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PubMed1991

Effects of temperature and pressure during compression on polymorphic transformation and crushing strength of chlorpropamide tablets.

The effects of temperature on the polymorphic transformation of chlorpropamide during compression and on the physical properties of the tablet have been investigated. A heater and liquid nitrogen pool were mounted on the die of a single punch eccentric tableting machine, and the die temperature was controlled by a thermocontroller. A tableting machine with two load cells (upper and lower punches) and a non-contact displacement transducer were used to measure compression stress, distance and energy. The X-ray diffraction profiles of the deagglomerated compressed sample powder were measured to calculate the polymorphic content. The amount of form C transformed from form A at 45 degrees C was about twice that at 0 degree C with the same compression energy. The amount of form A transformed from form C by compression at 45 degrees C was almost the same as that at 0 degree C. This suggests that the mechanochemical effect of form A depended on the compression temperature, but that of form C was independent of temperature. The crushing strength of tablets of form A was about twice that of form C, even at the same porosity. The plots of log (crushing strength of tablet) against porosity of form A tablets compressed at 0 and 45 degrees C were linear with the same slope; the slope for form C tablets compressed at 45 degrees C was less than that at 0 degree C.

Chemistry, Pharmaceutical↗

PubMed1978

Chlorpropamide-alcohol flushing: a definition of its relation to non-insulin-dependent diabetes.

The single-challenge test for chlorpropamide-alcohol flushing (CPAF) was used to study two groups of patients with non-insulin-dependent diabetes and a family history of the disease who were distinguished only by their age at diagnosis (under and over 30). Their relatives were also studied. The proportions of patients showing CPAF in both groups were similar, and the family histories suggested dominant inheritance. When offspring of diabetics in whom the disease was diagnosed early were studied CPAF seemed to precede the appearance of diabetes. We conclude that the patients in both groups had the same, distinct syndrome, which is characterised by diabetes diagnosed at any age that is inherited as an autosomal dominant trait and associated with CPAF. This syndrome, which constitutes about one-fifth of all cases of non-insulin-dependent diabetes, may be detected with a single-challenge CPAF test before the onset of glucose intolerance. CPAF therefore acts as a genetic marker for the syndrome.

Adolescent↗

PubMed1977

Chlorpropamide-induced thrombocytopenia.

Thrombocytopenia is a rare complication of chlorpropamide therapy. An immunological mechanism is generally held responsible, but has never previously been proved. In the present case the existence of such a mechanism has been established.

Antibodies↗

PubMed2000

Chlorpropamide upregulates antidiuretic hormone receptors and unmasks constitutive receptor signaling.

The mechanism by which chlorpropamide (CP) treatment promotes antidiuresis is unknown. CP competitively inhibited antidiuretic hormone (ADH) binding and adenylyl cyclase (AC) stimulation (inhibition constants K(i) and K'(i) of 2.8 mM and 250 microM, respectively) in the LLC-PK(1) cell line. CP (333 microM) increased the apparent K(a) of ADH for AC activation (0.31 vs. 0.08 nM) without affecting a maximal response, suggesting competitive antagonism. Because CP lowers "basal" AC activity and the AC activation-ADH receptor occupancy relationship (A-O plots), it is an ADH inverse agonist. Twenty-four-hour CP exposure (100 microM) upregulated the ADH receptors without affecting affinity. This lowered K(a) and increased basal AC activity and maximal response (1. 86 vs. 1.35 and 14.9 vs. 10.6 fmol cAMP. min(-1). 10(3) cells(-1), n = 6, P<0.05). NaCl, which potentiates ADH stimulation, also increased basal AC activity. This, together with the CP-ADH inverse agonism and increased basal AC activity at higher receptor density, unmasks constitutive receptor signaling. The CP-ADH inverse agonism explains receptor upregulation and predicts the need for residual ADH with functional isoreceptors for CP-mediated antidiuresis. This could be why CP ameliorates partial central diabetes insipidus but not nephrogenic diabetes insipidus.

Adenylyl Cyclases↗

PubMed1983

Chlorpropamide action on renal concentrating mechanism in rats with hypothalamic diabetes insipidus.

To determine vasopressin (VP)-potentiating effect of chlorpropamide (CPMD), we studied the effect of CPMD in vivo and in vitro in kidneys and in specific tubule segments of rats with hypothalamic diabetes insipidus, homozygotes of the Brattleboro strain (DI rats). Rats on ad lib. water intake were treated with CPMD (20 mg/100 g body wt s.c. daily) for 7 d. While on ad lib. water intake, the urine flow, urine osmolality, urinary excretion of Na +, K +, creatinine, or total solute excretion did not change. However, corticopapillary gradient of solutes was significantly increased in CPMD-treated rats. Higher tissue osmolality was due to significantly increased concentration of Na +, and to a lesser degree urea, in the medulla and papilla of CPMD-treated rats. Consequently, the osmotic gradient between urine and papillary tissue of CPMD-treated rats (delta = 385 +/- 47 mosM) was significantly (P less than 0.001) higher compared with controls (delta = 150 +/- 26 mosM). Minimum urine osmolality after water loading was higher in CPMD-treated DI rats than in controls. Oxidation of [14C]lactate to 14CO2 coupled to NaCl cotransport was measured in thick medullary ascending limb of Henle's loop (MAL) microdissected from control and CPMD-treated rats. The rate of 14CO2 production was higher (delta + 113% +/- 20; P less than 0.01) in CPMD-treated MAL compared with controls, but 14CO2 production in the presence of 10(-3) M furosemide did not differ between MAL from control and from CPMD-treated rats. These observations suggest that CPMD treatment enhances NaCl transport in MAL. Cyclic AMP metabolism was analyzed in microdissected MAL and in medullary collecting tubule (MCT). MCT from control and from CPMD-treated rats did not differ in the basal or VP-stimulated accumulated of cAMP. The increase in cAMP content elicited by 10(-6) M VP in MAL from CPMD-treated rats (delta + 12.0 +/- 1.8 fmol cAMP/mm) was significantly (P less than 0.02) higher compared with MAL from control rats (delta + 5.1 +/- 1.0 fmol cAMP/mm). Preincubation of MAL dissected from Sprague-Dawley rats with 10(-4) M CPMD in vitro increased cAMP accumulation in the presence of VP, but no such enhancement was found in preincubated MCT. Adenylate cyclase activity, basal or stimulated by VP, 5'guanylimidodiphosphate, or by NaF, assayed in isotonic medium did not differ between MAL or MCT from control rats and MAL or MCT from CPMD-treated rats. When assayed in hypertonic medium (800 mosM), the adenylate cyclase activity in the presence of 10(-6) M VP was significantly higher in MAL of CPMD-treated rats. MAL and MCT from control and CPMD-treated rats did not differ in the activities of cAMP phosphodiesterase. The rate of [(14)C]prostaglandin E2 by medullary and papillary microsomes was not different between the control and CPMD-treated rats; likewise, there was no difference in accumulation of immunoreactive prostaglandin E2 in the medium of in vitro incubated medullary or papillary slices prepared from control and CPMD-treated rats. Based on the findings recounted above, we propose a hypothesis that CPMD administration enhances the antidiuretic effect of VP, primarily by increasing medullary and papillary tonicity dye to increased NaCl reabsorption in MAL. There is no evidence that CPMD sensitizes collecting tubules to the action of VP, at least at the camp-generation step. Therefore, increased antidiuretic response to VP in the kidneys of CPMD-treated DI rats is due to enhanced osmotic driving force for water reabsorption (lumen-to-interstitium osmotic gradient) in collecting tubules, rather than due to increased VP-dependent water permeability of tubular epithelium.

Animals↗

PubMed1984

Hypoglycemia induced by the interaction of chlorpropamide and co-trimoxazole.

Sulfonylureas hypoglycemic action may be potentiated by sulfonamides. This case report describes a 69-year-old female with a hypoglycemic episode suggestive of an interaction between chlorpropamide and sulfamethoxazole (co-trimoxazole). The patient had no renal or liver dysfunction. This interaction is rare but one should be aware of it, especially with combination products.

Aged↗

PubMed1992

Chlorpropamide-induced hyponatremia in the veteran population.

OBJECTIVE: To determine the incidence and possible risk factors associated with chlorpropamide (CPA)-induced hyponatremia in the veteran population. DESIGN: Retrospective cohort study. SETTING: Federal tertiary care medical center. PATIENTS: Veterans receiving CPA from our facility with at least one serum sodium concentration below 135 mmol/L within the past year were eligible. A randomly selected control group consisting of patients taking CPA with normal sodium concentrations was also chosen. One hundred forty-five of 799 patients who had received CPA were included in the study. RESULTS: The average daily dose of CPA was 425 +/- 207 mg (+/- SD). The incidence of hyponatremia associated with CPA was 7.1 percent (57/799 patients). The majority of patients were mildly hyponatremic (48/57 patients, 84 percent) with serum sodium concentrations between 130 and 134 mmol/L. The incidence of CPA-induced syndrome of inappropriate antidiuretic hormone was 2.1 percent. Concurrent angiotensin-converting enzyme (ACE) inhibitor use was identified as a risk factor; thiazide diuretic use was not. CONCLUSIONS: The incidence of hyponatremia related to CPA use in elderly veterans is consistent with other reports in the literature. ACE inhibitors may be a predisposing factor for CPA-induced hyponatremia.

Aged↗

PubMed1981

Essential hypernatraemia, antidiuretic hormone and neurophysin secretion: response to chlorpropamide.

An adolescent boy with essential hypernatremia, absent corpus callosum, mental retardation, hypodipsia, and partial diabetes insipidus with "inappropriate" ADH regulation and secretion was studied regarding factors controlling ADH and neurophysin release. Persistent hyperosmolality was noted while on 100 mEq sodium intake daily. Endogenous vasopressin activity was demonstrated after prolonged water deprivation. Hypertonic saline infusion produced increased volumes but dilute urine. Aqueous pitressin increased urinary osmolality, decreased serum osmolality, urine flow rate, and free water clearance. Stable water diuresis was induced by water loading and on normal saline infusion. Nicotine-stimulated neurophysin remained unexpectedly low and below the level of detectability when sampled during the physiologic studies, whereas oestrogen-stimulated neurophysin was elevated during oestrogen stimulation, water loading, and orthostasis procedures. Plasma vasopressin was suppressed with water loading but remained suppressed 90 min after tilt table testing. These data indicate impairment of the osmoreceptor mechanism: however, since the patient had a normal response of oestrogen-stimulated neurophysin, that part of the neurohypophysis appears intact. Chlorpropamide was effective in alleviating the hyperosmolar state acutely and maintained normal osmolar concentrations during two years of therapy.

Adolescent↗

PubMed1995

Chlorpropamide-induced ADH release, hyponatremia and central pontine myelinolysis in diabetes mellitus.

Chlorpropamide (CPM) has been reported to produce impaired water excretion due to the enhancement of renal vasopressin (ADH) action and/or due to centrally enhanced ADH release, but it is still unknown whether CPM gives rise to ADH release with a subsequent hyponatremia in diabetes mellitus (DM), which, in turn, causes an impairment of the central nervous system. In 3 patients with DM, who developed hyponatremia during the treatment with CPM, an acute water load (WL) was carried out in the presence and absence of the drug, and plasma ADH was determined with plasma and urine osmolalities. Moreover, in 2 cases, MRI scans of the brain were taken. In all the patients, acute WL tests failed to suppress completely ADH release in response to changes in plasma osmolality in the presence of CPM, which, in turn, resulted in the impaired water excretion. In the absence of CPM, an acute WL normally suppressed plasma ADH leading to the diuresis. MRI scans illustrated the presence of central pontine myelinolysis. It is likely that CPM might stimulate ADH release in DM with a subsequent hyponatremia and brain damages.

Aged↗

PubMed1977

Potentiation of hypoglycemic effect of chlorpropamide and phenfromin by halofenate.

The potentiation of oral hypoglycemic drugs by the antilipemic agent halofenate is reported. Forty-seven diabetic patients were treated for 48 weeks with halofenate, clofibrate, or placebo. Five patients in the halofenate group were taking phenformin plus either chlorpropamide or tolbutamide. Their average initial fasting plasma glucose was 160 mg./dl. All five patients experienced a slow but but substantial fall in fasting plasma glucose. The mean fasting plasma glucose for the five patients after 80 days of halofenate treatment was 63 mg./dl. As oral treatment for diabetes was reduced, the fasting plasma glucose returned to prehalofenate levels. In this study, we did ont detect an effect of halofenate on the fasting plasma glucose of diabetic patients treated with insulin or on the fasting plasma glucose levels of patients treated with diet alone.

Blood Glucose↗

PubMed1978

betacell function during insulin or chlorpropamide treatment of maturity-onset diabetes mellitus.

Maturity-onset diabetic patients usually have raised overnight-fasting plasma glucose levels associated with "normal" basal plasma insulin levels. The basal hyperglycemia is proportional to the degree of insulin deficiency. Basal insulin or C-peptide levels become subnormal if normal fasting plasma glucose levels are attained with insulin. Basal hyperglycemia is probably a compensatory response to maintain near-normal basal insulin levels. A logical therapy of maturity-onset diabetes is to produce basal normoglycemia by means of a constant basal insulin supplement, which can be provided by ultralente insulin. The reduced insulin response of diabetics to intravenous glucose is slightly increased when basal normoglycemia is established, suggesting that the high plasma glucose levels compromise beta cell function. The insulin response to meals in a mild diabetic is not affected by mild hyperglycemia but can be depleted if gross hyperglycemia occurs. Maintenance of normoglycemia then allows beta cell "recovery". In mild diabetics (c. less than 9 mmol per liter basal plasma glucose), chlorpropamide sufficiently stimulates beta cell secretion so that basal normoglycemia can be produced. The C-peptide response to meals is improved, whereas comparable reduction of the plasma glucose with insulin does not alter the meal response. Thus basal normoglycemia can be produced by "resting" beta cells with a basal insulin supplement or by stimulating them with sulfonylurea therapy.

Blood Glucose↗

PubMedDate not supplied

Glyburide and glipizide in treatment of diabetic patients with secondary failures to tolazamide or chlorpropamide.

We evaluated therapeutic usefulness of the second-generation sulfonylurea agents glyburide and glipizide in non-insulin-dependent diabetic patients who were secondary failures on chlorpropamide or tolazamide. Twenty patients were treated with glyburide, and 10 of them were subsequently treated with glipizide. Fasting and postprandial serum glucose, insulin, C-peptide, glycosylated hemoglobin, urinary C-peptide, and glucose levels all failed to show significant improvement. We concluded that both glyburide and glipizide proved ineffective in the treatment of secondary failures to first-generation sulfonylureas.

Blood Glucose↗

PubMed1989

Comparative bioavailability of two brands of chlorpropamide in Kenyans.

The relative bioavailability of two brands of chlorpropamide, Dibonis, and Diabinese has been evaluated in four healthy male volunteers in a randomized, balanced, cross-over study. No statistically significant differences were observed in the absorption rate constant, ka, time to reach peak serum concentration, tp, maximum serum concentration, Cmax, the overall elimination rate constant, kel, and the area under the curve, AUC, at 95% confidence level.

Adult↗

PubMedDate not supplied

Risk factors for micro- and macroangiopathic complications in type 2 diabetes: lack of association with acetylator phenotype, chlorpropamide alcohol flush and ABO and Rh blood groups.

Genetic markers would be useful to study the transmission of type 2 diabetes and to identify patients with enhanced risk of development of late diabetic complications. The aim of this study was to evaluate the influence of selected possible genetic markers on the development of diabetic complications. One hundred and eighty patients with type 2 diabetes (79 males, 101 females) were therefore studied with respect to ABO and Rh blood grouping and chlorpropamide alcohol flush (CPAF) and acetylator phenotype status, in addition to life style (smoking, dietary, alcohol and drug taking habits) and metabolic indexes (HbA1, M-value, serum cholesterol, serum triglycerides), with regard to late complications coronary heart disease (CHD), arterial hypertension (AH), peripheral vascular disorders (PVD), retinopathy and nephropathy. None of the genetic markers considered appeared to be associated with diabetic complications. Multiple logistic analysis identified different risk-factors for each complication: AH and age for CHD; hyperlipidaemia for AH; age of patients for PVD; duration of diabetes for retinopathy; AH for nephropathy. It is concluded that the possible genetic markers evaluated in this study do not identify a higher or lower risk for late complications. On the contrary, most of the risk factors identified support previous studies. Active correction of these risk-factors might improve the overall prognosis of patients with type 2 diabetes.

ABO Blood-Group System↗

PubMed1978

The interaction between alcohol, chlorpropamide and phenformin in a severe combined poisoning: case report.

A young non-diabetic woman ingested 2.5-3.7 g of chlorpropamide and 0.6-0.9 g of phenformin together with a large dose of alcohol, nitrofurantoin and promethazine in a suicidal attempt. She developed severe metabolic acidosis, hypokalemia, polyuria and prolonged hypoglycemia in the absence of typical hypoglycemic symptoms. These unusual clinical features were in part explained on the basis of the interactions between alcohol and the other drugs.

Adult↗

PubMedDate not supplied

Liquid chromatographic determination of chlorpropamide in tablet dosage forms: collaborative study.

A reverse-phase liquid chromatographic method was developed for determining chlorpropamide in tablet dosage forms. Linearity was established over the range 0.2-2.0 micrograms at a wavelength of 240 nm. The Associate Referee obtained a mean recovery for a synthetic tablet mixture of 99.2%, with a relative standard deviation (RSD) of 1.41. For an authentic tablet mixture, collaborators obtained a mean recovery of 99.6% with an RSD of 0.60%. RSDs were 1.24% for 250 mg/tablet commercial product and also for 100 mg/tablet commercial product. The method has been adopted official first action.

Chlorpropamide↗

PubMed1987

Chlorpropamide-induced pure white cell aplasia.

We investigated the mechanism for isolated agranulocytosis and marrow pure white cell aplasia in an elderly man receiving 0.5 to 1.0 g per day of chlorpropamide (Chl) without other toxic drug exposure or overt systemic illness. Patient marrow revealed an absence of recognizable granulocytic precursors; megakaryocytes and erythroid precursors were normal. The WBC count was 1800/mm3 on admission with only 2% neutrophils; the absolute neutrophil count first exceeded 500/mm3 on the 17th day following cessation of Chl. A serum Chl level on admission was 100 micrograms/mL (acute phase, AP); no Chl was detected in serum (convalescent phase, CP) assessed on the 22nd hospital day. Antineutrophil antibodies were not detected, and T cell depletion failed to augment patient in vitro granulopoiesis. Patient AP serum produced potent complement-mediated inhibition (87% +/- 7%) of autologous granulocyte progenitors (CFU-GM) with minimal inhibition of erythroid (11% +/- 5%) or multipotent (5% +/- 4%) progenitor cells. Selective inhibition by patient AP serum of CFU-GM (74% +/- 11%) was also seen against two allogeneic marrows. Patient CP serum no longer inhibited (6% +/- 4%) autologous CFU-GM. Addition of Chl (5 to 120 micrograms/mL) to CP serum but not to control serum resulted in potent drug concentration-dependent complement-mediated inhibition of autologous and allogeneic CFU-GM. Inhibition of CFU-GM in the presence of Chl was no longer demonstrable following immunoabsorbent removal of IgG from patient serum. Patient serum in the presence of Chl had limited activity against morphologically recognizable marrow granulocytic precursors in a microimmunofluorescence assay. These results are most consistent with the development of Chl-dependent, selective antibody-mediated immune inhibition of granulopoiesis.

Aged↗

PubMed1986

[Frequency of a positive result in the chlorpropamide-alcohol flush test in type I and type II diabetes].

146 newly manifested diabetics (91 type I, 55 type II) and 20 non-diabetics were examined with the help of the chlorpropamide alcohol flush test. Also under different criteria of valuation of the increase of skin temperature (1.5 and 1.8 degrees C, respectively) no significant differences between the positive findings of the test in type I and type II diabetics were the result. Decisive for a positive result is according to our investigations the pre-existing initial temperature of the skin area, the room temperature and the air humidity. In such a case the initial temperature of the skin area depends on the moment of the last food intake.

Adolescent↗