Predicting post one-year durability of glucose-lowering monotherapies in patients with newly-diagnosed type 2 diabetes mellitus - A MASTERMIND precision medicine approach (UKPDS 87).

AIMS: Predicting likely durability of glucose-lowering therapies for people with type 2 diabetes (T2D) could help inform individualised therapeutic choices. METHODS: We used data from UKPDS patients with newly-diagnosed T2D randomised to first-line glucose-lowering monotherapy with chlorpropamide-glibenclamide-basal insulin or metformin. In 2339 participants who achieved one-year HbA1c values <7.5% (<59 mmol/mol)-we assessed relationships between one-year characteristics and time to monotherapy-failure (HbA1c ≥ 7.5% or requiring second-line therapy). Model validation was performed using bootstrap sampling. RESULTS: Follow-up was median (IQR) 11.0 (8.0-14.0) years. Monotherapy-failure occurred in 72%-82%-75% and 79% for those randomised to chlorpropamide-glibenclamide-basal insulin or metformin respectively-after median 4.5 (3.0-6.6)-3.7 (2.6-5.6)-4.2 (2.7-6.5) and 3.8 (2.6- 5.2) years. Time-to-monotherapy-failure was predicted primarily by HbA1c and BMI values-with other risk factors varying by type of monotherapy-with predictions to within ±2.5 years for 55%-60%-56% and 57% of the chlorpropamide-glibenclamide-basal insulin and metformin monotherapy cohorts respectively. CONCLUSIONS: Post one-year glycaemic durability can be predicted robustly in individuals with newly-diagnosed T2D who achieve HbA1c values < 7.5% one year after commencing traditional monotherapies. Such information could be used to help guide glycaemic management for individual patients.

Pharmacogenomic analysis of ATP-sensitive potassium channels coexpressing the common type 2 diabetes risk variants E23K and S1369A.

OBJECTIVES: The common ATP-sensitive potassium (KATP) channel variants E23K and S1369A, found in the KCNJ11 and ABCC8 genes, respectively, form a haplotype that is associated with an increased risk for type 2 diabetes. Our previous studies showed that KATP channel inhibition by the A-site sulfonylurea gliclazide was increased in the K23/A1369 haplotype. Therefore, we studied the pharmacogenomics of seven clinically used sulfonylureas and glinides to determine their structure-activity relationships in KATP channels containing either the E23/S1369 nonrisk or K23/A1369 risk haplotypes. RESEARCH DESIGN AND METHODS: The patch-clamp technique was used to determine sulfonylurea and glinide inhibition of recombinant human KATP channels containing either the E23/S1369 or the K23/A1369 haplotype. RESULTS: KATP channels containing the K23/A1369 risk haplotype were significantly less sensitive to inhibition by tolbutamide, chlorpropamide, and glimepiride (IC50 values for K23/A1369 vs. E23/S1369=1.15 vs. 0.71 µmol/l; 4.19 vs. 3.04 µmol/l; 4.38 vs. 2.41 nmol/l, respectively). In contrast, KATP channels containing the K23/A1369 haplotype were significantly more sensitive to inhibition by mitiglinide (IC50=9.73 vs. 28.19 nmol/l for K23/A1369 vs. E23/S1369) and gliclazide. Nateglinide, glipizide, and glibenclamide showed similar inhibitory profiles in KATP channels containing either haplotype. CONCLUSION: Our results demonstrate that the ring-fused pyrrole moiety in several A-site drugs likely underlies the observed inhibitory potency of these drugs on KATP channels containing the K23/A1369 risk haplotype. It may therefore be possible to tailor existing therapy or design novel drugs that display an increased efficacy in type 2 diabetes patients homozygous for these common KATP channel haplotypes.

Comparative bioavailability study with two chlorpropamide tablet formulations in healthy volunteers.

OBJECTIVE: The aim of this study was the assessment of the bioequivalence of two formulations (250 mg tablet) of chlorpropamide (CAS 94-20-2) in 36 healthy volunteers of both sexes. METHODS: The study was conducted using an open, randomized, two-period crossover design with a 3-week washout interval. Plasma samples were obtained over a 72-h period. Plasma chlorpropamide concentrations were analyzed by liquid chromatography coupled to tandem mass spectrometry (LC-MS-MS) with positive ion electrospray ionization using multiple reaction monitoring (MRM). From the chlorpropamide plasma concentration vs time curves, the following pharmacokinetic parameters were obtained: AUC(0-72h), AUC(inf) and C(max). RESULTS: The limit of quantification was 0.1 microg/mL for plasma chlorpropamide analysis. The geometric mean and respective 90 % confidence interval (CI) of Test/ Reference percent ratios were 93.99% (87.11%-101.41%) for C(max), 92.45% (85.96%-99.44%) for AUC(0-72h) and 90.30% (83.35%-97.82%) for AUC(0-inf). CONCLUSION: Since the 90 % CI for AUC(0-72h), AUC(0-inf) and C(max) ratios were within the 80-125%interval proposed by the US FDA, it was concluded that chlorpropamide 250 mg tablet (test formulation) was bioequivalent to the reference 250 mg tablet for of both the rate and extent of absorption.

Kinetic analysis of chlorpropamide dissolution from solid dispersions.

Solid dispersions (SDs) of chlorpropamide were prepared by the solvent deposition technique using two grades of microcrystalline cellulose as carrier materials with different ratios of drug to carrier. The dissolution rate of chlorpropmide from the SDs was carried out at two physiological pH values of 1.1 and 7.25 simulating gastric and intestinal environments. The dissolution was dependent on the grade, the ratio of drug to carrier and pH. The higher dissolution was observed for more hydrophilic grade of the carrier as well as the higher ratio of carrier to drug. At the higher pH the drug dissolved much faster than the lower pH. X-ray diffraction showed some reduced drug crystallinity in SDs whereas infrared spectroscopy revealed no drug interactions with solvent and the carriers. The enhanced dissolution was attributed to the reduced drug crystallinity, decreased particle size, increased wettability and reduced aggregation of the hydrophobic drug particles. A novel model denoted as reciprocal powered time model with its theoretical justification was employed to analyze the dissolution data and proved to be superior to commonly used models for the analysis of the data. There was a quantitative relation between the model parameter and the ratio of carrier to drug which could be of value in dissolution rate prediction.

Hypoglycemic effect of Sclerocarya birrea [(A. Rich.) Hochst.] [Anacardiaceae] stem-bark aqueous extract in rats.

This study was undertaken to evaluate the hypoglycemic effect of Sclerocarya birrea [(A. Rich.) Hochst.] subspecies caffra (Sond.) Kokwaro [family: Anacardiaceae] stem-bark aqueous extract in normal (normoglycemic) and in streptozotocin (STZ)-treated, diabetic Wistar rats. In one set of experiments, graded doses of S. birrea stem-bark aqueous extract (SB, 100-800 mg/kg p.o.) were separately administered to groups of fasted normal and fasted diabetic rats. In another set of experiments, a single dose of the plant aqueous extract (SB, 800 mg/kg p.o.) was used. The hypoglycemic effect of this single dose (SB, 800 mg/kg p.o.) of S. birrea stem-bark aqueous extract was compared with that of chlorpropamide (250 mg/kg p.o.) in both fasted normal and fasted diabetic rats. Following acute treatment, relatively moderate to high doses of S. birrea stem-bark extract (SB, 100-800 mg/kg p.o.) produced dose-dependent, significant reductions (P < 0.05-0.001) in the blood glucose concentrations of both fasted normal and fasted diabetic rats. Chlorpropamide (250 mg/kg p.o.) also produced significant reductions (P < 0.05-0.001) in the blood glucose concentrations of the fasted normal and fasted diabetic rats. Administrations of the single dose of S. birrea stem-bark aqueous extract (SB, 800 mg/kg p.o.) significantly reduced (P 0.01 < 0.001) the blood glucose levels of both fasted normal (normoglycemic) and fasted STZ-treated, diabetic rats. The results of this experimental animal study indicate that aqueous extract of Sclerocarya birrea possesses hypoglycemic activity, and thus lend credence to the suggested folkloric use of the plant in the management and/or control of adult-onset, type-2 diabetes mellitus in some African communities.

Investigation of hypoglycemic properties of rectal suppositories with chlorpropamide.

Rectal suppositories with chlorpropamide and suppositories with chlorpropamide in the dispersion system with urea were prepared. Witepsol H15 and H19 and a polyoxyethyleneglycol mixture were used as bases. Rabbits were tested for blood-glucose level. The animals have been administered with prepared suppositories and commercial tablets. It was found that the suppositories prepared on the basis Witepsol H 15 with the dispersed chlorpropamide caused a much higher decrease of blood-glucose level than commercial tablets.

Hypodipsic hypernatremia and diabetes insipidus following anterior communicating artery aneurysm clipping: diagnostic and therapeutic challenges in the amnestic rehabilitation patient.

Hypodipsic hypernatremia (HH) represents a pathological increase in serum sodium due to a lack of thirst and defect in hypothalamic osmoreceptors. While 15% of patients with HH have a vascular aetiology, few cases have been described. Moreover, the presence of such abnormalities in the amnestic patient can have particularly threatening implications, as HH tends to recur unless the patient complies with a regimen of water intake. This study reports the case of a 46-year-old male admitted for rehabilitation of functional deficits following subarachnoid haemorrhage (SAH), with clipping of an anterior communicating artery (ACoA) aneurysm. Clinical examination was remarkable for profound short-term memory loss and inability to retain new information. Blood chemistry on admission showed a serum sodium level of 160 mEq/L, increasing to 167 mEq/L the following day. The patient denied thirst, and showed no clinical signs of dehydration. Neuroendocrine evaluation revealed diabetes insipidus (DI) and HH. Treatment initially included DDAVP and intravenous hydration, later supplemented with chlorpropramide. Stabilization of serum sodium and osmolality did not ensue until the treatment regimen included hydrochlorothiazide and supervision of enforced fluid intake. Endocrine abnormalities may be encountered among patients with vascular lesions adjacent to the hypothalamus. Rehabilitation interventions include establishing a structured medication regimen with fluid administration in the amnestic patient with hypothalamic dysfunction.

Influence of a carrier and basis upon liberation of chlorpropamide from rectal suppositories with an active substance in the dispersion system.

Twelve series of rectal suppositories with chlorpropamide in two dispersion systems, containing different quantities of active substance and urea, were prepared upon lipophilic and hydrophilic bases. Liberation of chlorpropamide from suppositories was examined by the dialysis method. It was found out that the process of chlorpropamide liberation from the suppositories depends on the quantity of the carrier included in the dispersion systems and on the type of the medium used.

Auditing prescription practice using explicit criteria and computerized drug benefit claims data.

Bringing information on patterns of existing practice together with information on appropriate practice is an essential component of efforts to improve health care. In this study, computerized claims from a universal and comprehensive drug benefit plan for the elderly were brought together with explicit criteria for appropriate prescribing in the elderly in order to provide an estimate of the extent of potentially inappropriate prescribing in the covered population and the degree to which inappropriate prescribing was associated with defined physician characteristics. The analysis showed that 38% of elderly people who received antidepressants, 19% of those who received oral hypoglycemics, 18% of those who received sedative hypnotics and 13% of those who received non-steroidal anti-inflammatory drugs were defined as having received a potentially inappropriate drug. Older physicians and physicians without speciality certification were more likely to prescribe potentially inappropriate drugs. This analysis shows that criteria-based audits of drug claims databases can be used to provide an overview of prescribing problems at a population level and can reveal physician characteristics that may predict poor prescription practice. However, since neither explicit criteria nor claims databases can accurately capture the clinical details that ultimately define the appropriateness of care, audits of claims data should be linked to a more definitive measure of appropriateness and strategies designed to improve care.

Photohemolytic potency of oral antidiabetic drugs in vitro: effects of antioxidants and a nitrogen atmosphere.

The sulphonamide-derived oral antidiabetic drugs carbutamide, chlorpropamide, glibenclamide, glibornuride, gliclazide, glipizide, gliquidone, glisoxepide, glymidine, tolazamide and tolbutamide were investigated for photohemolytic properties in vitro. Irradiation with a SOL 3 apparatus (solar simulating irradiation) revealed hemolysis in the presence of chlorpropamide, glipizide, gliquidone, glymidine and tolbutamide (all in the concentration 10(-3) mol/l). Except for glymidine, which exerted photohemolysis in the concentration 10(-4) mol/l, no hemolytic effects were seen in the concentration of 10(-4) mol/l or 10(-5) mol/l. Irradiation with TL 12 light bulbs (UVB), a UVASUN 5000 apparatus (UVA) or an experimental lamp (visible light) did not induce phototoxic hemolysis with either of the test substances. Addition of the antioxidants ascorbic acid, alpha-tocopherol or superoxide dismutase significantly inhibited the phototoxic hemolysis. Investigations carried out in a nitrogen-rich atmosphere reduced the hemolysis as well. These findings indicate an involvement of reactive oxygen species in the mechanism of action of the hemolytic process in the presence of oral antidiabetic drugs.

Water retention after oral chlorpropamide is associated with an increase in renal papillary arginine vasopressin receptors.

Chlorpropamide (CP), a sulfonylurea used for treatment of non-insulin dependent diabetes mellitus, is known to potentiate the antidiuretic action of arginine vasopressin (AVP), predisposing to hyponatremia. It has been suggested that CP acts directly on the antidiuretic vasopressin receptor. Detailed studies on the influence of CP on the AVP receptor, however, have been hampered by lack of a suitable radioligand. Using a newly developed radioiodinated derivative of AVP with high specific activity and high affinity for the AVP V2-receptor (125I-[8-(p-(OH)-phenylpropionyl)]-LVP), we studied the role of AVP V2-receptors in CP-induced water retention. Male-Sprague-Dawley rats were treated orally with 40 mg CP/day or placebo for 7 days, after which Scatchard analysis was performed using membranes prepared from homogenized renal papilla. After oral water load, CP-treated rats but not control rats showed a significant decrease in plasma osmolality (289 +/- 2.2 to 284 +/- 0.8 mosmol/kg, p < 0.05). The Kd was 0.69 +/- 0.16 nmol/l in controls and 0.70 +/- 0.12 nmol/l after CP treatment (NS); Bmax was 129 +/- 5.3 nmol/kg protein in controls (N = 8). Chlorpropamide significantly increased receptor density (Bmax) to 167 +/- 8.4 nmol/kg protein (N = 8) (p < 0.05). Plasma AVP did not change significantly during CP treatment. These data show for the first time that CP in vivo increases the density of AVP V2 receptors without altering plasma AVP. This is associated with an impairment in water excretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Drug utilization review on high blood pressure and diabetes mellitus in St. Lucia - abstract

During a three-month period in 1991, the Eastern Caribbean Drug Service conducted a drug utilization review of hypertension and diabetes mellitus in St. Lucia. The survey was designe to assess the prescribing trends of drugs for these two highly prevalent diseases with emphasis on ther resulting medical and financial consequences. This prospective study utilized a quota sampling technique whereby an equal number of prescriptions were drawn from selected private and public clinics. One thousand, four hundred and eighteen prescriptions were collected. The percentage of women (68.3 percent) treated was more than double that of the men (31.7 percent). Seventy-three per cent (73 percent) of patient visits were for the treatment of hypertension, while the remaining twenty-seven per cent (27 percent) were for diabetes mellitus. As many as 10.4 percent of all prescriptions were for patients with co-existing hypertension and diabetes mellitus. The most commonly prescribed anti-hypertensive drug was bendrofluazide, which is inexpensive and highly effective in black populations. However, the traditional daily dose of 5 mg or more was usually given rather than the current recommended lower dose of 2.5 mg. Chlorpropamide was the most frequently prescribed hypoglycaemic agent (50 percent). It was surprising that metformin, useful in the treatment of obese diabetics, accounted for only 4 percent of all diabetic prescriptions. For a population of only 140,000, the Government issued 130,000 insulin syringes. The Ministry of Health could realise significant savings if patients who self-administer insulin reuse the syringe, and by conducting sharing the cost of health care with the private sector (AU)

Drug prescribing for diabetes mellitus in primary care: a comparison of public and private practice in three Caribbean countries - abstract

Examining the appropriateness of drug prescribing for people with diabetes mellitus in Caribbean countries is important because of the high cost of drug treatment, the potential for improved control of the disease and the possibility of reducing adverse side effects of treatment. This study examined patterns of drug prescribing for diabetes mellitus in public and private sector primary care settings in three Caribbean countries. The sample included 690 patients in Barbados (BDS, 24 percent private), 791 in Trinidad and Tobago (TT, 13 percent private) and 180 in Tortola (BVI, 31 percent private). Patients treated in public health care facilities were prescribed significantly more drugs than those treated in private practice. Few patients had diabetes mellitus managed by diet alone (8 percent public, 15 percent private). Metformin was rarely used as single agent therapy (3 percent public, 6 percent private). Most patients were treated with sulfonylurea drugs alone or in combination with metformin (75 percent public, 67 percent). The proportion of sulfonylurea prescriptions for chlorpropamide varied (Public: BVI 80 percent, TT 60 percent, BDS 10 percent; Private: BVI 41 percent, TT 28 percent, BDS 7 percent) as did prescriptions for gliclazide and glipizide (Public: BDS 41 percent, BVI 3 percent, TT 1 percent; Private: BVI 51 percent, BDS 46 percent, TT 19 percent). A high proportion of patients were treated for hypertension (public 49 percent, private 40 percent). In private practice, ACE inhibitors and diuretics were the most frequently prescribed drugs. In the public sector, Brinderin accounted for 53 percent of prescriptions in TT while thiazides, methyldopa, betablockers and ACE inhibitors were the most frequently prescribed drugs in BDS and BVI. These variations in prescribing practice among countries of the region suggest that factors other than patients' needs or the cost effectiveness of treatment are important in determining prescribing practices. Individual countries should examine how efficiency and effectiveness of drug use could be improved (AU)

Effect of bed time intermediate acting insulin in NIDDM subjects refractory to a combination of sulphonylureas and biguanides.

The effect of a single dose of intermediate acting (Lente) insulin given subcutaneously at 9.00 P.M. in 22 NIDDM subjects refractory to a combination of Sulphonylureas and Biguanides was analysed. Euglycemia was achieved and maintained during the study period of three months with a mean insulin requirement of 14.22 +/- 5.98 units/day. Plasma FFA, Total cholesterol, triglyceride and VLDL-cholesterol also showed significant reduction. The level of FFA modulates hepatic glucose production, which in turn correlates positively with the fasting blood glucose. The therapeutic modality of bed time Lente Insulin based on physiological principles is an effective way of achieving glycemic control in NIDDM subjects who have become non-responsive to oral hypoglycemic agents.

The effect of serum Ca2+ compensation on the efficacy of chlorpropamide in alloxan-diabetic rabbits.

A decrease in serum Ca2+ concentration was observed in alloxan-diabetic rabbits, with recovery of serum Ca2+ levels achieved following insulin therapy. This suggested that the diabetic condition directly relates to the decrease in serum Ca2+ levels. The efficacy of chlorpropamide in alloxan-diabetic rabbits after intravenous injection (150 mumol kg-1) was less than that in normal rabbits as measured by the serum insulin levels, and the efficacy did not change when the dose was increased. However, compensation of serum Ca2+ levels in alloxan-diabetic rabbits caused an increase in the efficacy of chlorpropamide observed as an increase in serum insulin and a decrease in serum glucose levels.

Combination daytime chlorpropamide-metformin/bedtime insulin in the treatment of secondary failures in non insulin dependent diabetes

OBJETIVOS. Determinar la efectividad de la combinación clorpropamida-metformin diurna e insulina nocturna en el tratamiento de las fallas secundarias a hipoglucemiantes orales en pacientes diabéticos no insulinodependientes y estudiar sus efectos sobre la secreción de insulina. DISEÑO. Estudio no aleatorizado, abierto, con diseño antes-después de dos meses de duración. Al término del estudio los pacientes fueron seguidos por seis meses más. SITIO. Clínica de Diabetes y Metabolismo de Lípidos del Instituto Nacional de la Nutrición Salvador Zubirán, ciudad de México. DATOS DE LOS PACIENTES. Nueve pacientes, siete mujeres y dos hombres. Todos tenían diabetes mellitus no insulinodependiente y falla secundaria a hipoglucemiantes orales. Su glucosa de ayuno era 14.5 ñ 2 mM/L y su HbA1c 13.37 ñ 2.9 por ciento a pesar de consumir una dieta adecuada y clorpropamida (750 mg/día) más metformin (2400 mg/día). A su ingreso y al final del estudio, una curva de tolerancia oral a la glucosa de cinco horas fue realizada midiéndose en cada muestra glucosa plamática y péptido C. TRATAMIENTO. Clorpropamida (375 mg/día) más metformin (1200 mg/día) e insulina de acción intermedia (0.1 U/kg/día) aplicada en la noche. MEDICIONES Y RESULTADOS. Después de dos meses de tratamiento, la glucosa plasmática de ayuno y la HbA1c disminuyeron considerablemente (7.3 ñ 0.6 mM/L y 9.1 ñ 1.02 por ciento respectivamente, p < 0.002). La dosis de insulina requerida fue baja (6.77 ñ 2.09 U/día). Los efectos colaterales fueron mínimos y poco frecuentes. Durante la curva de tolerancia oral de cinco horas, el área bajo la curva de glucosa disminuyó. La tasa de secreción de insulina no se modificó; sin embargo, la relación péptido-C/glucosa aumentó. Al final del estudio se intentó suspender la insulina nocturna a los pacientes que se mantenían bien controlados. Los cuatro pacientes que lograron el mejor control metabólico durante el estudio, pudieron suspender la insulina sin modificarse el control metabólico durante los siguientes seis meses de la terminación del estudio. CONCLUSIONES. Esta terapia combinada es útil en el tratamiento de las fallas secundarias a hipoglucemiantes orales en pacientes diabéticos no insulinodependientes. Sus principales ventajas son el empleo de dosis pequeñas de insulina, la baja incidencia de efectos colaterales y, si se alcanza una HbA1c menor de 8.7 por ciento, se recupera la capacidad de respuesta a los hipoglucemiantes orales. La dosis baja de insulina requerida en

Combination daytime chlorpropamide-metformin/bedtime insulin in the treatment of secondary failures in non insulin dependent diabetes.

OBJECTIVES: To determine the effectiveness of the combination therapy with daytime chlorpropamide-metformin and bedtime NPH insulin in the treatment of secondary failures in NIDDM and to study its effects on insulin secretion. DESIGN: Non randomized open study with a duration of two months. The patients were followed six months after ending the study. INSTITUTION: Department of Diabetes and Lipid Metabolism. Instituto Nacional de la Nutrición "Salvador Zubirán", Mexico City. CHARACTERISTICS OF THE PATIENTS: Nine patients (seven women and two men) were included. All had NIDDM and secondary failure to antidiabetic oral drugs. Their fasting plasma glucose was 14.5 +/- 2 mM/L and their HbA1c 13.37 +/- 2.9%. At the entry and at the end of the study a 5h-OGTT was done with assays of plasma glucose and C-peptide. TREATMENT: Chlorpropamide (375 mg/day) plus metformin (1200 mg/day) and bedtime insulin (0.1 U/kg/day). RESULTS: After two months on combination therapy, fasting plasma glucose and HbA1c levels were remarkably improved (decreases of 7.3 +/- 0.6 and 9.1 +/- 1.02 respectively, p less than 0.002). The insulin dose was small (6.77 +/- 2.09 U/day). Side effects were minimal and infrequent. During the 5h-OGTT, the mean glucose area under the curve also decreased. The insulin secretion did not change but the C-peptide/glucose ratio increased. At the end of the study, the insulin dose was tapered off and stopped when possible. The four patients with the best glycemic control during the study were able to suspend the bedtime insulin and maintain a good control six months after the insulin suspension. CONCLUSIONS: The combination therapy is useful in the treatment of secondary failures in NIDDM: Its advantages are the very low mean daily insulin dose needed, the low incidence of side effects and, if a HbA1c less than 8.7% is achieved, the restoration of oral antidiabetic drugs efficacy. The very low insulin dose used in this study could be explained by complementary effects of metformin and bedtime insulin on hepatic glucose output and a putative decrease in peripheral resistance attributable both to sulfonylurea and metformin.