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Chlorpropamide was found to be an effective antidiuretic agent in vasopressin-sensitive diabetes insipidus. Full clinical use of this action is limited by the frequent occurrence of hypoglycemia on higher doses. This complication can be avoided, however, by restricting the dose and by employing combination therapy with hydrochlorothiazide.
Diabetics well controlled on chlorpropamide received, in randomized manner either 1200 mg of ibuprofen or 300 mg of phenylbutazone per day for rheumatic pains, for a period of 4 weeks. Fasting and postlunch, whole blood, true sugars (FBS and PLBS) were estimated at weekly intervals. Subjects taking phenylbutazone showed reduction in FBS values throughout the treatment; the reduction became statistically significant at the 3rd and 4th week. Clinical hypoglycemia, however, was not observed. The FBS values returned to pretreatment levels after stopping phenylbutazone. No significant reduction was seen in FBS in subjects taking ibuprofen. There was no significant change in PLBS values in either group.
In order to study the objective value of the chlorpropamide alcohol flush (CPAF) the facial skin temperature and plasma acetaldehyde methods were compared to the visible response (flush/no flush) on standardized CPAF and alcohol challenge tests in 137 type 2 diabetics. Three criteria of CPAF are defined. A visible facial flush was noted in 53% of the diabetics. An increase in facial skin temperature of at least 1.0 degrees C was found in 90% of the subjects with a visible facial flush (flushers), but in only 14% of non-flushers. An increase in plasma acetaldehyde of at least 4 mumol/l was found in 86% of the flushers and in only 15% of non-flushers. Using these criteria to study CPAF all flushers satisfied at least two and 78% fulfilled all three criteria, while no non-flusher fulfilled more than one and 74% satisfied no CPAF criteria. However, with the alcohol test 5% could be identified as alcohol flushers having a falsely positive CPAF-test. In conclusion, it was possible to evaluate the CPAF test objectively with the facial skin temperature and plasma acetaldehyde methods.
The chlorpropamide alcohol flush test (CPAF) has been described as a dominantly inherited feature in NIDDM, particularly of young people (MODY-type). Validity and usefulness of the CPAF were analyzed in 40 MODY-patients recruiting from a population study (criteria acc. to Tattersall and Fajans, 1975), 59 first degree relatives (24 diabetics, 35 non-diabetics), 40 NIDDM of maturity onset, 40 IDDM, and 40 healthy controls. The CPAF (single challenge test, placebo control, subjective evaluation by questionnaire acc. to Köbberling, 1980) proved to be positive in only 8 MODY-patients and 5 of diabetic first-degree relatives. In comparison to NIDDM of maturity onset (40/8), IDDM (40/6) and healthy controls (40/2) the frequency of positive CPAF showed no significant differences. Between flushers and non-flushers within the MODY-group no relationship to vascular findings, metabolic and genetic data (including HLA-typing) could be found. It is concluded that the CPAF is a real but rather nonspecific phenomenon unsuitable as a genetic marker.
Methanolic solutions of the phototoxic antidiabetic drug chlorpropamide (CAS 94-20-2, 1) are photolabile towards UVB light under aerobic conditions. Irradiation of 1 produces the formation of the stable compounds p-chlorobenzenesulfonamide (2), N-(p-chlorophenylsulfonyl)formamide (3) and the dimer 4. A radical intermediate was evidenced by thiobarbituric acid that was used as a radical sonde, as well as by the dimerization of cysteine. The compound 1 showed moderate lytic activity upon the photohemolysis in vitro test on human erythrocytes which was increased with the addition of traces of its aggregate excipient. Inhibition of this process on addition of reduced glutathione (GSH), superoxide dismutase (SOD) or ascorbic acid suggests the involvement of radicals and superoxide ion in the photohemolysis process. The absence of inhibition with 1,4-diazabicyclo[2.2.2]octane (DABCO) and sodium azide (NaN3), and the lack of formation of singlet oxygen during the photolysis (confirmed with 2,5-dimethylfuran) rule out the possibility of participation of 1O2 in this process. Glutathione depletion was also observed. No photohemolysis was detected in the presence of the isolated photoproduct.
A thin-layer chromatographic procedure is described for the identification and quantitative determination of chlorpropamide, glibenclamide and tolbutamide in both powder and tablet form. The coefficient of variation of the method is 0.6-0.7%, and results show good agreement with those obtained by the B.P. methods of assay. The TLC procedure has the advantage of greater specificity, and can also be used to identify and limit degradation products that may be present.
Chlorpropamide-N1-peracetyl glucoside was synthesized by a phase transfer catalysed method. The synthetic product was analysed by spectroscopic techniques (NMR and MS).
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