Normal persons and hypertensives at the early stage of the disease (corresponding to ‘mild hypertension’ as classified by the WHO) of male sex between 15 and 25 years were examined during a psychic stress situation (repeated mental arithmetic under time-pressure). The stress situation effected: rise of the pulse rate, of systolic and diastolic blood pressure in both groups; a prolonged persistence of increased pulse rate and blood glucose in hypertensives; increased oxygen consumption and muscular tonus (both the initial values and the values after stress situations were higher in hypertensives than in the control group); rise of noradrenalin, free fatty acids, cortisol and renin activity (orthostasis effect) in the plasma. In contrast to the control group the adaptation of hypertensives to repeated experimental stress situations was markedly disturbed.
We reported previously that intraperitoneal administration of a bis(benzyl)polyamine analog, MDL 27,695, suppressed both pentavalent antimony (Sbv)-susceptible and -resistant Leishmania donovani in vivo. The present studies were performed to optimize parasite suppression by parenteral administration and to evaluate the efficacy of oral treatment with MDL 27,695. L. donovani infections in BALB/c mice were suppressed >99% after intraperitoneal dosing for 20 days with a total dose of 150 mg of MDL 27,695 per kg of body weight or 560 mg of SbV per kg. Suppression was not increased by a total dose of 400 mg of MDL 27,695 per kg given for 20 days. In mice treated for 2, 4, or 7 days with either MDL 27,695 or Sb" (total doses of 60, 120, and 210 mg/kg, respectively), more liver parasites were killed with MDL 27,695 than with Sb". Assessment of livers posttreatment showed that parasite killing continued for at least 3 days in MDL 27,695-treated mice but not for longer than 1 day in SbW-treated mice. Intramuscular administration of drugs resulted in 92% parasite suppression by MDL 27,695 (15 mg/kg three times per day for 5 days) and 64% suppression by Sbv (60 mg/kg once per day for 5 days). Dosing of mice by oral gavage with 100 mg of MDL 27,695 per kg twice per day for 14 days resulted in 99.7% parasite suppression, and the 50% effective dose was approximately 11 mg of MDL 27,695 per kg. MDL 27,695 represents an effective new drug potentially useful for oral or parenteral treatment of visceral leishmaniasis.
The diaminopimelic acid (DAP) analog, 3-chloro-DAP, was synthesized and tested as the racemic acid for antibacterial activity and for inhibition of DAP epimerase. 3-Chloro-DAP was a potent inhibitor of DAP epimerase purified from Escherichia coli (K, = 200 nM), and it is argued that 3-chloro-DAP is converted to a tight-binding transition state analog at the active site of this enzyme. Furthermore, 3-chloro-DAP inhibited growth of two E. coli mutants. In one of the mutants known for supersusceptibiity to P-lactams, inhibition was not seen until the mid-log phase of growth, while in the other mutant, a DAP auxotroph, inhibition occurred much earlier. Growth inhibition was reversed by DAP in both strains. In the auxotroph, the reversal was specific for meso-DAP, indicating that DAP epimerase was the target for 3-chloro-DAP. Thus we suggest a novel mechanism of bacterial growth inhibition which depends on DAP epimerase inhibition by a DAP analog.
The 2-amino-1,3-thiazoline, 2-(p-n-hexylphenylamino)-1,3-thiazoline (MDL 20,245) killed 105 logarithmic or stationary phase Candida albicans/ml in less than 1 h. Miconazole killed logarithmic phase cells at that rate, but miconazole, clotrimazole or econazole killed stationary phase cells at a slower rate of 102–104 cells/ml in 24 h. MDL 20,245 induced efflux of K+ and L[U-14C] lysine from C. albicans, indicating that the candicidal mechanism is to exert direct damage upon the cytoplasmic membrane. The activity of MDL 20,245 in vitro was antagonized by fatty acids, triglycerides and phospholipids. Topical application of MDL 20,245 ointment (10% w/v) twice per day for 4 days to rats suppressed C. albicans-induced vaginitis 100%. Single-dose regimens of MDL 20,245, miconazole or clotrimazole correlated with 97, 90 and 73% suppression, respectively. These data suggest that MDL 20,245 may be effective in the treatment of C. albicans-induced vaginitis in humans.
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