A spectrophotometric determination of CO-Hb content was investigated on the basis of double wavelength spectrophotometry. Absorbance differences at the two wavelengths at which O2-Hb has the same absorbance reflect only the CO-Hb component because the O2-Hb component is nulled out from the mixture of O2-Hb and CO-Hb. After measurement of absorbance difference, the measuring solution was saturated with pure CO and remeasured. CO-Hb % was calculated from the ratio of the absorbance differences. Since temperature significantly influences the spectrum of hemoglobin pigment, the wavelength pair changed with temperature. For accurate measurement, it was necessary to control temperature of diluting solution before dilution. Liberation of CO from CO-Hb was observed at more than 80% CO-Hb, and 5% and 2% liberation from 100% CO-Hb occured at 100-fold dilution with 10mm cuvette and 20-fold dilution with 2 mm cuvette respectively. Advantages of this method are that the standard curve or equation for calculation and accurate dilution are not necessary because the interfering component is nulled out and 100% CO-Hb of the standard sample is made with the same sample ; and measurement is very rapid, taking less than 2 min.
Physical dependence liability to cinepazide was studied, and the following were found : 1. Rats were applied cinepazide for 96 days by the cinepazide-admixed food method (DAF method) on gradedly increasing dosage schedules from low cinepazide dose; of 1/4 and 1/2 mg/g food (the average intake being 40 mg/kg/day) to 6 and 8 mg/g food (the average intake being 277 mg/kg/day) which caused toxic signs to evolve, e.g., suppressed righting reflex, urinary incontinence, dacryohemorrhed, hypothermia, and weight loss. No abstinence signs evolved on withdrawal at any dosage level. 2. The challenge with levallorphan (2 mg/kg, s.c.) at each dosage level during the application of cinepazide on the gradedly increasing dosage schedules precipitated no abstinence signs. 3. Cross-application at 3- to 6-hour intervals of 0 (the vehicle only), 10, 30, 100 and 300 mg/kg (p.o.) of cinepazide (doses prolonging the duration of hexobarbital-induced sleep) to animals with the manifestation of moderate to severe barbital abstinence signs, unlike the similar application of diazepam (10, 30 and 100 mg/kg, p.o.) as the positive control, failed to suppress but rather tended to aggravate the abstinence signs. 4. Cross-application at 3- and 6-hour intervals of 0, 10, 30, 100 and 300 mg/kg (p.o.) of cinepazide and similar s.c. application of 30 mg/kg of pethidine resulted in a significant suppression of weight loss due to withdrawal of morphine in the groups of animals treated with 100 and 300 mg/kg of cinepazide. Naloxone challenge at the stage when weight loss was suppressed significantly (p<0.05) in the animals on the cross-application of pethidine precipitated the abstinence signs but no significant weight loss in the groups on the cross-application of cinepazide. Thus, the suppressive action of cinepazide on the morphine abstinence signs proved to be derived from its non-specific action on drug dependence, and failed to maintain morphine dependence. In conclusion, cinepazide cannot be considered either to have physical dependence liability or maintain barbital- or morphine-dependence.
Inducibility of chromosome aberrations of cultured mammalian cells was examined on 11 clinical medicines which are used for a long term mainly in the field of internal medicine. P-aminosalicilic acid, isonicotinic acidhydrazid, streptomycin A, hydralazine hydrochloride, methimazole and theophylline induced definite increase of chromosome aberrations. Among them P-aminosalicilic acid was a little weak in its effect. The effects of rifamycin SV, aminophylline and isosorbide dinitrate were judged as suspicious, because only a slight increase of the aberrations were caused. Reserpine and propylthiouracil induced little chromosome aberrations. Effective concentrations of these medicines in our chromosome test were compared with their maximum blood concentrations in clinical use in human quoted from the published papers. Their ratios by isonicotinic acid hydrazid, streptomycin A, methimazole, theophylline and issorbide dinitrate were very high and those by others were relatively low. Because p-aminosalicilic acid, rifamycin SV, hydralazine hydrochloride and aminophylline were positive or suspicious in our chromosome test, further pursue for the safety evaluation seems necessary.
Carbaryl and dieldrin were accumulated mostly in the liver, and paraquat was accumulated in the kidney of normal diet (casein 24.5%) rats at 1 hr after the oral administration. At 5 hr after the administration, the concentration of carbaryl in liver or fat, and that of paraquat in kidney were markedly decreased. However, dieldrin in liver, kidney, lung, fat or others was significantly increased at the same period. The absorption of paraquat from gastrointestinal tract was the least among the chemicals used. Biliary excretion of carbaryl was the highest and that of paracluat was the least by 5 hr after intravenous administration. The excretion ratio was about 100 : 10 : 1 for carbaryl, dieldrin and paraquat in normal diet rats. Biliary excretion of these chemicals was higher in high protein diet (casein 45%) rats and retention of the chemicals in tissue was higher in low protein diet (casein 5%) rats.
l-1, 4-Dimethyl-10-hydroxy-2, 3, 4, 5, 6, 7-hexahydro-1, 6-methano-1H-4-benzazonine hydrobromide (l-ST-2121) is a new narcotic-antagonist analgesic possessing remarkable analgesic activity, and this activity is equal to or more potent than that of pentazocine. A single administration of l-ST-2121 produced a moderate CNS depression in rats, such as sedation, systemic muscle relaxation and decrease in motor activity. Rats were inter-mittently medicated for 1 to 6 days at one hour intervals through an implanted intravenous cannula. In a physical dependence producing test, physical dependence on morphine was developed rapidly in the rats maintained with as low as 9.6 mg/kg/day. Physical dependence on pentazocine and l-ST-2121 was also developed with the maintenance dose of 96 mg/kg/day, but not with 9.6 mg/kg/day. However, physical dependence on pentazocine was developed with the maintenance dose of 19.2 mg/kg/day, but l-ST-2l2l was not. In a naloxone-precipitated withdrawal test, rats treated with l-ST-2121 (24mg/kg/day, 48mg/kg/day and 96 mg/kg/day) showed withdrawal signs when they were given naloxone. Rats treated with morphine or pentazocine also showed withdrawal signs after naloxone challenge. In a substitution test, l-ST-2121 suppressed the withdrawal signs of morphine- and pentazocine-dependent rats, and pentazocine suppressed those of morphine-dependent rats. l-ST-212l has physical dependence liability of morphine type. The results show that all three drugs induce physical dependence in the order of severity of morphine>pentazocine≥l-ST-2121.
Chronic toxicity of clobetasone-17-butyrate, an anti-inflammatory corticosteroid, was investigated in rats. Subcutaneous administration with the drug at dose of 0.003, 0.0l and 0.03 mg/kg/day for three and six months induced no significant changes in the rats. At 0.1 and 0.3 mg/kg/day, however, some dose-dependent symptoms such as suppression of body weight gain, emaciation, regressive changes in adrenals, lymphatic and hematopoietic tissues, decrease in circulating white blood cell and lymphocyte counts, which have been known as toxic effects of synthetic corticosteroids, were induced. The results indicates that the maximum non-toxic dose of clobetasone -17 butyrate was 0.03 mg/kg/day on this experimental condition. In the recovery test for two months no significant differences in the treated rats from controls were found, suggesting that the toxic effects were reversible in the animals treated at 0.3 mg/kg/day and lower than that.