TOLBUTAMIDE SUMMARY
Tolbutamide is an oral blood-glucose-lowering drug of the sulfonylurea class. Tolbutamide is a pure, white, crystalline compound which is practically insoluble in water.
Tolbutamide is indicated as an adjunct to diet to lower the blood glucose in patients with non-insulin-dependent diabetes mellitus (type II) whose hyperglycemia cannot be controlled by diet alone.
In initiating treatment for non-insulin-dependent diabetes, diet should be emphasized as the primary form of treatment. Caloric restriction and weight loss are essential in the obese diabetic patient. Proper dietary management alone may be effective in controlling the blood glucose and symptoms of hyperglycemia. The importance of regular physical activity should also be stressed, and cardiovascular risk factors should be identified and corrective measures taken where possible.
If this treatment program fails to reduce symptoms and/or blood glucose, the use of an oral sulfonylurea or insulin should be considered. Use of tolbutamide must be viewed by both the physician and patient as a treatment in addition to diet, and not as a substitute for diet or as a convenient mechanism for avoiding dietary restraint. Furthermore, loss of blood glucose control on diet alone may be transient, thus requiring only short-term administration of tolbutamide.
During maintenance programs, tolbutamide should be discontinued if satisfactory lowering of blood glucose is no longer achieved. Judgments should be based on regular clinical and laboratory evaluations.
In considering the use of tolbutamide in asymptomatic patients, it should be recognized that controlling the blood glucose in non-insulin dependent diabetes has not been definitely established to be effective in preventing the long-term cardiovascular or neural complications of diabetes.
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NEWS HIGHLIGHTS
Published Studies Related to Tolbutamide
No relevant interaction with alprazolam, caffeine, tolbutamide, and digoxin by treatment with a low-hyperforin St John's wort extract. [2005.04]
We evaluated the pharmacokinetic interaction between a low-hyperforin St John's wort (SJW) extract and alprazolam, caffeine, tolbutamide, and digoxin. Previous reports on other SJW products had shown remarkably decreased plasma concentrations of certain co-medicated drugs, which was attributed to an inducing effect of SJW on cytochrome P-450 (CYP) and p-glycoprotein (p-gp) activity...
Is acarbose equivalent to tolbutamide as first treatment for newly diagnosed type 2 diabetes in general practice? A randomised controlled trial. [2004.01]
We performed a double blind randomised controlled trial in general practice to assess equivalence between tolbutamide and acarbose with respect to the effect on mean HbA(1c) in newly diagnosed patients with type 2 diabetes. Secondary objectives were to compare the effects of both treatments on fasting and post-load blood glucose and insulin levels, lipids, and adverse events...
Tolbutamide, flurbiprofen, and losartan as probes of CYP2C9 activity in humans. [2003.01]
The metabolic activity of CYP2C9 in 16 subjects expressing four different genotypes (CYP2C9*1/*1, *1/*2, *1/*3, and *2/*2) was evaluated. Single oral doses of tolbutamide, flurbiprofen, and losartan were administered in a randomized, crossover design...
Effects of CYP2C19 and CYP2C9 genetic polymorphisms on the disposition of and blood glucose lowering response to tolbutamide in humans. [2002.03]
Several recent in-vitro data have revealed that CYP2C19, in addition to CYP2C9, is also involved in the 4-methylhydroxylation of tolbutamide. We evaluated the relative contribution of CYP2C9 and CYP2C19 genetic polymorphisms on the disposition of blood glucose lowering response to tolbutamide in normal healthy Korean subjects in order to reappraise tolbutamide as a selective in-vivo probe substrate of CYP2C9 activity...
Fluvoxamine inhibits the CYP2C9 catalyzed biotransformation of tolbutamide. [2001.01]
OBJECTIVE: Our objective was to examine the interaction between fluvoxamine and tolbutamide to confirm that fluvoxamine inhibits CYP2C9... CONCLUSION: Fluvoxamine is a moderate inhibitor of CYP2C9 in vivo.
Clinical Trials Related to Tolbutamide
AZD2066 Cocktail Study [Recruiting]
Blockade of Vascular Potassium Channels During Human Endotoxemia [Completed]
Background: Activation of NO-synthase and vascular potassium (K) channels may play a role
in the sepsis-induced attenuated sensitivity to norepinephrine. We examined whether various K
channel blockers and NO-synthase inhibition could restore norepinephrine sensitivity during
experimental human endotoxemia.
Methods and Results: Volunteers received 2ng/kg E. coli endotoxin. The brachial artery was
cannulated for infusion of drugs. Forearm blood flow (FBF) was measured using venous
occlusion plethysmography. Intrabrachial norepinephrine infusion (1-3-10-30ng/min/dl)
decreased FBF to 84±4, 70±4, 55±4, and 38±4% of baseline ratio, mean±SEM). Following
endotoxin administration, norepinephrine-induced vasoconstriction was attenuated: 101±4,
92±4, 83±6, and 56±7% (P=0. 0018, pooled data, n=30). Intrabrachial infusion of the K channel
blocker tetra-ethyl ammonium (TEA) completely restored the vasoconstrictive effect of
norepinephrine: from 104±5, 93±7, 93±12, and 69±12% to 89±9, 73±4, 59±5, and 46±8% (n=6,
P=0. 045), whereas other K channel blockers had no effect. NO-synthase inhibitor L-NMMA
(0. 2mg/min/dl) also restored the norepinephrine sensitivity (from 92±5, 85±4, 68±11, and
43±13% after endotoxin to 71±3, 66±7, 48±11, and 21±3% in the presence of L-NMMA, n=6,
P=0. 009). Furthermore, in the presence of L-NMMA, TEA did not have an additional effect on
the norepinephrine-induced vasoconstriction (n=6, P =0. 9).
Conclusions: The K channel blocker TEA completely restores the attenuated vasoconstrictive
effects of norepinephrine during experimental human endotoxemia. Co-administration of L-NMMA
abolishes this potentiating effect of TEA, suggesting that NO mediates the endotoxin-induced
effect on K channels. In the absence of an effect of the selective KATP channel blocker
tolbutamide we conclude that endotoxin-induced vasorelaxation is the result of NO-mediated
activation of KCa channels.
Study Evaluating the Pharmacokinetics of the Potential Drug Interaction Between CYP2C9 Inhibitor and Substrate [Completed]
This is an open-label, randomized, 2-period crossover, inpatient study to be performed in healthy subjects. The study will consist of 2 treatment periods: There will be 2 parallel cohorts of 12 subjects each who will be enrolled to receive single doses of tolbutamide or AGG-523 plus tolbutamide in periods 1 and 2 in a crossover design. Doses of test article will be administered after an overnight fast of at least 10 hours.
Increased Gluconeogenesis is One Cause of Cystic Fibrosis Related Diabetes (CFRD) [Recruiting]
People with CF have a high incidence of diabetes, called CFRD. CFRD is an important cause of
worsened morbidity and mortality, thus understanding the pathophysiology underlying its
development is imperative. Insulin deficiency has been well recognized as one cause of CFRD;
however the clinical presentation and studies of pathogenesis indicate that the etiology is
more complex. There is strong evidence that normal metabolism of carbohydrate, protein and
fat is altered in CF. We believe that the inflammatory response to chronic underlying lung
disease is responsible for insulin resistance and alters substrate metabolism, and that these
changes, in addition to insulin deficiency cause CFRD. Our global hypothesis is that
hyperglycemia is caused, in part, by high rates of gluconeogenesis resulting from excessive
amino acid substrate availability caused by cytokine-mediated protein catabolism. We further
hypothesize that inflammation alters normal fatty acid metabolism leading to lipogenesis, an
energy wasteful pathway. We will recruit 24 adult CF subjects and 10 controls (similar in
distribution in lean tissue mass, age and gender) and will categorize them according to
glucose tolerance (OGTT), as well as insulin secretion and insulin sensitivity using the
Tolbutamide-stimulated IVGTT and the Minimal Model. Clinical status will be characterized by
measuring pulmonary function and modified NIH scores, in addition to measuring levels of
circulating cytokines. Gluconeogenesis (GNG) will be quantified by measuring the
incorporation 2H into the 2nd, 5th and 6th carbons of glucose. Amino acid turnover rates
will be measured using stable isotopes of lactate and alanine and whole body protein turnover
(WBPT) will be measured using [1-13C]leucine and [15N2]urea. Fat metabolism will be
evaluated by measuring ketone body turnover using stable isotopes, and by quantifying
lipogenesis using the isotopomer equilibration method. Key enzymes of fatty acid metabolism
will also be measured. We will utilize indirect calorimetry to measure resting energy
expenditure. Subjects will be recruited from the CF centers at the University of Texas-
Southwestern and the South Central CF Consortium.
Our proposal is intended to better describe the unique metabolism of people with CF, and to
provide a comprehensive evaluation of pathophysiologic changes which contribute to the
development of CFRD and to wasting; and are part of the applicant's long-range goal which is
to identify the underlying causes of CF related diabetes and catabolism so that
disease-specific therapies can be developed. We fully expect that the proposed studies will
provide new and important information.
Effects of CYP2B6 Genetic Polymorphisms on Efavirenz Pharmacokinetics [Recruiting]
1. To see how the liver breaks down efavirenz by an enzyme called CYP2B6. It is suggested
that when Efavirenz is taken repeatedly it may increase the amount of CYP2B6 in your
liver and thus speed up your liver's ability to get rid of efavirenz from your body.
This may render efavirenz and other medications ineffective.
2. To see how efavirenz interact with other drugs taken at the same time with it.
3. To see if genetic differences can change the way how the liver breaks down efavirenz
and its interactions with other co-administered drugs.
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Page last updated: 2007-10-18
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