Generic Name and Dose Metformin + glipizide 500 mg 5 mg Metformin + glipizide 500 mg 5 mg Metformin + glyburide 250 mg 1.25 mg Metformin + glyburide 250 mg 1.25 mg Metformin + glyburide 500 mg 2.5 mg Metformin + glyburide 500 mg 2.5 mg Metformin + glyburide 500 mg 5 mg6 Metformin + glyburide 500 mg 5 mg6 Pioglitazone + metformin 15mg 850 tablet Pioglitazone + metformin 15mg 500 tablet Pioglitazone + metformin 15mg 850 tablet Rosiglitazone + glimepiride 4mg 1 mg tablet Rosiglitazone + glimepiride 4mg 2 mg tablet Rosiglitazone + glimepiride 4mg 4 mg tablet Rosiglitazone + glimepiride 4mg 8 mg tablet Brand Name or Generic ; Metaglip Generic Glucovance Generic Glucovance Generic Glucovance Generic Actoplus Met Number of Pills Per day ; 1 Two Two Two Two Two Two Three Three One Total Daily Dose1 Average Monthly Cost2 9 5.
Glucovance is a combination of 2 drugs— glyburide and metformin— that attack high blood sugar levels in several ways.
Common uses: glucovance glyburide ; is an anti-diabetic medicine sulfonylurea-type ; used along with a proper diet and exercise program to control high blood sugar.|
With hypoglycaemic symptoms and concomitant blood glucose of less than 2.8 mmol L. The study identified 589 people with a first episode of serious hypoglycaemia during 33, 048 person-years of insulin or sulphonylurea use. The overall RR of serious hypoglycaemia was 1.81 CI 1.67- 1.95 ; per 100 person years of hypoglycaemic drug exposure. Specifically, RR was 1.23 CI 2.47 3.06 ; among sulphonylurea users, 2.76 CI 2.47- 3.06 ; among insulin users and 3.38 CI 1.50 5.26 ; among users of both. Compared with people aged 65-70 years, people aged 80 or older had a higher RR 1.8 ; of developing hypoglycaemia CI 1.4- 2.3; p 0.05 ; . People using five or more concomitant medications and those new to hypoglycaemic drug therapy were also at higher risk of hypoglycaemia RR 1.3, CI 1.1-1.5; RR 1.4, CI 1.0-1.9, respectively ; . These results demonstrate that elderly people, those using multiple medications, and those who are frequently hospitalised are at higher risk of drug-associated hypoglycaemia. Van Staa et al 1997 ; retrospectively studied 33, 243 people with diabetes treated with sulphonylureas to determine risk factors for hypoglycaemia. Participants were 20 years or older and had received at least one prescription for Glibenclamide, Gliclazide, Chlorpropamide, Glipizide or Tolbutamide. Of 34, 052 person years of therapy, 605 cases of hypoglycaemia were identified, translating into an annual risk of 1.8%. Risk factors for hypoglycaemia identified included age greater than 65, RR 1.27 CI 1.06-1.51 ; , renal impairment, RR 3.5 CI 1.95-6.47 ; , polypharmacy, RR 1.84 CI 1.55-2.17 ; and sulphonylurea type [Gliclazide v Glibenclamide RR 0.74 CI 0.590.92 ; and Tolbutamide v Glibenclamide RR 0.75 CI 0.58-0.97 ; ]. These findings indicate that the rate of hypoglycaemia is higher for Glibenclamide than for other sulphonylureas, and that there is an increased risk of hypoglycaemia with increasing age, renal impairment and polypharmacy. A retrospective analysis of 51 people mean age 76 years ; with Glibenclamide induced hypoglycaemic coma GIHC ; identified several risk factors Ben-Ami et al, 1999a ; . Risk factors associated with GIHC included age 60 years, renal dysfunction, reduced calorie intake, infection, overdose, liver cirrhosis and metastatic liver disease. Factors found to explain the occurrence of GIHC in these people were their advanced age and prolonged duration of diabetes, which resulted in impaired counter-regulatory responses and the presence of concomitant risk factors for hypoglycaemia. Of 51 participants, 38 were found to have renal insufficiency. Use of Glibenclamide in these people may cause hypoglycaemia arising from the accumulation of biologically active metabolites, reduced renal gluconeogenesis and decreased caloric intake. Drug-induced hypoglycaemic coma was examined in a 7-year retrospective cohort of 102 people mean age 72 years ; with Type 1 10% ; and Type 2 90% ; diabetes BenAmi et al, 1999b ; . Of the 102 participants, drug-induced hypoglycaemic coma was the primary cause for hospitalisation. Medications examined were insulin alone, insulin and Glyburide, Glyburide alone, insulin and Metformin, and Glyburide and Metformin. Results demonstrated that drug-induced hypoglycaemic coma occurred mostly in people taking Glyburide Glibenclamide ; , followed by insulin, Glyburide plus insulin, Glyburide plus Metformin and insulin plus Metformin. Contributing risk factors identified included age greater than 60 years 82.3% of the population ; , renal dysfunction, reduced energy intake 26.5% of the population had both renal dysfunction and reduced energy intake ; , infection and hypoglycaemia-potentiating medications such as beta-blockers 13.7% of the population.
If the other medication is a sulfonylurea glyburide.
Laboratory tests therapeutic response to glyburide tablets should be monitored by frequent urine glucose tests and periodic blood glucose tests and hydrochlorothiazide.
BASIC INFORMATION DESCRIPTION: A non-contagious, inflammatory, scaling disease of the skin. It may involve the chest; back; face; arms and can affect adults of both sexes. By age 60, almost everyone has a few seborrheic keratoses. FREQUENT SIGNS AND SYMPTOMS: Papules small, raised bumps ; with the following characteristics: Papules are flat-topped with well-defined borders. Young papules are relatively flat and light brown. More advanced papules are dark brown or black. Papules are wider than tall, and they appear "stuck on." Papules measure 5mm to 20min in diameter. They are distributed on the chest, back, face and arms. Papules don't itch or hurt. There may be only I or 2 papules, or there may be up to 100. CAUSES: Unknown. RISK INCREASES WITH: Aging. Family history of the disorder. Excessive sun exposure or other skin injury. PREVENTIVE MEASURES: No specific preventive measures. EXPECTED OUTCOME: The number of lesions increases with time. Each lesion is permanent unless removed. Seborrheic keratoses are harmless and require no treatment, but most people want them removed especially if they are unsightly or irritated by clothing ; . POSSIBLE COMPLICATIONS: Seborrheic keratoses on the eyelid borders may require special treatment. TREATMENT: GENERAL MEASURES Removal of lesions if they are unsightly, are irritated by clothing or interfere with grooming. Removal methods include cryosurgery, chemocautery, light electrosurgery or shave biopsy. After removal, a blister sometimes with blood ; will develop at the treatment site. The top of the blister will come off spontaneously in about 2 weeks. You should have little or no scarring. Wash and use makeup or cosmetics as usual. If clothing irritates the blister, cover it with a small adhesive bandage. MEDICATION: Medicine usually is not necessary for this disorder. ACTIVITY.
Ealing with a mental illness can be difficult for anyone. But immigrants and refugees face additional challenges including language barriers, immigration requirements and the different cultural taboos of mental illness. Ignoring or denying mental health problems is common in many immigrant families. Some immigrants may lie to officials and doctors about their mental health because they fear deportation, while others may ignore their mental health needs because they are isolated from services which reflect their cultural perspective. Cultural differences including language ; often make it difficult for doctors and patients to communicate with one another and hydrocodone.
Detoxification involves reducing the dose of drug or substituting it temporarily by other substances like methadone.
Contra-indications known hypersensitivity to the drug or its components and hyzaar.
Glyburide is used to control high blood sugar, not to cure diabetes.
Pharmacokinetics, A938 vasodilating properties. A938 and ibuprofen.
6-F. Oral Antidiabetics diabetes ; acarbose. PRECOSE M ; L ; chlorpropamide M ; . * DIABINESE glimepiride. AMARYL M ; L ; glipizide M ; . * GLUCOTROL glipizide CR M ; L ; GLUCOTROL XL glyburide M ; . * DIABETA glyburide micronized M ; L ; . * GLYNASE.
Patient education & monograph glyburide diabeta® glycron glynase® prestab® micronase® click pictures above to see more drug photos and imitrex.
Hypoglycemia: See PRECAUTIONS and OVERDOSAGE Sections. Gastrointestinal Reactions: Cholestatic jaundice and hepatitis may occur rarely; Diaeta should be discontinued if this occurs. Liver function abnormalities, including isolated transaminase elevations, have been reported. Gastrointestinal disturbances, e.g., nausea, epigastric fullness, and heartburn, are the most common reactions and occur in 1.8% of treated patients. They tend to be dose-related and may disappear when dosage is reduced. Dermatologic Reactions: Allergic skin reactions, e.g., pruritus, erythema, urticaria, and morbilliform or maculopapular eruptions, occur in 1.5% of treated patients. These may be transient and may disappear despite continued use of Diaeta; if skin reactions persist, the drug should be discontinued. Porphyria cutanea tarda and photosensitivity reactions have been reported with sulfonylureas. Hematologic Reactions: Leukopenia, agranulocytosis, thrombocytopenia, which occasionally may present as purpura, hemolytic anemia, aplastic anemia, and pancytopenia have been reported with sulfonylureas. Metabolic Reactions: Hepatic porphyria reactions have been reported with sulfonylureas; however, these have not been reported with Diaeta. Disulfiram-like reactions have been reported very rarely with Diaeta. Cases of hyponatremia have been reported with glyburide and all other sulfonylureas, most often in patients who are on other medications or have medical conditions known to cause hyponatremia or increase release of antidiuretic hormone. The syndrome of inappropriate antidiuretic hormone SIADH ; secretion has been reported with certain other sulfonylureas, and it has been suggested that these sulfonylureas may augment the peripheral antidiuretic ; action of ADH and or increase release of ADH. Other Reactions: Changes in accommodation and or blurred vision have been reported with glyburide and other sulfonylureas. These are thought to be related to fluctuation in glucose levels. In addition to dermatologic reactions, allergic reactions such as angioedema, arthralgia, myalgia and vasculitis have been reported. OVERDOSAGE Overdosage of sulfonylureas, including Diaeta, can produce hypoglycemia. Mild hypoglycemic symptoms without loss of consciousness or neurologic findings should be treated aggressively with oral glucose and adjustments in drug dosage and or meal patterns. Close monitoring should continue until the physician is assured that the patient is out of danger. Severe hypoglycemic reactions with coma, seizure, or other neurological impairment occur infrequently, but constitute medical emergencies requiring immediate hospitalization. If hypoglycemic coma is diagnosed or suspected, the patient should be given a rapid intravenous injection of concentrated 50% ; glucose solution. This should be followed by a continuous infusion of a more dilute 10.
If sulfonylurea treatment is necessary, glyburide or gliclazide may be the preferred sulfonylureas for use in patients at risk for conditions causing cardiac hypoxia and isosorbide.
Kozer E, Scolnik D, Jarvis AD, Koren G: The effect of detection approaches on the reported incidence of tenfold errors. Drug Safety 2006: 29: pp 169-174. Kraemer J, Klein J, Lubetsky A, Koren G: Perfusion studies of glyburide transfer across the human placenta: Implications for fetal safety.The American Journal of Obstetrics and Gynecology 2006: March 30 [Epub ahead of print]. Kulaga V: Prevalence of alcohol consumption among women poses a significant health risk for the unborn population. Journal of Fetal Alcohol Syndrome 2005: 3: p e6. Kulaga V: Cognitive processing speed among children exposed to fetal alcohol. Journal of Fetal Alcohol Syndrome International 2006: 4: p e3. Kwok B, Yamauchi A, Rajesan R, Chen L, Dhillon U, Gao W, Xu H, Wang B, Takahashi S, Semple J, Tamai I, Nezu J, Tsuji A, Harper P, Ito S: Carnitine xenobiotics transporters in the human mammary gland epithelia, MCF12A. American Journal of Physiology: Regulatory, Integrative and Comparative Physiology 2006: 290: pp R793-R802. LaKind JS, Brent RL, Dourson ML, Kacew S, Koren G, Sonawane B, Tarzian AJ, Uhl K: Human milk biomonitoring data: Interpretation and risk assessment issues. Journal of Toxicology and Environmental Health Part A 2005: 68: pp 1713-1769. Lavi E, Sarkar M, Djulus J, Moretti M, Koren G: Characteristics of the callers to the Motherisk alcohol and substance use line. Journal of Fetal Alcohol Syndrome International 2005: 3: p e1. Many A, Koren G: Low-molecular-weight heparins during pregnancy. Canadian Family Physician 2005: 51: pp 199-201. Many A, Koren G: Toxoplasmosis during pregnancy. Canadian Family Physician 2006: 52: pp 29-30. McKenna K, Koren G, Tetelbaum M, Wilton L, Shakir S, Diav-Citrin O, Levinson A, Zipursky RB, Einarson A: Pregnancy outcome of women using atypical antipsychotic drugs: A prospective comparative study. Journal of Clinical Psychiatry 2005: 66: pp 444-449. Mills E, Montori V, Perri D, Phillips E, Koren G: Natural health product-HIV drug interactions: A systematic review. International Journal of STD and AIDS 2005: 16: pp 181-186. Mirabella G, Westall CA, Asztalos E, Perlman K, Koren G, Rovet J: Development of contrast sensitivity in infants with prenatal and neonatal thyroid hormone insufficiencies. Pediatric Research 2005: 57: pp 902-907. Moretti ME, Bar-Oz B, Fried S, Koren G: Maternal hyperthermia and the risk for neural tube defects in offspring: Systematic review and meta-analysis. Epidemiology 2005: 16: pp 216-219. Nash K, Rovet J, Greenbaum R, Fantus E, Nulman I, Koren G: Identifying the behavioural phenotype in fetal alcohol spectrum disorder: Sensitivity, specificity and screening potential. Archives of Women's Mental Health 2006: May 3 [Epub ahead of print]. Nava-Ocampo AA, Pastrak A, Cruz T, Koren G: Pharmacokinetics of high doses of cyanocobalamin administered by intravenous injection for 26 weeks in rats. Clinical and Experimental Pharmacology and Physiology 2005: 32: pp 13-18.
Table 1 Distribution of statin use in patients after myocardial infarction, Tayside, 1993-2001. Values are numbers percentages ; of patients unless otherwise indicated and ketamine.
On July 1, 2003, a 69-year-old white female patient weighing 175 lb presented at Mercy Medical Center in Mason City, Iowa, for a transesophageal echocardiogram to assist in the evaluation of intracardiac thrombus in preparation for synchronized cardioversion. The patient had a history of ischemic heart disease, postcoronary artery bypass surgery, hypertension, postmenopausal hyperlipidemia, type 2 diabetes mellitus, obesity, and symptomatic atrial fibrillation that was believed to be recent though the specific time of onset was unclear. She was a nonsmoker and reported an unconfirmed allergy to diazepam. The patient was currently taking the following medications: amiodarone, aspirin, enoxaparin, glyburide, levothyroxine sodium, metoprolol succinate, niacin as a dietary supplement, rabeprazole sodium, simvastatin, and warfarin sodium. Her physical examination preprocedure was notable only for atrial fibrillation, and her oxygen saturation level was 99% by room-air pulse oximetry. Previous laboratory studies were within normal ranges, and an electrocardiogram performed the previous day demonstrated atrial fibrillation with a controlled heart rate and nonspecific changes. During transesophageal echocardiogram, the patient's oxygen saturation level was measured at 90% by room-air pulse oximetry, so the oxygen level as delivered by nasal cannula ; was adjusted to a saturation level of 92%. Results from the procedure were within normal limits; therefore, synchronized cardioversion was completed and was successful. At 15 minutes postprocedure, however, the patient developed central cyanosis, and her oxygen saturation level suddenly decreased to 70%. Her lung fields were clear and she did not exhibit chest pain or arrhythmia. Vital signs were stable. An arterial blood sample was taken and appeared chocolate in color Figure 1 ; . Methemoglobinemia was suspected and then confirmed by arterial blood gases that were obtained using co-oximetry. Oxygen was administered at 100% by mask. Arterial blood gases were taken with pH, 7.47; PCO2, 33.1; PO2, 293; oxygen saturation, 56.7%; and methemoglobin at 41.1% of total hemoglobin. Methylene blue, 2 mg, was delivered intravenously, and, as a result, one hour later, methemoglobin levels had decreased to 18.4% with an improvement in the symptoms of cyanosis. Two hours later, methemoglobin levels were at 4% of total hemoglobin.
Gemfibrozil lopid ; , glyburide micronase ; , niacin niaspan ; , omeprazole prilosec ; , phenytoin dilantin ; , ranitidine zantac ; , or rifampin rifadin and lanoxin.
Corticosteroids are produced naturally by the body itself but if there aren't enough of them, the doctor prescribes the medicine.
The above not be the threshold their fees glyburide intubation and lescol and glyburide.
If 15 hours have passed since my last dose, is it still okay to take the pill.
Results Primary: Hepatic glucose production in the patients receiving glipizide GITS in the morning P 0.05 ; or glibenclamide P 0.01 ; was significantly reduced at the end of the study compared to baseline. There were no significant differences in hepatic glucose production found when comparing glipizide GITS in the morning, glipizide GITS in the evening, and glibenclamide. Secondary: Fasting and 24 hour glucose were significantly reduced from baseline to a similar degree by glipizide GITS in the morning 33%, P 0.001; 39%, P 0.0001, respectively ; , glipizide GITS in the evening 33%, P 0.0001; 32%, P 0.0001 ; , and glibenclamide 37%, P 0.05; 37%, P 0.0001 ; . There were no P values reported comparing active treatments to each other. Fructosamine and HbA1c were significantly reduced from baseline by glipizide GITS in the morning 28%, P 0.001; 22%, P 0.0001, respectively ; , glipizide GITS in the evening 25%, P 0.005; 24%, P 0.005 ; , and glibenclamide 17%, P 0.001; 14%, P 0.05 ; . Each active treatment group improved glycemic control and resulted in beneficial effects on fructosamine and HbA1c, no P values were reported comparing active treatments to each other. Primary: There was a comparable reduction in HbA1c by both active treatments versus placebo throughout the study. There was a marked initial decrease in the glipizide and glyburide groups, but all three groups showed gradually increasing HbA1c levels. Glipizide and glyburide achieved and maintained lowered postprandial glucose levels and increased fasting and postprandial insulin levels compared to placebo. Secondary and levaquin.
Of the 96 randomly assigned patients, 88 completed the study. Four patients 8% [3 receiving bedtime insulin plus metformin and 1 receiving bedtime insulin plus metformin and glyburide] ; developed side effects associated with metformin severe diarrhea, metallic taste, abdominal discomfort, and a rash ; . Four other patients dropped out for reasons that seemed unrelated to treatment among patients receiving bedtime insulin plus glyburide, 1 had hepatocellular carcinoma and 1 had normoglycemia at.
AUC by 127%, compared to the administration of rosiglitazone 4 mg once daily ; alone. Given the potential for dose-related adverse events with rosiglitazone, a decrease in the dose of rosiglitazone may be needed when gemfibrozil is introduced see PRECAUTIONS ; . Rifampin: Rifampin administration 600 mg once a day ; , an inducer of CYP2C8, for 6 days is reported to decrease rosiglitazone AUC by 66%, compared to the administration of rosiglitazone 8 mg ; alone see PRECAUTIONS ; .1 Glyburide: Rosiglitazone 2 mg twice daily ; taken concomitantly with glyburide 3.75 to 10 mg day ; for 7 days did not alter the mean steady-state 24-hour plasma glucose concentrations in diabetic patients stabilized on glyburide therapy. Repeat doses of rosiglitazone 8 mg once daily ; for 8 days in healthy adult Caucasian subjects caused a decrease in glyburide AUC and Cmax of approximately 30%. In Japanese subjects, glyburide AUC and Cmax slightly increased following coadministration of rosiglitazone. Digoxin: Repeat oral dosing of rosiglitazone 8 mg once daily ; for 14 days did not alter the steady-state pharmacokinetics of digoxin 0.375 mg once daily ; in healthy volunteers. Warfarin: Repeat dosing with rosiglitazone had no clinically relevant effect on the steadystate pharmacokinetics of warfarin enantiomers. Additional pharmacokinetic studies demonstrated no clinically relevant effect of acarbose, ranitidine, or metformin on the pharmacokinetics of rosiglitazone. Glimepiride: The hypoglycemic action of sulfonylureas may be potentiated by certain drugs, including nonsteroidal anti-inflammatory drugs NSAIDs ; and other drugs that are highly protein bound, such as salicylates, sulfonamides, chloramphenicol, coumarins, probenecid, monoamine oxidase inhibitors, and beta-adrenergic blocking agents. When these drugs are administered to a patient receiving glimepiride, the patient should be observed closely for hypoglycemia. When these drugs are withdrawn from a patient receiving glimepiride, the patient should be observed closely for loss of glycemic control. Certain drugs tend to produce hyperglycemia and may lead to loss of control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, and isoniazid. When these drugs are administered to a patient receiving glimepiride, the patient should be closely observed for loss of control. When these drugs are withdrawn from a patient receiving glimepiride, the patient should be observed closely for hypoglycemia. Drugs Metabolized by Cytochrome P450: A potential interaction between oral miconazole and oral hypoglycemic agents leading to severe hypoglycemia has been reported. Whether this interaction also occurs with the IV, topical, or vaginal preparations of miconazole is not known. There is a potential interaction of glimepiride with inhibitors e.g. fluconazole ; and inducers e.g., rifampicin ; of cytochrome P450 2C9. Aspirin: Coadministration of aspirin 1 g three times daily ; and glimepiride led to a 34% decrease in the mean glimepiride AUC and, therefore, a 34% increase in the mean CL F. The mean Cmax had a decrease of 4%. Blood glucose and serum C-peptide concentrations were unaffected and no hypoglycemic symptoms were reported.
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An explanation of this method ; . The solubilized enzyme was not inhibitedby carboxytolbutamide or tetradecylglycidic acid in the absence of added coenzyme A, Mg2 + , or ATP; the addition of these substrates resulted in inhibition by tetradecylglycidic acid, but had no effect on the results obtained with tolbutamide or carboxytolbutamide results not shown ; . The rat heart and skeletal muscle carnitine palmitoyltransferases are very much more sensitive than the liver enzyme but to inhibition by malonyl-CoA 14, 19 ; , when the enzymes from the heart and skeletal muscle were assayed under conditions identical to those in 1, 100 p M glyburide inhibited Fig. the heart enzyme by 57 f 6% and the skeletalmuscle enzyme by 60 f 7% indicating that the heart, skeletal muscle, and liver enzymes were very similar in their response ll[Palmitoyl-CoA], uM" l [Carnitinel, m ~ " to inhibitionby glyburide. Carboxytolbutamide had very little FIG. 5 . Inhibition of rat liver carnitine palmitoyltransfer- inhibitory effect on carnitine palmitoyltransferases from ase CPT ; glyburide. Carnitine palmitoyltransferase was asby heart and skeletalmuscle less than10% inhibition ; . sayed without inhibitor O ; , with 50 p M glyburide , ; . or with 100 p~ glyburide m ; under the conditions described under "Experimental DISCUSSION Procedures, " except that in panel A carnitine was 0.2 mM and in panel B palmitoyl-CoA was 40 p ~ The experiments illustrated here . The data presented here indicate that sulfonylureas are the are representative of three different preparations of rat liver mito- potent, reversible inhibitors of liver, heart, and skeletal muschondria. cle carnitinepalmitoyltransferases. Glyburide, which is a much more potent hypoglycemic drug than tolbutamide, is also a much better inhibitorof carnitine palmitoyltransferase, but carboxytolbutamide, which is an inactive metabolite of loo tolbutamide, hasno effect on enzymeactivity.Two other 80 inhibitors of carnitine palmitoyltransferase, + ; -decanoylcarnitine 25 ; and pentaenoic acid 26 ; , are known to inhibit hepatic gluconeogenesis by inhibiting fatty acidoxidation. The studies of Menahan and Wieland 27 ; have established that maximal rates of hepatic gluconeogenesis require the 40 oxidation of fatty acids to meet the energy demand. A recent investigation has demonstrated that the carnitine palmitoyltransferase inhibitor 2- 5- 4-chlorophenyl ; -pentyl ; -oxirane-2 carboxylate ; not only inhibits fatty acid oxidation but also stimulates glycolysis 28 ; .The mechanism for stimulation of glycolysis may be by the activation of pyruvate dehydrogenase, since recent investigations have shown that oxidation of 0 fatty acids inactivates pyruvate dehydrogenase in liver 29 ; 0 100 200 300 and heart 30 ; by modulating pyruvate dehydrogenase kinase activity. The proposed mechanism is that inhibition of car[Inhibitor] , uM nitine palmitoyltransferase inhibits oxidation of fatty acids FIG. 6. Comparison of the effects of malonyl-CoA and tol- causing the mitochondrial [NAD + ] [NADH] ratio to become butamide on detergent-solubilized carnitine palmitoyltransferase from rat liver mitochondria. Carnitine palmitoyltransfer- more oxidized and the mitochondrial [acetyl-CoA] [CoA] radecreased. Such changes these mitochondrial ratios in ase was assayed at 40 p~ palmitoyl-CoA and 0.5 mM carnitine to tio to be determine the effect of malonyl-CoA m ; , and at 0.1 mM palmitoyl- inactivatepyruvate dehydrogenase kinaseand lead toinCoA and 0.1 rnM carnitine to determine the effects of tolbutamide creased conversion of pyruvate dehydrogenase to the active 0 ; . Data are reported as means k S.E. for three different prepara- form 29 ; .These considerationssuggest that at least part of a tions of enzyme. The specific activity of these preparations, measured at optimal concentrations of 0.15 mM palmitoyl-CoA and 2.5 mM the hypoglycemic action of the sulfonylureas could be excarnitine, was 89 k 8 nmol min mg protein. This enzyme preparation plained by the inhibition of carnitine palmitoyltransferase which would result in a ; inhibition of hepatic gluconeogenesis was not inhibited by tetradecylglycidic acid in the absence of CoA, Mg2 + , and ATP. by decreasing energy supply and b ; stimulation of glycolysis by increasing the relative amount of the active form of pyrution by malonyl-CoA 24 ; .We also found no inhibitionof the vate dehydrogenase. This idea is supported by the recentwork solubilized enzyme by malonyl-CoA Fig. 6 ; , but this prepa- of Tutwiler et al. 31 ; which indicated that tetradecylglycidic in ration of enzyme could be completely inhibited by tolbutam- acid, when administered to animals uiuo, not only inhibited ide. Intheseexperiments, inhibition by malonyl-CoA was ketogenesis but also lowered blood glucose. The sulfonylureas are apparently different from other tested at a low palmitoyl-CoA concentration 40 ; and like inhibition by tolbutamide and carboxytolbutamide tested known carnitine palmitoyltransferase inhibitors malonylwas at a low carnitine concentration 0.1 mM ; so that conditions CoA and tetradecylglycidic acid, which inhibit in the form of in each case non-saturating concentrationsof the competing the coenzymeA ester 32-33 ; , and they are also different substrate ; would be mostconducive toinhibition by that from oxfenicine, which must be converted to thefree which was esti- ylic acid form before inhibition will occur 34 ; .The mechamated by extrapolatingthe line obtained by plotting % nisms by which these compoundsproduce their inhibitory inhibition by tolbutamide ; " versus [tolbutamide]" to infinite effects are all quite different. While malonyl-CoA is cooperinhibitor concentration was 106 f 7% n 3 ; see Ref. 27 for atively competitive with respect to palmitoyl-CoA and non.