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Biomedical subjects

H Kalant

Publications and source records attributed to H Kalant.

At least 19 recordsLinked to original sources
PubMed1979

Cross-tolerance between ethanol and morphine with respect to their hypothermic effects.

Daily administration of ethanol (10-12 g/kg) to rats in a liquid diet resulted in tolerance to the hypothermic effects of ethanol. The rats also developed cross-tolerance to the hypothermic effect of morphine (15 and 30 mg/kg), whereas no cross-tolerance to the hyperthermic effect of morphine (5 mg/kg) was seen. Administration of morphine (30 mg/kg i.p.) for 3 days resulted in tolerance to morphine hypothermia and also cross-tolerance to ethanol-induced hypothermia. These studies fit with our hypothesis that tolerance and cross-tolerance among drugs develop to drug effects rather than to the drug per se. Therefore drugs sharing a common effect, even by different mechanisms, might show cross-tolerance for that effect.

Animals↗
PubMed1979

Effect of L-tryptophan on the acquisition of tolerance to ethanol-induced motor impairment and hypothermia.

Rats were rendered tolerant to ethanol by daily gavage of 4--5 g/kg. The degree of motor impairment on the moving belt test and of hypothermia after i.p. test doses of ethanol was measured prior to and at various times during the chronic treatment, to assess the rates of tolerance development. L-Tryptophan (75 mg/kg twice daily) was administered chronically to elevate brain serotonin level. This treatment did not alter the motor impairment or hypothermia produced by the initial test doses of ethanol (2.0 and 2.5 g/kg respectively). However, the development of tolerance to both the motor impairment and hypothermia effects of ethanol was accelerated in the tryptophan-treated rats. This finding complements our earlier observations that depletion of 5-HT with p-CPA slows down tolerance. Blood ethanol measurements at 20 min (motor impairment) or 90 min (hypothermia) after the administration of the test dose reveal no significant difference between the control and tryptophan-treated rats, suggesting that tryptophan did not influence the metabolism of ethanol. This finding supports the hypothesis that brain serotonin modulates the development of tolerance to ethanol.

Animals↗
PubMed1979

Increased weight gain as a morphine withdrawal response in rats.

Adult male Wistar rats injected daily with 20 or 200 mg/kg morphine-SO4 for 35 days suffered a dose-dependent weight loss over the first 3 days of morphine withdrawal. However, during the next 28 days they gained weight more rapidly than controls, the rates being related to the previous morphine dosage. These findings were replicated in Sprague-Dawley rats treated for 26 days with 60 mg/kg morphine. Food-restricted controls suffering weight losses equal to those of the morphine-treated or morphine-withdrawn groups did not subsequently gain weight as rapidly as the latter groups. Therefore the rapid post-withdrawal weight gain may be a true adaptive response to the weight suppressing effects of morphine. Also, comparisons of weight changes during treatment in the two experiments indicated possible strain differences for tolerance to morphine's direct weight-reducing effect.

Animals↗
PubMed1979

Effect of desglycinamide(9)-lysine(8)-vasopressin and prolyl-leucyl-glycinamide on oral ethanol intake in the rat.

Rats given ethanol in their drinking water at a concentration that permitted adequate fluid intake gradually accepted higher concentrations and consumed larger amounts of ethanol. These increases were augmented when daily subcutaneous injections of 1 microgram of desglycinamide9-lysine8-vasopressin (DGLVP) or 10 microgram of prolyl-leucyl-glycinamide (PLG) were given concomitantly. Nonsignificant changes in ethanol consumption were seen with injections of 1 microgram PLG, or 0.42 or 42 microgram of lysine8-vasopressin (LVP). In a second experiment 4 microgram DGLVP given every second day as a long-acting zinc phosphate complex, commencing after the increases in ethanol intake had taken place, failed to produce any change in ethanol consumption subsequently. In both Experiments 1 and 2, the rats were switched from forced ethanol intake to a choice between ethanol and tap water. On these tests there was only marginal evidence of peptide-produced changes in ethanol intake.

Alcohol Drinking↗
PubMed1979

Effect of modification of brain serotonin (5-HT) on ethanol tolerance.

The effects of 5,7-dihydroxytryptamine and L-tryptophan treatment on ethanol tolerance in the rat, as measured by the moving-belt test of motor impairment and by hypothermia, were examined in separate studies. A 2 x 2 design was used for all experiments. 5,7-Dihydroxytryptamine (200 microgram in 20 microliter CSF) or vehicle alone was administered once into both lateral ventricles of the rat. Desmethylimipramine was administered intraperitoneally prior to an intraventricular injection of 5,7-dihydroxytryptamine to prevent the destruction of norepinephrine. L-Tryptophan (75 mg/kg p.o. twice daily) or water was administered chronically. Ethanol (4--5 g/kg p.o.) or sucrose was given daily, and the development of tolerance was monitored at 5--7-day intervals. Chronic ethanol treatment produced tolerance to both the motor impairment and hypothermia effects of ethanol. 5,7-Dihydroxytryptamine and L-tryptophan treatment did not alter either the motor impairment or hypothermia produced by the initial dose of ethanol. 5,7-Dihydroxytryptamine produced a 75% depletion of brain 5-HT and slowed the development of tolerance to ethanol in both measurements. In contrast, elevation of 5-HT by L-tryptophan (39% increase by a single dose) facilitated the development of tolerance to ethanol, as seen in both measures. These findings support our hypothesis that brain 5-HT has a modulating role in the development of tolerance to ethanol.

5,7-Dihydroxytryptamine↗
PubMed1979

Serum triiodothyronine and other clinical and laboratory indices of alcoholic liver disease.

Admission serum triiodothyronine (T3) values in 124 patients hospitalized for alcoholic liver disease were correlated with clinical and laboratory indices of liver function and commonly used determinants of thyroid function. Patients with low admission serum T3 levels had significant alterations in serum albumin, bilirubin, prothrombin time, and alkaline phosphatase associated with clinical signs of portal hypertension and collateral circulation, with little difference in serum glutamic-oxaloacetic transaminase, serum gamma glutamyl transpeptidase, or serum ornithine carbamyl transferase. This group also had a significant decrease in free T3 index despite an increase in T3 uptake; the slight reduction in total thyroxine (T4) was associated with an increase in free T4 index and no change in serum thyrotropin (TSH). For patients with alcoholic liver disease, low admission serum T3 and free T3 index values when accompanied by normal serum T4, free T4 index, and TSH levels appear to be indicative of severe liver dysfunction and increased mortality risk.

Humans↗
PubMed1979

Effect of short-term therapy with propylthiouracil in patients with alcoholic liver disease.

The effect of propylthiouracil (PTU; 300 mg/day) on alcoholic liver disease was evaluated in 133 patients in a short-term randomized double-blind trial. Severity of the disease was assessed by a composite clinical and laboratory index (CCLI). A normalization rate (NR) representing the rate of improvement in CCLI was calculated. Patients with alcoholic hepatitis, with and without cirrhosis, showed a significantly higher NR on PTU (43.6 +/- 4.6) than on placebo (19.8 +/- 3.3; P less than 0.001). A similar effect was observed in patients with abnormal prothrombin (no biopsy): NR was 32.9 +/- 6.9 on PTU and 2.6 +/- 3.7 on placebo (P less than 0.005). The effect of PTU on each clinical and laboratory component of the CCLI was also compared in these two groups. In 38 patients with alcoholic hepatitis and in 25 with abnormal prothrombin, those on PTU showed a greater improvement in 15 of 15 items (P less than 0.001) and 14 of 15 (P less than 0.01), respectively. When patients were divided according to the severity of the disease into those in the lower and upper halves of the CCLI range (81 and 52 patients, respectively), PTU was shown to have a significant effect only in the latter: The NR was 41.4 +/- 3.8 on PTU and 22.5 +/- 4.2 on placebo (P less than 0.005). PTU was ineffective in patients with inactive cirrhosis.

Double-Blind Method↗
PubMed1979

Thyroid hormones in alcoholic liver disease. Effect of treatment with 6-n-propylthiouracil.

The relationship between alcoholic liver disease and circulating thyroid hormones was investigated in 124 hospitalized patients treated with placebo or propylthiouracil (PTU) for a maximum of 46 days in a double-blind study. Serum triiodothyronine (T3) levels on admission were significantly (P less than 10(-6) and inversely correlated with the severity of alcoholic liver disease. After hospitalization, changes in T3-levels in patients with low admission T3 significantly correlated (P less than 0.001) with the degree of spontaneous improvement of liver function (placebo group). Treatment with 300 mg of PTU daily (Orrego et al. Gastroenterology 76:105--115, 1979) markedly increased the rate of improvement in severely ill patients with low T3 on admission. In this group, serum T3-levels were also increased after PTU, but this increase did not correlate with the change in the patient's condition. It is suggested that the known inhibitory effect of PTU on peripheral deiodination of T4 to T3 is marked by a more marked improvement in liver function in this group. PTU treatment in this group reduced the free T4-index and increased TSH levels markedly (16%; P less than 0.02) toward levels found in hypothyroidism. PTU did not improve the condition of mildly ill patients with normal admission T3-levels, nor did it alter free T4-index or serum TSH levels in these patients. Serum T3-levels provide a sensitive indicator of the severity of alcoholic liver disease and of its response to conventional treatment. Serum T3-levels also distinguish between a group of patients, in whom low-dose PTU administration results in a beneficial effect, and another group, in whom no therapeutic effect of PTU is observed.

Humans↗
PubMed1978

Accelerated development of tolerance during repeated cycles of ethanol exposure.

Adult male rats were subjected to 1--4 cycles of daily gastric intubation with ethanol (6 g/kg) for 16 days, separated by 17-day alcohol-free periods. Tolerance produced by this treatment (designated 'physiological tolerance') was measured by change in effect of a 2.2 g/kg i.p. dose of ethanol on the moving-belt test. It occurred in each cycle, disappeared completely in the drug-free periods, and developed more rapidly in the second and later cycles than in the first. Tolerance produced by the 'behavioral augmentation' technique (daily test practice under the influence of ethanol) also developed more rapidly on a second than on a first cycle. The progression from within-session to between-session tolerance was still evident, but accelerated. With 25-day alcohol cycles, separated by a one-month drug-free period, the 'carry-over' effect (i.e., more rapid acquisition of tolerance in the second cycle) applied equally, regardless of whether or not tolerance was produced by the same technique in both cycles, or by a crossover in either direction between the two techniques.

Animals↗
PubMed1978

Effect of p-chlorophenylalnine on the loss and maintenance of tolerance to ethanol.

Rats were rendered tolerant to the motor-impairing effects of ethanol by daily oral administration. Subsequently, ethanol was withdrawn and the effect of p-chlorophenylalanine (p-CPA) on tolerance loss was examined. In two separate studies it was demonstrated that p-CPA, in a dosage regimen that produces extensive depletion of brain serotonin (5-HT), accelerated tolerance loss. These experiments suggest that at least part of p-CPA's inhibitory effect on net tolerance development to ethanol can be accounted for by its accelerating effect on tolerance loss; however, an inhibitory effect on tolerance acquisition cannot be excluded. On the other hand, once tolerance was established, p-CPA did not affect the maintenance of tolerance to ethanol.

Animals↗