By 1 month after therapy, all placebo-treated patients demonstrated new lesions or one lesion that was 23% to 875% larger than before therapy. CONCLUSION: Both ketoconazole and Pentostam were more effective than placebo against L. braziliensis panamensis cutaneous leishmaniasis. Oral ketoconazole is comparable in efficacy to this parenteral Pentostam regimen and can be recommended as initial treatment for this disease.

Adolescent↗
PubMed1990

Diminished adrenocorticotropin response to insulin-induced hypoglycemia in nondepressed, actively drinking male alcoholics.

Although changes in hypothalamic-pituitary-adrenal axis function have frequently been reported in alcoholics, the majority of studies have used recently detoxified subjects in whom abstinence phenomena and clinical depression may contribute to observed stress axis alterations. To isolate the primary effects of alcohol dependence on the stress axis, the ACTH and cortisol responses to insulin-induced hypoglycemia were measured in seven actively drinking male alcoholics recruited from the general public through a newspaper advertisement along with eight age-matched male controls. The alcoholic subjects met current American Psychiatric Association diagnostic criteria for alcohol dependence, were stably employed, and had no concurrent psychiatric disorders, cognitive impairment, or psychometric evidence of depression. While relatively young (30.0 yr; range, 22-48 yr), they had lengthy histories of alcohol-related problems (11.9 yr; range, 5-30 yr). Insulin administration resulted in similar nadirs in blood sugar in both alcoholic and control groups. However, the plasma ACTH response was markedly blunted in the alcoholics (P = 0.040, by Mann-Whitney U test). There was a nonsignificant trend toward increased cortisol levels in the alcoholic group. The findings suggest that altered hypothalamic-pituitary-adrenal axis function in alcoholics is a primary results of chronic ethanol exposure rather than a confounding effect of clinical depression or recent detoxification.

Adrenocorticotropic Hormone↗
PubMed1989

Prevention of muscarinic acetylcholine receptor down-regulation by chloroquine: antilysosomal or antimuscarinic mechanisms.

The effect of the antimalarial drug chloroquine on the carbachol-induced down-regulation of muscarinic acetylcholine receptors (mAChRs) was studied in the neuroblastoma-glioma hybrid NG108-15 cells. Chloroquine, which is proposed to have both antilysosomal and antimuscarinic effects (4,11), blocked the loss of both cell surface and total mAChRs as monitored by [3H]N-methyl-scopolamine (NMS) and [3H] quinuclidinyl benzilate (QNB) bindings respectively. To the contrary, NH4Cl, only an antilysosomal agent, had no effect on the loss of surface receptors, but blocked degradation of internalized receptors following the effect of carbachol. These findings demonstrate that chloroquine prevents the agonist-induced mAChR down-regulation in NG108-15 cells by both its antilysosomal and antimuscarinic effects.

Ammonium Chloride↗
PubMed1989

Mechanism of agonist-induced down-regulation and subsequent recovery of muscarinic acetylcholine receptors in a clonal neuroblastoma x glioma hybrid cell line.

The mechanisms of carbachol-induced muscarinic acetylcholine receptor (mAChR) down-regulation, and recovery following carbachol withdrawal, were studied in the neuroblastoma x glioma hybrid NG108-15 cell line by specific ligand binding assays. N-[3H]Methylscopolamine ([3H]NMS) and [3H]quinuclidinyl benzilate ([3H]QNB) were used as the ligands for the cell surface and total cellular mAChRs, respectively. Exposure of cells to 1 mM carbachol for 16 h decreased the specific binding of [3H]NMS and [3H]QNB by approximately 80%. Bacitracin (1-4 mg/ml) and methylamine (1-15 mM), inhibitors of transglutaminase and of endocytosis, prevented agonist-induced loss of surface mAChRs. Pretreatment of cells with the antimicrotubular agents nocodazole (0.1-10 microM) and colchicine (1-10 microM) prevented carbachol-induced loss of [3H]QNB binding, but not that of [3H]NMS binding. These results indicate that agonist-induced mAChR down-regulation occurs by endocytosis, followed by microtubular transport of receptors to their intracellular degradation sites. When carbachol was withdrawn from the culture medium following treatment of cells for 16 h, receptors recovered and were incorporated to the surface membrane. This recovery process was antagonized by monovalent ionophores monensin (0.1 microM) and nigericin (40 nM), which interfere with Golgi complex function. Receptor recovery was also prevented by the antimicrotubular agent nocodazole. Thus, recovery of receptors appears to be mediated via Golgi complex and microtubular transport to the surface membrane.

Animals↗
PubMed1989

Antileishmanial activities of 2,4-diaminoquinazoline putative dihydrofolate reductase inhibitors.

2,4-Diaminoquinazoline analogs of folate were assessed as antileishmanial agents and as dihydrofolate reductase inhibitors. Against Leishmania major in human macrophages in vitro, two compounds with tertiary amines attached directly to the quinazoline ring were remarkably active. The 50% effective doses were in the picogram per milliliter range (12 to 91 pg/ml), and the in vitro therapeutic indices were approximately 10(5). These compounds were 1,000 times more active on an absolute basis and had a 100 times more favorable therapeutic index than any compound previously tested in this model. Antileishmanial activity was not correlated with activity against Leishmania mexicana promastigote reductase, which suggests that folate utilization in general, rather than reductase activity specifically, was being inhibited.

Animals↗
PubMed1989

Biochemistry of Pentostam resistant Leishmania.

Promastigotes of Leishmania mexicana amazonensis WR 669 clone 4 were made resistant to antimony in the form of Pentostam (sodium stibogluconate) by exposure to media containing increasing concentrations of Sb. The dose of Sb expected to kill 50% of promastigotes and amastigotes of the parent sensitive clone (WR 669) and the resistant clone (WR 669R) was determined by exposure of suspensions in physiologic salt solution for 3 hr. The approximate Ed50s in microgram Sb/ml were: 10,000 for WR 669R promastigotes; 7,000 for WR 669R amastigotes; 200 for WR 669 promastigotes; and 150 for WR 669 amastigotes. Thus, Sb resistance and Sb sensitivity expressed by promastigote clones are also expressed by their respective amastigotes. Studies with 125Sb-Pentostam showed that WR 669R amastigote resistance was not due to altered Sb uptake over 1 hr. When amastigotes pretreated with Pentostam were incubated with 14C labeled metabolic precursors, susceptibility to Sb was correlated with inhibition of glycolytic enzymes and of fatty acid beta-oxidation.

Animals↗
PubMed1988

Leishmania mexicana: chemistry and biochemistry of sodium stibogluconate (Pentostam).

The chemical properties of the primary antileishmanial agent sodium stibogluconate (Pentostam), and the interaction of Pentostam with Leishmania mexicana amastigotes, have been investigated with the aid of [125Sb]Pentostam. The molecular weight by P2 chromatography showed [125Sb]Pentostam to be of multiple species of MW = 100-4000 Da, rather than the one species of 746 Da predicted by the commonly hypothesized structural formula. Nonradioactive Pentostam had a lower osmolarity (789 mOsm for a 100 mg Sb/ml solution) than predicted (1644 mOsm), which indicates that the multiple components of Pentostam (Sb and derivatives of gluconic acid) are more closely complexed with each other than previously thought. When incubated with L. mexicana amastigotes, labeled drug was bound to at least six polypeptides of molecular weights ranging from 14,000 to 68,000 Da as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Interaction with the polypeptides is presumed to contribute to the antileishmanial action of Pentostam.

Absorption↗
PubMed1988

Immunochemotherapy for intracellular Leishmania donovani infection: gamma interferon plus pentavalent antimony.

To determine if the macrophage-activating T cell lymphokine gamma interferon (IFN-gamma) can enhance the effect of conventional chemotherapy against intracellular Leishmania donovani, we treated human macrophages in vitro with both recombinant (r) IFN-gamma and sodium stibogluconate (Pentostam). After pretreatment with a nonactivating dose of rIFN-gamma (10 U/mL), ineffective concentrations of Pentostam (1 and 5 micrograms/mL) were converted to leishmanistatic concentrations, and a leishmanistatic dose (10 micrograms/mL) was converted to uptake of Pentostam. In a model of visceral leishmaniasis, infected mice were treated with ineffective concentrations of rIFN-gamma (10(4) U) plus suboptimal doses of Pentostam (10 or 50 mg/kg). With combination therapy, the doses of Pentostam required to achieve 50% inhibition or killing of visceral L. donovani were reduced by 10-fold and fourfold, respectively. These results suggest that IFN-gamma therapy may be a useful adjunct in visceral leishmaniasis and illustrate one potential role for IFN-gamma in the treatment of systemic intracellular infections.

Animals↗
PubMed1988

Inhibition of leishmanial protein kinase by antileishmanial drugs.

Protein kinase was isolated from both amastigotes and promastigotes of Leishmania mexicana amazonensis. Unlike the previously described enzyme from L. donovani promastigotes, activity of the L. mexicana kinases was 2-3 times higher at low ionic strength than at high ionic strength, and was 3-10-fold augmented by removal of endogenous low molecular weight inhibitors. The Km of the L. mexicana kinases was 123-223 microM, compared to the value of 70 microM for the beef heart kinase. Purine nucleoside analogs are potent antileishmanial agents that are phosphorylated to their respective triphosphates. The mechanism of the analogs is thought to involve competition of the triphosphates with ATP. Cordycepin triphosphate inhibited the amastigote, promastigote, and beef heart protein kinases approximately equally. However, the Kis of formycin A triphosphate for the leishmanial kinases (Ki 40-120 microM) were far less than that of the beef heart kinase (Ki 1,380 microM). The mechanisms of certain chemotherapeutic purine nucleosides may involve specific inhibition of leishmanial protein kinase by the nucleoside triphosphate.

Adenosine Triphosphate↗
PubMed1988

Pharmacokinetics of pentavalent antimony (Pentostam) in hamsters.

Pentavalent antimony (Sb) is the classical treatment for visceral and cutaneous leishmaniasis. We investigated Sb levels in serum, liver, spleen, and skin of hamsters administered therapeutic dosages of Sb (600 and 300 mg Sb/kg). Single administration of Sb was more effective against hepatic parasites than dividing the same total dose into multiple administrations, which suggests that for elimination of hepatic parasites in vivo, peak Sb concentration is more important than total area-under-the-curve levels. Serum Sb declined with an initial half-life of 1 hr. Skin Sb levels (352 micrograms Sb/g 1 hr after 600 mg Sb/kg) were initially higher than liver levels (77 micrograms Sb/g) or splenic levels (156 micrograms Sb/g), but levels were comparable (7-24 micrograms Sb/g) in the three organs by 8 hr after dosing. The generally comparable levels of Sb in the skin and in the visceral organs support the present clinical practice of administering the same dosage of Sb for cutaneous and visceral leishmaniasis.

Animals↗
PubMed1987

Safety and efficacy of high-dose sodium stibogluconate therapy of American cutaneous leishmaniasis.

40 patients with American cutaneous leishmaniasis caused primarily by Leishmania braziliensis panamensis were treated with sodium stibogluconate in a double-blind, randomised controlled trial. Nine weeks after starting treatment, all 19 patients treated with 20 mg Sb/kg per day for twenty days were cured but 5 of 21 patients treated with 10 mg Sb/kg per day for twenty days had persistent active disease (p less than 0.05). Both treatment regimens were well tolerated and they were associated with a similar incidence of reversible toxic effects. Existing recommendations for therapy of American cutaneous leishmaniasis with sodium stibogluconate are inadequate for some patients, and higher doses are both safe and efficacious.

Adolescent↗
PubMed1987

Sodium stibogluconate (Pentostam) inhibition of glucose catabolism via the glycolytic pathway, and fatty acid beta-oxidation in Leishmania mexicana amastigotes.

The biochemical mechanism of action of antimony (Sb) in pentavalent form complexed to gluconic acid (sodium stibogluconate)--the drug of choice for the leishmaniases--has been only slightly investigated. We recently reported that, in stibogluconate-exposed Leishmania mexicana amastigotes, there is a dose-dependent decrease in the ATP/ADP ratio [Berman et al., Antimicrob. Agents Chemother. 27, 916 (1985)]. To investigate mechanisms by which ADP phosphorylation to ATP might be inhibited, stibogluconate-exposed amastigotes were incubated with [14C]glucose, fatty acid, or acetate, and 14CO2 production was determined. In organisms exposed to 500 micrograms Sb/ml, formation of 14CO2 from [6-14C]glucose and [1-14C]palmitate was inhibited 69 and 67% respectively. In comparison, formation of 14CO2 from [1-14C]glucose and [2-14C]acetate was inhibited less than 15%. These results suggest that glucose catabolism via glycolytic enzymes and fatty acid beta-oxidation, but not glucose metabolism via the hexosemonophosphate shunt or the citric acid cycle, is specifically inhibited in stibogluconate-exposed Leishmania mexicana amastigotes. Inhibition of these pathways suggests a mechanism for the inhibition of ADP phosphorylation previously reported.

Acetates↗
PubMed1987

Activity of purine analogs against Leishmania donovani in vivo.

The dose of orally administered 9-deazainosine calculated to suppress 50% of Leishmania donovani amastigotes in hamster livers was 19 mg/kg (body weight) per day; 96 to 99% of Leishmania organisms were eliminated from the liver and spleen of squirrel monkeys by 50 mg/kg per day. Because these activities were greater than that of the experimental clinical agent allopurinol and comparable to that of the classical agent parenteral pentavalent antimony, 9-deazainosine should be considered for clinical development for visceral leishmaniasis.

Administration, Oral↗