Fate of the monoamine oxidase inhibitor pargyline in cultured hepatocytes

The interaction of the monoamine oxidase inhibitor pargyline with cultured hepatocytes has been studied. [Phenyl-3, benzyl-3H] pargyline (38 nM) rapidly enters the cells and a plateau of incorporation into a trichloroacetic acid insoluble form (monoamine oxidase) is reached after 2 hr. The level of labelling is lower in freshly isolated cells than in those in later culture. The maximum incorporation accounts for only 6% of the added radioactivity and produces a 9% inhibition of monoamine oxidase activity. The remaining [3H] pargyline is metabolized and quickly accumulates in the cell culture medium in a form which cannot label exogenous mitochondria. The metabolism of pargyline varies both qualitatively and quantitatively with culture age. In 0 hr and 20 hr-cultured cells one metabolite preferentially appears whilst in 140 hr cultured hepatocytes at least three metabolites are formed. The metabolism of [3H] pargyline in early culture is consistent with a cytochrome P-450 involvement. The use of [3H] pargyline to label monoamine oxidase in cultured hepatocytes offers several attractive features for studying the turnover of this enzyme. These include speed of interaction, non-reutilization, application to normal cells, controlled inhibition of monoamine oxidase and metabolism of non-specific label.     

Long-lasting effects of chronic chlorimipramine treatment of rats on exploratory activity on a hole-board, and on immobility in the forced swimming test

The study concerned the effects of acute and chronic clomipramine administration to male rats on exploratory activity in a novel environment (hole-board) and on immobility in the forced swimming test. Acute clomipramine administration did not alter either exploratory activity on a hole-board as measured 3 or 20 h after drug administration, or immobility in the forced swimming test as measured 20 h after drug administration. Approximately 20 h after the last injection of clomipramine, the rats chronically treated with the drug showed reduced exploratory activity on the hole-board. In contrast, chronic clomipramine treatment significantly increased the activity in the forced swimming test. The effects of the drug on exploratory and forced swimming activities persisted for 14 days after the cessation of clomipramine administration. These data indicate that chronic clomipramine administration exerted profound and long-lasting effects on central nervous system function. The long-lasting action of the drug on behaviour in the forced swimming test might explain the long-term beneficial effect of antidepressant drugs in counteracting behavioral depression.     

Juvenile Parkinsonism: clinical and metabolic characteristics.

Twenty one patients with idiopathic Parkinsonism beginning before the age of 40 years were investigated. The mean duration of the disease was 19 years. There was a good and sustained response to levodopa. Only four patients reached stages IV and V (Hoehn and Yahr). Intolerance to levodopa was observed in the more advanced stages of the disease. In the series the familial incidence of Parkinsonism (2 cases) and essential tremor (3 cases) was very low. Thyroid disorder, diabetes mellitus or macrocytic anaemia was not found in any of the cases.     

Biomechanical comparison of stimulated and nonstimulated skeletal muscle pulled to failure

We compared the biomechanical properties of passive and stimulated muscle rapidly lengthened to failure in an experimental animal model. The mechanical parameters compared were force to tear, change in length to tear, site of failure, and energy absorbed by the muscle-tendon unit before failure. Paired comparisons were made between 1) muscles stimulated at 64 Hz (tetanic stimulation) and passive (no stimulation) muscles, 2) muscles stimulated at 16 Hz (wave-summated stimulation) and passive muscles, and 3) muscles stimulated at 64 Hz and at 16 Hz. Both tetanically stimulated and wave-summation contracted muscles required a greater force to tear (at 64 Hz, 12.86 N more, P less than 0.0004; and at 16 Hz, 17.79 N more, P less than 0.003) than their nonstimulated controls, while there was no statistical difference in failure force between muscles stimulated at 16 Hz and 64 Hz. The energy absorbed was statistically greater for the stimulated muscles than for the passive muscles in Groups 1 and 2 (at 64 Hz, 100% more, P less than 0.0003; and 16 Hz, 88% more, P less than 0.0002). In Group 3, the tetanically contracted muscle-tendon units absorbed 18% more energy than the wave-summated stimulated muscles (P less than 0.01). All muscles tore at the distal musculotendinous junction, and there was no difference in the length increase at tear between muscles in each group. These findings may lead to enhanced understanding of the mechanism and physiology of muscle strain injuries.     

Obesity and beta-blockers: influence of body fat on their kinetics and cardiovascular effects

Beta-blockers are among the most widely used antihypertensive drugs. They differ from each other in regard to several factors such as: beta-agonist activity, beta 1-selectivity and solubility. Aim of this work was to evaluate the influence of obesity on the kinetics and the antihypertensive effect of two Beta-blockers with different solubility such as: the water-soluble, atenolol and the liposoluble, metoprolol. The study was carried out according to an open randomized cross-over design. Eight obese hypertensive patients, after a two week washout period, were randomly allocated to a four week treatment. After a two week intermediate washout period, each patient switched to the other treatment for an additional four week period. On the first and the last day of each treatment the subjects were hospitalized to collect blood samples for the assay of the two drugs and to measure cardiovascular parameters. Obesity does not exert any effect on the kinetics of the water-soluble beta-blocker, atenolol, while markedly interferes with that of the liposoluble, without any apparent influence on its anti-hypertensive effect. These findings extend to obese hypertensives the concept that the plasma concentrations of beta-blocking agents are not reliable predictors of their therapeutic effect.     

Total-body protein turnover in parenterally fed neonates: effects of energy source studied by using [15N]glycine and [1-13C]leucine

The effects of nonprotein energy source (ie, glucose only vs glucose and lipid) on nitrogen retention and total-body protein turnover were studied in 20 parenterally fed newborn infants. All infants received approximately 3 g amino acids and 80-90 kcal.kg body wt.d. Total-body protein synthesis was estimated by using three constant-infusion, end-product methods: enrichment of urinary urea and ammonia in response to a [15N]glycine label and exhaled carbon dioxide enrichment in response to a [1-13C]leucine label. No differences were seen in nitrogen retention between the two energy sources. The estimate of total-body protein turnover obtained from the 13C label was similar to that obtained with the [15N]urea label. No differences in turnover rates were observed between the two diet groups. Use of the glucose-plus-lipid fuel system enhanced energy storage and the reutilization of amino acid for protein synthesis.     

Retained pacemaker leads

Increasingly, functionless pacemaker leads are being abandoned in place because they cannot be safely removed. One hundred eighty-nine intact or partially removed pacemaker leads were abandoned in situ in 152 patients between Jan. 1, 1965, and Dec. 31, 1985. The leads, sometimes several leads in a single patient, were deemed uninfected at the time of abandonment in 137 patients and contaminated with Staphylococcus epidermidis in 15 patients. All of the contaminated leads have remained clinically uninfected during follow-up. One clean lead became infected early after implantation and the patient died after an open cardiac operation to remove that lead and an adjacent abandoned lead that was adherent to the subclavian vein. No other patient has had a late complication during follow-up to 256 months (mean 47.6). Properly managed abandonment of an uninfected lead can carry a very low complication rate.     

Studies of the induction and maintenance of long-term graft acceptance by treatment with FK506 in heterotopic cardiac allotransplantation in rats

Immunosuppressive activities of the newly discovered FK506, isolated from Streptomyces tsukubaensis, were examined by using cardiac allotransplantation in the rat, and the mechanisms underlying induction and maintenance of FK506-induced long-term allograft survival were studied. Male rats of WKA (RT1k) and F344 (RT1lvl) strains were used as recipients and donors, respectively, and those of BN (RT1n) strain were used as third-party donors. Treatment with FK506, beginning from the day of allografting for 14, 10, or as few as 4 days, prolonged allograft survival significantly across the major histocompatibility barrier. The minimum doses for prolonging graft survival were 0.1 mg/kg/day by intramuscular treatment and 1.0 mg/kg/day by oral treatment. Treatment with FK506 at a dose of 0.32 mg/kg/day from day 4 until day 10 resulted in all the grafts surviving indefinitely and from days 5 to 10, half the grafts survived indefinitely, suggesting that the agent inhibited ongoing rejection. On the other hand, cyclosporine treatment at a dose of 20 mg/kg/day from day 2 did not prolong graft survival time statistically significantly. Induction of prolonged graft survival was not obtained by pretreatment of the prospective donor or recipient; prolonging effects were observed only when the agent was administered after allografting. Thus, the primary effect of the agent is exerted on responder lymphocytes reacting to the donor antigens in the induction phase of long-term graft acceptance. The mechanisms underlying the maintenance of long-term grafts were analyzed by testing the capacity of lymphocytes or serum of long-term graft-bearing rats to inhibit graft rejection in irradiated grafted hosts. Transfer of 2 x 10(8) lymphocytes from FK506-induced long-term F344 graft-bearing WKA rats resulted in indefinite survival of F344 heart allografts, but it did not prolong survival of third-party BN hearts. Transfer of 2.5 ml serum from long-term graft-bearing rats also prolonged graft survival of F344 hearts, but not BN hearts. These results suggest that donor strain-specific suppressor cells and humoral factor(s) are induced by treatment with FK506 in the presence of allografts, and that they play at least partial roles in the maintenance of long-term allograft acceptance.