Acarbose (Precose, Glucobay)

Acarbose is a drug used in the treatment of non-insulin dependent diabetes of type II when medical intervention is needed to control blood sugar levels. It works by slowing down the digestion of carbohydrates in the body and preventing blood sugar levels from increasing after meals. This is why it’s important to take it at the beginning of each meal. It slows down the actions of enzymes in breaking sugars and maltose, but it does not affect the absorption of glucose and lactose and thus diet is needed in combination with the drug to control their effect on blood glucose levels. Acarbose could be administered with other dugs for Type II diabetes, as well as to aid insulin injections in cases of Type I diabetes. Several studies have suggested that acarbose also has the property of delaying the development of type II diabetes. Thus the medication is an important part of any prophylactic or prevention program. Another very significant benefit of Acarbose is the protective effects it has against hypertension and high blood sugar. Several studies have seen a notable decrease in the incidence of these diseases as a result of a decreased risk of high blood sugar levels affecting the heart. It has also been observed that unlike some other anti-diabetic medications, acarbose administration does not result in weight gain; the drug actually is known to exhibit anti-obesity actions.
Acarbose is sold in the United States under the brand name Precose™ and in Europe under the brand name Glucobay™.

Curr Opin Pharmacol. 2005 Apr;5(2):184-9.
Acarbose in the prevention of cardiovascular disease in subjects with impaired glucose tolerance and type 2 diabetes mellitus.
Delorme S, Chiasson JL.
Division of Endocrinology-Metabolism and Nutrition, Centre hospitalier de l'Universite de Montreal, Quebec, Canada.

The prevalence of glucose intolerance is increasing dramatically worldwide. Both impaired glucose tolerance (IGT) and type 2 diabetes are associated with excess mortality from cardiovascular disease. It is now generally accepted that these cardiovascular complications are related to prevailing hyperglycemia, particularly postprandial hyperglycemia. Acarbose specifically decreases the postprandial glycemic surge in IGT and diabetic subjects. The Study To Prevent Non-insulin-dependent Diabetes Mellitus (STOP-NIDDM) trial has shown that acarbose treatment in IGT subjects decreased the risk of progression to diabetes by 36%. Furthermore, it was associated with a 49% risk reduction of cardiovascular events. In a subgroup of subjects, acarbose treatment was accompanied by a 50% decrease in the progression of intima-media thickness of the carotids. Finally, a meta-analysis of seven major studies on the use of acarbose in the treatment of diabetes indicated that acarbose treatment was associated with a 35% risk reduction of cardiovascular disease. It is proposed that the mechanism by which acarbose can lower the risk of cardiovascular events is through diminution of oxidative stress induced by postprandial glycemic excursion.

Cochrane Database Syst Rev. 2005 Apr 18;(2):CD003639.
Alpha-glucosidase inhibitors for type 2 diabetes mellitus.
Van de Laar F, Lucassen P, Akkermans R, Van de Lisdonk E, Rutten G, Van Weel C.
Department of General Practice and Family Medicine, 229 HAG, University Medical Centre Nijmegen, P.O. Box 9101, Nijmegen, NETHERLANDS, 6500 HB.

BACKGROUND: Alpha-glucosidase inhibitors such as acarbose or miglitol, have the potential to improve glycemic control in type 2 diabetes mellitus. The true value of these agents, especially in relation to diabetes related mortality and morbidity, has never been investigated in a systematic literature review and meta-analysis. OBJECTIVES: To assess the effects of alpha-glucosidase inhibitors s in patients with type 2 diabetes mellitus. SEARCH STRATEGY: We searched The Cochrane Library, MEDLINE, EMBASE, Current Contents, LILACS, databases of ongoing trials, reference lists of reviews on the topic of alpha-glucosidase inhibitors and we contacted experts and manufacturers for additional trials. Date of most recent search: December 2003 (Current Contents) and April 2003 (other databases). SELECTION CRITERIA: Randomised controlled trials of at least 12 weeks duration comparing alpha-glucosidase inhibitor monotherapy in patients with type 2 diabetes with any other intervention and that included at least one of the following outcomes: mortality, morbidity, quality of life, glycemic control, lipids, insulin levels, body weight, adverse events. DATA COLLECTION AND ANALYSIS: Two reviewers read all abstracts, assessed quality and extracted data independently. Discrepancies were resolved by consensus or by the judgement of a third reviewer. A statistician checked all extracted data entrance in the database. We attempted to contact all authors for data clarification. MAIN RESULTS: We included 41 trials (8130 participants), 30 investigated acarbose, seven miglitol, one trial voglibose and three trials compared different alpha-glucosidase inhibitors. Study duration was 24 weeks in most cases and only two studies lasted amply longer than one year. We found only few data on mortality, morbidity and quality of life. Acarbose had a clear effect on glycemic control compared to placebo: glycated haemoglobin -0.8% (95% confidence interval -0.9 to -0.7), fasting blood glucose -1.1 mmol/L (95% confidence interval -1.4 to -0.9), post-load blood glucose -2.3 mmol/L (95% confidence interval -2.7 to -1.9). The effect on glycated haemoglobin by acarbose was not dose-dependent. We found a decreasing effect on post-load insulin and no clinically relevant effects on lipids or body weight. Adverse effects were mostly of gastro-intestinal origin and dose dependent. Compared to sulphonylurea, acarbose decreased fasting and post-load insulin levels by -24.8 pmol/L (95% confidence interval -43.3 to -6.3) and -133.2 pmol/L (95% confidence interval -184.5 to -81.8) respectively and acarbose caused more adverse effects. AUTHORS' CONCLUSIONS: It remains unclear whether alpha-glucosidase inhibitors influence mortality or morbidity in patients with type 2 diabetes. Conversely, they have a significant effect on glycemic control and insulin levels, but no statistically significant effect on lipids and body weight. These effects are less sure when alpha-glucosidase inhibitors are used for a longer duration. Acarbose dosages higher than 50 mg TID offer no additional effect on glycated hemoglobin but more adverse effects instead. Compared to sulphonylurea, alpha-glucosidase inhibitors lower fasting and post-load insulin levels and have an inferior profile regarding glycemic control and adverse effects.

Metabolism. 2005 Mar;54(3):387-90.
Effect of two alpha-glucosidase inhibitors, voglibose and acarbose, on postprandial hyperglycemia correlates with subjective abdominal symptoms.
Fujisawa T, Ikegami H, Inoue K, Kawabata Y, Ogihara T.

Abstract To assess the possible difference in effectiveness of 2 alpha-glucosidase inhibitors, voglibose and acarbose, the relationship between postprandial hyperglycemia and subjective abdominal symptoms was investigated. A total of 21 inpatients with type 2 diabetes were recruited to a single-center, 2-period, crossover trial. The subjects were given acarbose (150 mg/d) or voglibose (0.9 mg/d) under an isocaloric diet, and the postprandial (2 hours) increment in blood glucose level, M value which is a marker for fluctuation of blood glucose levels, and subjective abdominal symptom score were monitored. There was no significant difference between the 2 agents in postprandial increment in blood glucose level, M value, and subjective symptom score. When patients were divided according to subjective symptoms, however, the sum postprandial glucose increments were significantly different according to the agent ( P = .03), with favorable efficacy in patients in whom the alpha-glucosidase inhibitor caused abdominal symptoms, demonstrating a significant interaction ( P = .04) between treatment and symptomatic grouping. The results demonstrated that 50 mg acarbose and 0.3 mg voglibose had similar overall effects on postprandial hyperglycemia as well as subjective symptoms, but marked interindividual variation existed. Subjective symptoms may be a predictor of the divergent clinical response to each agent.

Diabetes Care. 2005 Mar;28(3):736-44. Related Articles, Links
A systematic review of drug therapy to delay or prevent type 2 diabetes.
Padwal R, Majumdar SR, Johnson JA, Varney J, McAlister FA.
Department of Medicine, 2E3.22 Walter C. Mackenzie HSC, University of Alberta Hospital, 8440-112th St., Edmonton, AB, Canada, T6G 2B7. rpadwal@ualberta.ca.

OBJECTIVE: To systematically review the evidence for the prevention of type 2 diabetes by pharmacological therapies. RESEARCH DESIGN AND METHODS: Randomized controlled trials and cohort studies examining the effect of oral hypoglycemic agents, antiobesity agents, antihypertensive agents, statins, fibrates, and estrogen on the incidence of type 2 diabetes were identified from MEDLINE, EMBASE, the Cochrane Controlled Trials Registry, and searches of reference lists. Two reviewers independently assessed studies for inclusion and performed data extraction. RESULTS: Ten studies of oral hypoglycemic agents and 15 studies of nonoral hypoglycemic agents were found. Oral hypoglycemic agents and orlistat are the only drugs that have been studied in randomized controlled trials with diabetes incidence as the primary end point. In the largest studies of 2.5-4.0 years' duration, metformin (relative risk [RR] 0.69, 95% CI 0.57-0.83), acarbose (0.75, 0.63-0.90), troglitazone (0.45, 0.25-0.83), and orlistat (hazard ratio [HR] 0.63, 95% CI 0.46-0.86) have all been shown to decrease diabetes incidence compared with placebo; however, follow-up rates varied from 43 to 96%. Current evidence for statins, fibrates, antihypertensive agents, and estrogen is inconclusive. In addition, the critical question of whether drugs are preventing, or simply delaying, onset of diabetes remains unresolved. CONCLUSIONS: Currently, no single agent can be definitively recommended for diabetes prevention. Future studies should be designed with diabetes incidence as the primary outcome and should be of sufficient duration to differentiate between genuine diabetes prevention as opposed to simple delay or masking of this condition.

Am J Physiol Regul Integr Comp Physiol. 2005 Feb 17;
SEROTONIN-TYPE 3 RECEPTORS MEDIATE INTESTINAL POLYCOSE- AND GLUCOSE- INDUCED SUPPRESSION OF INTAKE.
Savastano DM, Carelle M, Covasa M.
Department of Nutritional Sciences, College of Health and Human Development, The Pennsylvania State University, University Park, PA, USA.

Ondansetron, a selective serotonin-type 3 (5-HT3) receptor antagonist, was used to test the hypothesis that duodenal infusion of isosmotic solutions of Polycose or its hydrolytic product glucose, suppressed intake through 5-HT3 receptors. Polycose suppressed sucrose intake across both concentrations infused (132mM, 7.6 +/- 0.6 ml; 263mM, 2.3 +/- 0.5 ml), compared to intake under control conditions (12.6 +/- 0.3 ml, P <0.001). Pretreatment with 1.0 mg/kg ondansetron attenuated reduction of sucrose intake induced only by the highest concentration of Polycose (4.6 +/- 0.8 ml, P=0.004). Dose response testing revealed that suppression of food intake by 263mM Polycose was attenuated by ondansetron administered at 1.0, 2.0, and 5.0mg/kg equally, but not when given at 0.125, 0.25, and 0.5 mg/kg. Acarbose, an alpha-glucosidase inhibitor, attenuated Polycose-induced suppression of food intake and pretreatment with 1.0 mg/kg ondansetron had no further effect. Suppression of intake following 990mM glucose, but not mannitol infusion, was attenuated by pretreatment with 1.0 mg/kg ondansetron. The competitive SGLT1 inhibitor, phloridzin had no effect on 60 min 990mM glucose-induced suppression of intake or the ability of ondansetron to attenuate this suppression of intake. Conversely, glucose-induced suppression of intake was attenuated by phloridzin at earlier time points, and further attenuated when rats were pretreated with 1.0 mg/kg ondansetron. Ondansetron administration alone had no effect on intake at any dose tested. We conclude that 5-HT3 receptors participate in the inhibition of food intake by intraduodenal infusion of carbohydrate solutions through a post-hydrolytic, preabsorptive mechanism.

Am J Physiol Endocrinol Metab. 2004 Nov;287(5):E906-11. Epub 2004 Jun 22.
Effect of lowering postprandial hyperglycemia on insulin secretion in older people with impaired glucose tolerance.
Chang AM, Smith MJ, Bloem CJ, Galecki AT, Halter JB.

Glucose tolerance declines with age, resulting in a high prevalence of diabetes and impaired glucose tolerance (IGT) in the older population. Hyperglycemia per se can lead to impaired beta-cell function (glucose toxicity). We tested the role of glucose toxicity in age-related beta-cell dysfunction in older people (65 +/- 8 yr) with IGT treated with the alpha-glucosidase inhibitor acarbose (n = 14) or placebo (n = 13) for 6 wk in a randomized, double-blind study. Baseline and posttreatment studies included 1) an oral glucose tolerance test (OGTT), 2) 1-h postprandial glucose monitoring, 3) a frequently sampled intravenous glucose tolerance test (insulin sensitivity, or S(I)), and 4) glucose ramp clamp (insulin secretion rates, or ISR), in which a variable glucose infusion increases plasma glucose from 5 to 10 mM. The treatment groups had similar baseline body mass index; fasting, 2-h OGTT, and 1-h postprandial glucose levels; and S(I). In these carefully matched older people with IGT, both fasting (5.7 +/- 0.2 vs. 6.3 +/- 0.2 mM, P = 0.002) and 1-h postprandial glucose levels (6.9 +/- 0.3 vs. 8.2 +/- 0.4 mM, P = 0.02) were significantly lower in the acarbose than in the placebo group. Despite this reduction of chronic hyperglycemia in the acarbose vs. placebo group, measures of insulin secretion (ISR area under the curve: 728 +/- 55 vs. 835 +/- 81 pmol/kg, P = 0.9) and acute insulin response to intravenous glucose (329 +/- 67 vs. 301 +/- 54 pM, P = 0.4) remained unchanged and impaired. Thus short-term improvement of chronic hyperglycemia does not reverse beta-cell dysfunction in older people with IGT.

Biochemistry. 2004 Oct 19;43(41):13204-13213.
Single Amino Acid Mutations Interchange the Reaction Specificities of Cyclodextrin Glycosyltransferase and the Acarbose-Modifying Enzyme Acarviosyl Transferase.
Leemhuis H, Wehmeier UF, Dijkhuizen L.
Department of Microbiology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Kerklaan 30, 9751 NN Haren, The Netherlands, and Chemische Mikrobiologie, Bergische Universitat, D-42079 Wuppertal, Germany.

Acarviosyl transferase (ATase) from Actinoplanes sp. SE50/110 is a bacterial enzyme that transfers the acarviosyl moiety of the diabetic drug acarbose to sugar acceptors. The enzyme exhibits 42% sequence identity with cyclodextrin glycosyltransferases (CGTase), and both enzymes are members of the alpha-amylase family, a large clan of enzymes acting on starch and related compounds. ATase is virtually inactive on starch, however. In contrast, ATase is the only known enzyme to efficiently use acarbose as substrate (2 μmol min(-)(1) mg(-) (1)); acarbose is a strong inhibitor of CGTase and of most other alpha-amylase family enzymes. This distinct reaction specificity makes ATase an interesting enzyme to investigate the variation in reaction specificity of alpha-amylase family enzymes. Here we show that a G140H mutation in ATase, introducing the typical His of the conserved sequence region I of the alpha-amylase family, changed ATase into an enzyme with 4-alpha-glucanotransferase activity (3.4 μmol min(-)(1) mg(-)(1)). Moreover, this mutation introduced cyclodextrin-forming activity into ATase, converting 2% of starch into cyclodextrins. The opposite experiment, removing this typical His side chain in CGTase (H140A), introduced acarviosyl transferase activity in CGTase (0.25 μmol min(-)(1) mg(-)(1)).

Biopolymers. 2004 Oct 5;75(2):95-108.
Putative implication of alpha-amylase loop 7 in the mechanism of substrate binding and reaction products release.
Andre G, Tran V.
Institut Pasteur, Unite de Biochimie Structurale, 25 rue du Dr Roux, 75724 Paris Cedex 15, France. gandre@pasteur.fr

Alpha-amylases are widespread endo-enzymes involved in the hydrolysis of internal alpha-(1,4) glycosidic linkages of starch polymers. Molecular modeling of amylose-amylase interactions is a step toward enzymatic mechanism understanding and rational design of new enzymes. From the crystallographic complex of barley alpha-amylase AMY2-acarbose, the static aspects of amylose-amylase docking have been characterized with a model of maltododecaose (DP12) (G. André, A. Buléon, R. Haser, and V. Tran, Biopolymers 1999, Vol. 50, pp. 751-762; G. André and V. Tran, Special Publication no. 246 1999, The Royal Society of Chemistry, H. J. Gilbert, G. J. Davies, B. Henrissat, and B. Svensson, Eds., Cambridge, pp. 165-174). These studies, consistent with the experimental subsite mapping (K. Bak-Jensen, G. André, V. Tran, and B. Svensson, Journal of Biological Chemistry, to be published), propose a propagation scheme for an amylose chain in the active cleft of AMY2. The topographical overview of alpha-amylases identified loop 7 as a conserved segment flanking the active site. Since some crystallographic experiments suspected its high flexibility, its putative motion was explored through a robotic scheme, an alternate route to dynamics simulations that consume CPU time. The present article describes the characteristics of the flexibility of loop 7: location and motion in AMY2. A back-and-forth motion with a large amplitude of more than 0.6 nm was evaluated. This movement could be triggered by two hinge residues. It results in the loop flipping over the active site to enhance the docking of the native helical substrate through specific interactions, it positions the catalytic residues, it distorts the substrate towards its transition state geometry, and finally monitors the release of the products after hydrolysis. The residues involved in the process are now rational mutation points in the hands of molecular biologists.

Appl Environ Microbiol. 2004 Oct;70(10):5988-5995.
Enzymatic Analysis of an Amylolytic Enzyme from the Hyperthermophilic Archaeon Pyrococcus furiosus Reveals Its Novel Catalytic Properties as both an {alpha}-Amylase and a Cyclodextrin-Hydrolyzing Enzyme.
Yang SJ, Lee HS, Park CS, Kim YR, Moon TW, Park KH.
Department of Food Science and Technology, Seoul National University, Shillim-dong, Kwanak-gu, Seoul 151-742, Korea. twmoon@snu.ac.kr; parkkh@plaza.snu.ac.kr.

Genomic analysis of the hyperthermophilic archaeon Pyrococcus furiosus revealed the presence of an open reading frame (ORF PF1939) similar to the enzymes in glycoside hydrolase family 13. This amylolytic enzyme, designated PFTA (Pyrococcus furiosus thermostable amylase), was cloned and expressed in Escherichia coli. The recombinant PFTA was extremely thermostable, with an optimum temperature of 90 degrees C. The substrate specificity of PFTA suggests that it possesses characteristics of both alpha-amylase and cyclodextrin-hydrolyzing enzyme. Like typical alpha-amylases, PFTA hydrolyzed maltooligosaccharides and starch to produce mainly maltotriose and maltotetraose. However, it could also attack and degrade pullulan and beta-cyclodextrin, which are resistant to alpha-amylase, to primarily produce panose and maltoheptaose, respectively. Furthermore, acarbose, a potent alpha-amylase inhibitor, was drastically degraded by PFTA, as is typical of cyclodextrin-hydrolyzing enzymes. These results confirm that PFTA possesses novel catalytic properties characteristic of both alpha-amylase and cyclodextrin-hydrolyzing enzyme.

Clin Chem. 2004 Oct;50(10):1785-96. Epub 2004 Aug 03.
Direct multiplex assay of lysosomal enzymes in dried blood spots for newborn screening.
Li Y, Scott CR, Chamoles NA, Ghavami A, Pinto BM, Turecek F, Gelb MH.
Department of Chemistry, University of Washington, Seattle 98195, USA.

BACKGROUND: Newborn screening for deficiency in the lysosomal enzymes that cause Fabry, Gaucher, Krabbe, Niemann-Pick A/B, and Pompe diseases is warranted because treatment for these syndromes is now available or anticipated in the near feature. We describe a multiplex screening method for all five lysosomal enzymes that uses newborn-screening cards containing dried blood spots as the enzyme source. METHODS: We used a cassette of substrates and internal standards to directly quantify the enzymatic activities, and tandem mass spectrometry for enzymatic product detection. Rehydrated dried blood spots were incubated with the enzyme substrates. We used liquid-liquid extraction followed by solid-phase extraction with silica gel to remove buffer components. Acarbose served as inhibitor of an interfering acid alpha-glucosidase present in neutrophils, which allowed the lysosomal enzyme implicated in Pompe disease to be selectively analyzed. RESULTS: We analyzed dried blood spots from 5 patients with Gaucher, 5 with Niemann-Pick A/B, 11 with Pompe, 5 with Fabry, and 12 with Krabbe disease, and in all cases the enzyme activities were below the minimum activities measured in a collection of heterozygous carriers and healthy noncarrier individuals. The enzyme activities measured in 5-9 heterozygous carriers were approximately one-half those measured with 15-32 healthy individuals, but there was partial overlap of each condition between the data sets for carriers and healthy individuals. CONCLUSION: For all five diseases, the affected individuals were detected. The assay can be readily automated, and the anticipated reagent and supply costs are well within the budget limits of newborn-screening centers.

Diabetes Obes Metab. 2004 Sep;6(5):384-90.
Acarbose lowers serum triglyceride and postprandial chylomicron levels in type 2 diabetes.
Ogawa S, Takeuchi K, Ito S.
Nephrology, Endocrinology and Hypertension, Department of Medicine, Tohoku University Hospital, Sendai, Japan. hek293@mail.cc.tohoku.ac.jp

AIM: This study was designed to examine the therapeutic effect of acarbose on serum triglyceride (TG), free fatty acid (FFA), very low-density lipoprotein (VLDL) and chylomicron (CM) in the meal tolerance test (MTT) before and after acarbose treatment in type 2 diabetes mellitus (DM2). METHODS: Effects of acarbose on postprandial lipid metabolism were examined in DM2 patients. The subjects with normotriglyceridaemia (TG > or = 1.7 mmol/l, n = 60) were divided to three groups (A, B and C), and DM2 patients with hypertriglyceridaemia (TG > 1.7 mmol/l, n = 20) were designated group D. Group A was a control, and group B was designed to examine the one-dose effect of acarbose (100 mg) on lipid levels in MTT using the balanced food of 400 kcal. In groups C and D, acarbose 300 mg/day was administered for 8 weeks, and MTT with the one-dose acarbose administration was performed. We determined the levels of fasting and postprandial levels of glucose, insulin, FFA and TG-rich lipoproteins such as CM and VLDL. RESULTS: Acarbose treatment lowered plasma glucose levels and insulin secretion. In comparison among study groups A, B and C, acarbose significantly lowered serum TG levels in postprandial state. In group D, after the 8-week acarbose administration, fasting or postprandial FFA, TG and VLDL levels were also lowered. Interestingly, postprandial increase in CM was suppressed by acarbose administration in group B, C or D. CONCLUSIONS: Acarbose lowers postprandial TG and CM levels in DM2 with either normotriglyceridaemia or hypertriglyceridaemia. Improvement of insulin resistance with acarbose may also reduce fasting TG levels in DM2 with hypertriglyceridaemia. Acarbose is a beneficial therapeutic agent to reduce TG levels in DM2 patients, thereby leading to suppression of cardiovascular events. Copyright 2004 Blackwell Publishing Ltd

Horm Metab Res. 2004 Sep;36(9):630-8.
Reduction of Postprandial Hyperglycemia in Patients with Type 2 Diabetes Reduces NF-kappaB Activation in PBMCs.
Rudofsky Jr G, Reismann P, Schiekofer S, Petrov D, Eynatten M, Humpert PM, Isermann B, Muller-Hoff C, Thai TP, Lichtenstein S, Bartsch U, Hamann A, Nawroth P, Bierhaus A.
Department of Medicine I, University of Heidelberg, Germany.

AIMS/HYPOTHESIS: Short-lasting hyperglycemia results in activation of the transcription factor NF-kappaB in peripheral blood mononuclear cells. We therefore studied whether the postprandial increase in glucose is sufficient to induce mononuclear NF-kappaB activation and whether blunting postprandial hyperglycemia with the alpha-glucosidase inhibitor acarbose reduces NF-kappaB activation. METHODS: 20 patients with type 2 diabetes were included in a double-blind randomized trial receiving 100 mg acarbose or placebo three times a day over a period of eight weeks. Peripheral blood mononuclear cells were isolated before and 120 minutes after a standardized breakfast. NF-kappaB binding activity was estimated by electrophoretic mobility shift assay and NF-kappaB-p65; translocation was determined by Western blot. RESULTS: Eight weeks of treatment with acarbose significantly reduced postprandial hyperglycemia (p = 0.004 when compared to placebo), postprandial mononuclear NF-kappaB-binding activity (p = 0.045) and nuclear translocation of NF-kappaB-p65 (p = 0.02). CONCLUSION: Reduction of postprandial glucose peak levels by acarbose reduces postprandial mononuclear NF-kappaB activation.

Appl Microbiol Biotechnol. 2004 Aug;65(3):273-80. Epub 2004 Jul 15.
Isolation and characterization of a novel intracellular glucosyltransferase from the acarbose producer Actinoplanes sp. CKD485-16.
Choi BT, Shin CS.
Department of Biotechnology, College of Engineering, Yonsei University, Seodaemun-gu, Seoul, 120-749, South Korea.

A novel intracellular glucosyltransferase (GTase) was isolated from cells of Actinoplanes sp. CKD485-16-acarbose-producing cells. The enzyme was purified by DEAE-cellulose and G75-40 Sephadex chromatography. The molecular mass of the enzyme was estimated to be 62 kDa by SDS-polyacrylamide gel electrophoresis, and its isoelectric point (pI) was pH 4.3. The N-terminal sequence of the GTase consisted of NH(2)-Ser-Val-Pro-Leu-Ser-Leu-Pro-Ala-Glu-Trp. The optimum pH and temperature were 7.5 and 30 degrees C. The enzyme was stable in a pH range of 5.5-9.0 and below 40 degrees C. Enzymatic reactions were performed by incubating the GTase with various substrates. The GTase converted acarbose into component C, maltose into trehalose, and maltooligosaccharides into maltooligosyl trehaloses. The reactions were reversible. Various acarbose analogs were tested as inhibitors against the GTase as a means to suppress component C formation. Valienamine was the most potent, with an IC(50) value of 2.4x10(-3) mM and showed a competitive inhibition mode.

Herz. 2004 Aug;29(5):510-8.
Cardiovascular effects of oral hypoglycemie drugs
Herrmann BL, Erbel R, Janssen OE, Mann K.
Klinik fur Endokrinologie, Zentrum fur Innere Medizin, Universitatsklinikum Essen, Essen, burkhard.herrmann@uni-essen.de

In the recent years there has been increasing interest in the effects of oral hypoglycemic drugs on the cardiovascular system. This has arisen because of recognitions that thiazolidine-diones, peroxisome proliferators-activated receptor gamma (PPAR-gamma), may have antiatherogenic actions and that sulphonylureas are capable of closing the ATP-dependent potassium channel. PPAR-gamma agonists exert antiatherogenic action by inhibition the production of monocyte inflammatory cytokines, inhibition of expression of adhesion molecules in endothelial cells, inhibition of the proliferation of vascular smooth muscle cells and have antioxidative effects. The United Kingdom Prospective Diabetes Study (UKPDS), published in 1998, found that the use of sulphonylureas had no increase in cardiovascular mortality and that metformin therapy in obese individuals with type 2 diabetes mellitus was associated with reduced cardiovascular death. Recently, the STOP-NIDDM trial has been shown that patients with impaired glucose tolerance treated with the alpha-glucosidase inhibitor acarbose had a significant reduction in the risk of cardiovascular disease.Currently, the results of the UKPDS trial are the only available clinical data on which to base the choice of treatment for type 2 diabetic patients. When a glucose-lowering oral drug is considered necessary and is not contraindicated, the firstline choice is a sulphonylurea or a glinide (repaglinide or nateglinide) for diabetics who are not overweight and metformin for those who are.

J Biomol Struct Dyn. 2004 Aug;22(1):59-63.
Computer-aided molecular design of novel glucosidase inhibitors for AIDS treatment.
Silva CH, Taft CA.
Departamento de Ciencias Farmaceuticas Faculdade de Ciencias Farmaceuticas de Ribeirao Preto Universidade de Sao Paulo, Av. do Cafe, s/n, Monte Alegre, 14040-903, Ribeirao Preto, Brasil.

Since the onset of the AIDS epidemic, some 20 million people have died and the estimate is that today close to 40 million are living with type 1 human immunodeficiency virus (HIV)/AIDS. About 14 thousands people are infected worldwide daily with this disease. Still, only a few pharmaceuticals are available for AIDS chemotheraphy. Some pharmaceuticals act against the virus before the entrance of the HIV into the host cells. One of these targets is the glucosidase protein. This class of enzymes has been recently explored because the synthesis of viral glycoproteins depends on the activity of enzymes, such as glucosidase and transferase, for the elaboration of the polysaccharides. In this work we study several glucosidase inhibitors. The DFT method is used to compute atomic charges and the ligand/receptor interaction was simulated with docking software. Analysis of the interactions of the proposed pharmaceutical, a pseudodisaccharide, with the Thermotoga maritima 4-alpha-glucanotransferase in complex with modified acarbose, the scores from docking as well as the graphical superposition of all the ligands, suggest that our molecular designed pseudo-disaccharide may be a potent glucosidase inhibitor. Copyright 2004 Adenine Press

J Biol Chem. 2004 Jul 23;279(30):31033-40. Epub 2004 May 11.
Complex structures of Thermoactinomyces vulgaris R-47 alpha-amylase 2 with acarbose and cyclodextrins demonstrate the multiple substrate recognition mechanism.
Ohtaki A, Mizuno M, Tonozuka T, Sakano Y, Kamitori S.
Department of Biotechnology and Life Science, Tokyo University of Agriculture and Technology, 2-24-16 Naka-cho, Koganei, Tokyo 184-8588, Japan.

Thermoactinomyces vulgaris R-47 alpha-amylase 2 (TVAII) has the unique ability to hydrolyze cyclodextrins (CDs), with various sized cavities, as well as starch. To understand the relationship between structure and substrate specificity, x-ray structures of a TVAII-acarbose complex and inactive mutant TVAII (D325N/D421N)/alpha-, beta- and gamma-CDs complexes were determined at resolutions of 2.9, 2.9, 2.8, and 3.1 A, respectively. In all complexes, the interactions between ligands and enzymes at subsites -1, -2, and -3 were almost the same, but striking differences in the catalytic site structure were found at subsites +1 and +2, where Trp(356) and Tyr(374) changed the conformation of the side chain depending on the structure and size of the ligands. Trp(356) and Tyr(374) are thought to be responsible for the multiple substrate-recognition mechanism of TVAII, providing the unique substrate specificity. In the beta-CD complex, the beta-CD maintains a regular conical structure, making it difficult for Glu(354) to protonate the O-4 atom at the hydrolyzing site as a previously proposed hydrolyzing mechanism of alpha-amylase. From the x-ray structures, it is suggested that the protonation of the O-4 atom is possibly carried out via a hydrogen atom of the inter-glucose hydrogen bond at the hydrolyzing site.

Biochem Biophys Res Commun. 2004 Jul 9;319(4):1265-71.
Inhibitory effects of tannin on human salivary alpha-amylase.
Kandra L, Gyemant G, Zajacz A, Batta G.
Institute of Biochemistry, Faculty of Sciences, University of Debrecen, H-4010 Debrecen, P.O. Box 55, Hungary. kandra@tigris.unideb.hu

Here, we first report on the effectiveness and specificity of tannin inhibition of 2-chloro-4-nitrophenyl-4-O-beta-d-galactopyranosylmaltoside hydrolysis that is catalyzed by human salivary alpha-amylase (HSA). Tannin was gallotannin in which quinic acid was esterified with 2-7 units of gallic acid. A number of studies establish that polyphenols-like tannins-may prevent oral diseases, e.g., dental caries. Kinetic analyses confirmed that the inhibition of hydrolysis is a mixed non-competitive type and only one molecule of tannin binds to the active site or the secondary site of the enzyme. Since Dixon plots were linear, product formation could be excluded from the enzyme-substrate-inhibitor complex (ESI). Kinetic constants calculated from secondary plots and non-linear regression are almost identical, thereby confirming the suggested model. Kinetic constants (K(EI) = 9.03 microgmL(-1), K(ESI) = 47.84 microgmL(-1)) show that tannin is as an effective inhibitor of HSA as acarbose and indicate a higher stability for the enzyme-inhibitor complex than ESI.

QJM. 2004 Jul;97(7):451-5.
The prevention of type 2 diabetes mellitus: recent advances.
Younis N, Soran H, Farook S.
Department of Diabetes and Endocrinology, University Hospital Aintree, Liverpool, UK. naveedy@tinyonlne.co.uk

Diabetes is a major public health problem that is approaching epidemic proportions globally. There is an urgent need for strategies to curb the rising prevalence of this disease, and prevention appears a logical approach. Lifestyle modifications with weight loss and moderate exercise can reduce the incidence of diabetes by >50% in patients with impaired glucose tolerance (IGT). The use of metformin, acarbose and other agents have been shown in randomized prospective trials to prevent type 2 diabetes in high-risk subjects with IGT. Other pharmacological interventions are currently being examined in large prospective studies. It is likely that one or a combination of these approaches could make diabetes prevention a reality in the near future.

Thromb Haemost. 2004 Jul;92(1):97-103.
Increased platelet activation in young Zucker rats with impaired glucose tolerance is improved by acarbose.
Schafer A, Widder J, Eigenthaler M, Bischoff H, Ertl G, Bauersachs J.
Department of Internal Medicine, Cardiology, University of Wurzburg,Wuerzburg, Germany.

Patients with diabetes display increased platelet activation. Recent data show a markedly increased risk for cardiovascular events already in pre-diabetic individuals with impaired glucose tolerance (IGT). We investigated whether IGT is associated with platelet activation. Blood samples were collected from young lean (control) and obese Zucker rats, an established model of IGT, after single oral application of sucrose (4 g.kg-1). Platelet-bound fibrinogen and platelet surface-expression of P-selectin were assessed as indices of platelet activation using flow cytometry. In lean Zucker rats, acute sucrose application induced fibrinogen-binding and P-selectin surface-expression, which was prevented by co-administration of acarbose (10 mg.kg-1). In obese Zucker rats, platelet activation was already maximally increased under baseline conditions with no significant increase after sucrose application. Chronic treatment with acarbose (15 mg.kg-1.day-1) significantly reduced platelet activation in these animals. Acute ingestion of sucrose induces platelet activation which is prevented by acarbose. IGT is associated with marked platelet activation that can be reduced by chronic administration of acarbose. The positive modulation of platelet activation by acarbose may contribute to the reduction of cardiovascular events in patients with IGT.

Presse Med. 2004 Jun 5;33(10):673-81.
Treatment principles for the metabolic syndrome
Boulogne A, Vantyghem MC.
Clinique endocrinologique Marc Linquette, Service d'endocrinologie et metabolisme, CHU de Lille. arnaudboulogne@hotmail.com

GENERAL PRINCIPLES: The general progression throughout the world in type 2 diabetes has lead medical Authorities to develop mass screening but also prevention measures, notably for "high-risk" subjects such as those exhibiting a metabolic syndrome. Studies on the topic have shown that preventing type 2 diabetes was possible via lifestyle changes, possibly in association with pharmacological therapy (metformine, acarbose, thiazolidinediones, orlistat). The other therapeutic stakes in the context of the metabolic syndrome also concern the management of all identified cardiovascular risk factors. REGARDING HYPERTENSION: there are currently no specific recommendations available in the framework of metabolic syndrome, with regard to lowering blood pressure and how to obtain it. However there is evidence that patients may benefit from the strict control of blood pressure (< or =130/85 mm Hg). REGARDING DYSLIPIDEMIA: LDL cholesterol remains the main target, with a goal depending on individual cardiovascular risk (<1 or 1.30 g/l in the case of metabolic syndrome). Statins are of major interest in this context. However, it is also established that normalisation of triglycerides and HDL cholesterol contributes to the improvement of cardiovascular Issues. The respective indications for fibrates or fibrate/statin associations still need to be defined in primary as in secondary prevention.

Diabetes Nutr Metab. 2004 Jun;17(3):137-42.
Modification of beta-cell response to different postprandial blood glucose concentrations by prandial repaglinide and combined acarbose/repaglinide application.
Rosak C, Hofmann U, Paulwitz O.
Hospital Sachsenhausen, Frankfurt, Germany. profrosak@gmx.net

This study was designed to compare the effects of repaglinide plus acarbose combination treatment to repaglinide alone on postprandial glucose, serum insulin, C-peptide and proinsulin concentrations. A total of 40 patients with Type 2 diabetes (T2DM) (fasting blood glucose: 120-180 mg/dl; postprandial blood glucose: 140-240 mg/dl) were included in this single-centre, controlled, randomised, single-dose, cross-over study. On two consecutive days, patients either received 2 mg repaglinide 15 min before breakfast followed by 100 mg acarbose with breakfast or repaglinide alone. Two fasting (7.30 h, 8.00 h) and five postprandial blood samples (from 8.30 h to 12.00 h) were taken for blood glucose, serum insulin, C-peptide and proinsulin determination. Repaglinide plus acarbose treatment significantly reduced the mean increase in postprandial blood glucose levels (24.2+/-18.2 mg/dl) compared to repaglinide alone (51.1+/-29.0 mg/dl; p<0.001). Serum insulin, C-peptide and proinsulin levels [mean area under the curve (AUC7.30-12.00h)] were significantly lower than those observed with repaglinide monotherapy (e.g. insulin: 1089.2+/-604.5 hr x pmol/l and 1596.8+/-1080.6 hr x pmol/l, resp., p<0.001), suggesting that acarbose modifies the rapid insulin release induced by repaglinide. Prandial treatment with a combination of acarbose and repaglinide results in an additive glucose lowering effect and modified insulin secretion compared to repaglinide alone. Postprandial hyperglycaemia is not abolished by rapid stimulation of insulin release induced by repaglinide. Additional reduction of postprandial blood glucose by acarbose modifies the stimulation of insulin release.

Diabetologia. 2004 Jun;47(6):969-75; discussion 976-7. Epub 2004 May 26.
Acarbose for the prevention of Type 2 diabetes, hypertension and cardiovascular disease in subjects with impaired glucose tolerance: facts and interpretations concerning the critical analysis of the STOP-NIDDM Trial data.
Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M; STOP-NIDDM Trial Research Group.
Research Centre, Centre hospitalier de l'Universite de Montreal-Hotel-Dieu, Department of Medicine, University of Montreal, 3850 St. Urbain Street, Rm 8-202, Montreal, Quebec H2W 1T7, Canada. jean.louis.chiasson@umontreal.ca

The STOP-NIDDM Trial has shown that acarbose treatment in subjects with impaired glucose tolerance is associated with a significant risk reduction in the development of diabetes, hypertension and cardiovascular complications. Kaiser and Sawicki have accused the investigators of the STOP-NIDDM Trial of major biases in the conduct of the study, of manipulating the data and of conflict of interest. The aim of this paper is to present data and explanations refuting these allegations.In the STOP-NIDDM Trial, 61 subjects were excluded from the efficacy analysis before unblinding for legitimate reasons: failure to satisfy major entry criteria (n=17) and lack of post-randomisation data (n=44). Blinding and randomisation were carried out by an independent biostatistician. Titration of placebo/acarbose is well described in the protocol and in the study design paper. Of the study population, 9.3% had a fasting plasma glucose of > or =7.0 mmol/l at screening and could have been diabetic according to the new diagnostic criteria. However, even if these subjects are excluded, patients having acarbose treatment still saw a significant risk reduction in the development of diabetes (p=0.0027). The changes in weight are consistent in different publications and are related to different times of follow-up and assessment. Weight change does have an effect on the development of diabetes, but acarbose treatment is still effective even after adjusting for this (p=0.0063). The cardiovascular endpoints were a clearly designated assessment in the original protocol, and only those defined in the protocol and ascertained by the independent Cardiovascular Event Adjudication Committee were used in the analysis. Hypertension was defined according to the most recent diagnostic criteria.The STOP-NIDDM Trial results are scientifically sound and credible. The investigators stand strongly behind these results demonstrating that acarbose treatment is associated with a delay in the development of diabetes, hypertension and cardiovascular complications in a high-risk population with IGT.

Eur J Biochem. 2004 Jun;271(12):2517-29.
Human salivary alpha-amylase Trp58 situated at subsite -2 is critical for enzyme activity.
Ramasubbu N, Ragunath C, Mishra PJ, Thomas LM, Gyemant G, Kandra L.
Department of Oral Biology, University of Medicine and Dentistry of New Jersey, Newark, NJ, USA. n.ramasubbu@umdnj.edu

The nonreducing end of the substrate-binding site of human salivary alpha-amylase contains two residues Trp58 and Trp59, which belong to beta2-alpha2 loop of the catalytic (beta/alpha)(8) barrel. While Trp59 stacks onto the substrate, the exact role of Trp58 is unknown. To investigate its role in enzyme activity the residue Trp58 was mutated to Ala, Leu or Tyr. Kinetic analysis of the wild-type and mutant enzymes was carried out with starch and oligosaccharides as substrates. All three mutants exhibited a reduction in specific activity (150-180-fold lower than the wild type) with starch as substrate. With oligosaccharides as substrates, a reduction in k(cat), an increase in K(m) and distinct differences in the cleavage pattern were observed for the mutants W58A and W58L compared with the wild type. Glucose was the smallest product generated by these two mutants in the hydrolysis oligosaccharides; in contrast, wild-type enzyme generated maltose as the smallest product. The production of glucose by W58L was confirmed from both reducing and nonreducing ends of CNP-labeled oligosaccharide substrates. The mutant W58L exhibited lower binding affinity at subsites -2, -3 and +2 and showed an increase in transglycosylation activity compared with the wild type. The lowered affinity at subsites -2 and -3 due to the mutation was also inferred from the electron density at these subsites in the structure of W58A in complex with acarbose-derived pseudooligosaccharide. Collectively, these results suggest that the residue Trp58 plays a critical role in substrate binding and hydrolytic activity of human salivary alpha-amylase.

Diabetes Res Clin Pract. 2004 Jan;63(1):57-65.
Is acarbose equivalent to tolbutamide as first treatment for newly diagnosed type 2 diabetes in general practice?. A randomised controlled trial.
van de Laar FA, Lucassen PL, Kemp J, van de Lisdonk EH, van Weel C, Rutten GE.
Department of General Practice, University Medical Centre Nijmegen, 229 HAG, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands

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. Patients were randomised to receive acarbose, titrated step-wise to a maximum of 100mg three times daily (n=48) or tolbutamide, similarly titrated to a maximum of 2000mg in three doses (n=48). The two treatments were considered equivalent if the two-sided 90% confidence interval (CI) for the difference in mean HbA(1c) levels was within the range -0.4 to 0.4%. Results were analysed on an intention-to-treat, per-protocol and on worst-case basis. Both agents reduced the HbA(1c) percentage and fasting blood glucose levels. The difference in mean decrease of HbA(1c) was 0.6% in favour of tolbutamide (90% CI 0.3, 0.9; 95% CI 0.2, 1.0). A worst-case analysis, assuming no change in HbA(1c) for dropouts, yielded a difference in mean decrease of 0.9% (90% CI 0.6, 1.2) in favour of tolbutamide. The difference in mean decrease of fasting blood glucose was 1.0mmol/l in favour of tolbutamide (95% CI 0.3, 1.7). There were no significant differences in post-load blood glucose, fasting and post-load insulin levels, or lipids. In the acarbose group significantly more patients (15 versus 3) discontinued therapy because of adverse effects, mostly of gastrointestinal origin. We conclude that the results of this study favour tolbutamide over acarbose as first treatment for patients with newly diagnosed type 2 diabetes.

Diabetes Obes Metab. 2004 Jan;6(1):63-8.
The effect of acarbose on insulin resistance in obese hypertensive subjects with normal glucose tolerance: a randomized controlled study.
Rachmani R, Bar-Dayan Y, Ronen Z, Levi Z, Slavachevsky I, Ravid M.
Department of Medicine, Meir Hospital Kfar Sava and the Sackler Faculty of Medicine, Tel-Aviv University, Israel.

AIM: Acarbose, a glucose oxidase inhibitor, delays the absorption of glucose thus reducing post-prandial blood glucose level, haemoglobin A1c (HbA1c) and insulin resistance in patients with diabetes mellitus and in subjects with impaired glucose tolerance. The effect of acarbose in subjects with normal glucose tolerance (NGT) has hitherto not been examined. The aim of the present study was to examine the effect of acarbose in obese hypertensive subjects with NGT. METHODS: A double-blinded, parallel group study was performed on 56 male subjects with hypertension, body mass index (BMI) 27-35 kg/m2, fasting blood glucose </= 6 mmol/l and a normal oral glucose tolerance test. Blood pressure, HbA1c, lipid profile and insulin resistance [homeostasis model assessment (HOMA) index] were determined initially and following 24 weeks of acarbose, 150 mg/day or placebo. The primary end point was the change in insulin resistance. Anti-hypertensive treatment and diet were kept constant during the study. RESULTS: Insulin resistance decreased in acarbose users but not on placebo. HOMA index declined from 5.36 +/- 1.7 to 4.10 +/- 1.6 (p = 0.001) on acarbose, the corresponding values on placebo were 5.44 +/- 1.9 and 5.53 +/- 1.7. A decrease in serum triglyceride values (2.16 +/- 0.16 mmol/l to 1.76 +/- 0.15 mmol/l, p = 0.02) took place on acarbose with no change on placebo. There was no change in BMI, low-density lipoprotein or high-density lipoprotein values in either group. Blood pressure declined equally in both the groups, probably due to better patient compliance. CONCLUSIONS: Acarbose may reduce insulin resistance and triglycerides also in obese hypertensive subjects with normal glucose tolerance.

Expert Opin Pharmacother. 2003 Nov;4(11):2065-78
Treatment of premenstrual dysphoric disorder with luteal phase dosing of sertraline.
Halbreich U, Kahn LS.

Biobehavioural Program, School of Medicine & Biomedical Sciences, Hayes C, Suite 1, 3435 Main St, Building 5, Buffalo, NY 14214-3016, USA.
Sertraline (Zoloft( trade mark ), Pfizer Inc.) is a selective serotonin re-uptake inhibitor (SSRI) which has been approved by the US FDA for the treatment of premenstrual dysphoric disorder (PMDD). PMDD is a severe form of premenstrual syndrome (PMS) which affects at least 5 - 8% of women of reproductive age. It is characterised by cyclic appearance at the late luteal phase of the menstrual cycle, and disappearance following the beginning of menses, with no symptoms during at least 1 week of the cycle - usually during the mid-follicular phase. Due to the cyclic luteal occurrence of PMDD, luteal phase dosing of SSRIs has been suggested and proven effective for sertraline as well as several other SSRIs. The clinical response of sertraline is reported to be within several days following initiation of treatment. Despite repeated cyclic discontinuation, no significant discontinuation adverse effects have been reported. In addition to its proven clinical efficacy, luteal-phase dosing may offer the advantages of minimising adverse effects of SSRIs while reducing the personal and economic burden of taking a prescription medication continuously for long periods and thus increasing compliance.

JAMA. 2003 Aug 27;290(8):1033-41.
Efficacy of sertraline in the treatment of children and adolescents with major depressive disorder: two randomized controlled trials.
Wagner KD, Ambrosini P, Rynn M, Wohlberg C, Yang R, Greenbaum MS, Childress A, Donnelly C, Deas D; Sertraline Pediatric Depression Study Group.
University of Texas Medical Branch, Department of Psychiatry and Behavioral Sciences, Galveston 77555-0188, USA.

CONTEXT: The efficacy, safety, and tolerability of selective serotonin reuptake inhibitors (SSRIs) in the treatment of adults with major depressive disorder (MDD) are well established. Comparatively few data are available on the effects of SSRIs in depressed children and adolescents. OBJECTIVE: To evaluate the efficacy and safety of sertraline compared with placebo in treatment of pediatric patients with MDD. DESIGN AND SETTING: Two multicenter randomized, double-blind, placebo-controlled trials were conducted at 53 hospital, general practice, and academic centers in the United States, India, Canada, Costa Rica, and Mexico between December 1999 and May 2001 and were pooled a priori. PARTICIPANTS: Three hundred seventy-six children and adolescents aged 6 to 17 years with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-defined MDD of at least moderate severity. INTERVENTION: Patients were randomly assigned to receive a flexible dosage (50-200 mg/d) of sertraline (n = 189) zoloft or matching placebo tablets (n = 187) for 10 weeks. MAIN OUTCOME MEASURES: Change from baseline in the Children's Depression Rating Scale-Revised (CDRS-R) Best Description of Child total score and reported adverse events. RESULTS: Sertraline-treated patients experienced statistically significantly greater improvement than placebo patients on the CDRS-R total score (mean change at week 10, -30.24 vs -25.83, respectively; P =.001; overall mean change, -22.84 vs -20.19, respectively; P =.007). Based on a 40% decrease in the adjusted CDRS-R total score at study end point, 69% of sertraline-treated patients compared with 59% of placebo patients were considered responders (P =.05). Sertraline treatment was generally well tolerated. Seventeen sertraline-treated patients (9%) and 5 placebo patients (3%) prematurely discontinued the study because of adverse events. Adverse events that occurred in at least 5% of sertraline-treated patients and with an incidence of at least twice that in placebo patients included diarrhea, vomiting, anorexia, and agitation. CONCLUSION: The results of this pooled analysis demonstrate that sertraline is an effective and well-tolerated short-term treatment for children and adolescents with MDD.

J Clin Psychiatry. 2003 Jul;64(7):785-92.
Efficacy of sertraline in severe generalized social anxiety disorder: results of a double-blind, placebo-controlled study.
Liebowitz MR, DeMartinis NA, Weihs K, Londborg PD, Smith WT, Chung H, Fayyad R, Clary CM.
New York State Psychiatric Institute, New York, NY, USA.

BACKGROUND: Generalized social anxiety disorder is an early onset, highly chronic, frequently disabling disorder with a lifetime prevalence of approximately 13%. The goal of the current study was to evaluate the efficacy and tolerability of sertraline for the treatment of severe generalized social anxiety disorder in adults. METHOD: After a 1-week single-blind placebo lead-in period, patients with DSM-IV generalized social phobia were randomly assigned to 12 weeks of double-blind treatment with flexible doses of sertraline (50-200 mg/day) or placebo. Primary efficacy outcomes were the mean change in the Liebowitz Social Anxiety Scale (LSAS) total score and the responder rate for the Clinical Global Impressions-Improvement scale (CGI-I), defined as a CGI-I score </= 2. Data were collected in 2000 and 2001. RESULTS: 211 patients were randomly assigned to sertraline (intent-to-treat [ITT] sample, 205), and 204 patients, to placebo (ITT sample, 196). At week 12, sertraline produced a significantly greater reduction in LSAS total score compared with placebo (mean last-observation-carried-forward [LOCF] change from baseline: -31.0 vs. -21.7; p =.001) and a greater proportion of responders (CGI-I score </= 2: 55.6% vs. 29% among week 12 completers and 46.8% vs. 25.5% in the ITT-LOCF sample; p <.001 for both comparisons). Sertraline was well tolerated, with 7.6% of patients discontinuing due to adverse events versus 2.9% of placebo-treated patients. CONCLUSION: The results of the current study confirm the efficacy of sertraline, zoloft in the treatment of severe social anxiety disorder.

J Am Pharm Assoc (Wash DC). 2003 Jul-Aug;43(4):497-502.
Evaluation of cost savings to a state Medicaid program following a sertraline tablet-splitting program.
Vuchetich PJ, Garis RI, Jorgensen AM.
Department of Pharmacy Sciences, School of Pharmacy and Health Professions, Creighton University Medical Center, Omaha, Neb. 68178, USA.

OBJECTIVES: To evaluate the economic impact of implementing a sertraline (Zoloft--Pfizer) tablet-splitting program on the Nebraska Medicaid program based on the change in total and per-member-per-month (PMPM) prescription drug costs and to identify any real or perceived problems with tablet splitting using switches among selective serotonin reuptake inhibitors (SSRIs) as a proxy indicator. DESIGN: Retrospective study of prescription claims before and after the tablet-splitting program was implemented. SETTING: Nebraska Medicaid. PATIENTS: All 14,520 patients who received an SSRI during the study period, including 5,466 patients who received at least one prescription for sertraline. INTERVENTIONS: The Nebraska Medicaid program implemented a mandatory tablet-splitting program for sertraline. Pharmacists were paid a supplemental fee to split tablets. MAIN OUTCOME MEASURES: Total costs, PMPM costs, and switches among SSRIs. RESULTS: Using regression analysis, sertraline was the only SSRI that showed a downward slope in total cost per month, although the decrease was not statistically significant (P = .1156). Fluoxetine (Prozac--Eli Lilly) and paroxetine (Paxil--GlaxoSmithKline) both showed an upward slope, but the increases were not statistically significant (P = .1164 and .0671, respectively). Citalopram (Celexa--Forest) and fluvoxamine showed significantly positive upward slopes (P = .0001 and .0391, respectively). Sertraline was also the only SSRI that showed a downward slope in PMPM costs (P = .0093). Citalopram, fluvoxamine, fluoxetine, and paroxetine all showed an upward slope in PMPM costs (P = .4494, .0008, .0448, and .0482, respectively). The tablet-splitting program was not associated with a net change in patients being switched to or from sertraline. CONCLUSION: Implementing the sertraline tablet-splitting program significantly decreased the PMPM cost of sertraline prescriptions, but it did not significantly decrease total costs of sertraline, nor did it result in disproportionate numbers of patients switching from sertraline to other SSRIs. Total costs and PMPM costs of the other four SSRI drugs did not decrease.

J Clin Psychiatry. 2003 Aug;64(8):959-65.
Sertraline as monotherapy in the treatment of psychotic and nonpsychotic depression.
Simpson GM, El Sheshai A, Rady A, Kingsbury SJ, Fayek M.
Department of Psychiatry and the Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.

BACKGROUND: Previous studies suggest that selective serotonin reuptake inhibitors (SSRIs) are effective when used alone in the treatment of unipolar depression with psychotic features. The purpose of the present study was to examine the response to sertraline for patients with and without psychotic features using standard criteria such as recovery and remission. METHOD: An 8-week open-label trial of sertraline in depressed inpatients was conducted. Twenty-five subjects had DSM-IV major depressive disorder with psychotic features, and 25 had DSM-IV major depressive disorder without psychotic features. After a 1-week open washout, all subjects were rated using the Hamilton Rating Scale for Depression (HAM-D) and Brief Psychiatric Rating Scale (BPRS) at baseline. The HAM-D was administered weekly, and the BPRS was administered again only at the end of the 8-week trial. Medication dosage was started at 50 mg/day, increased to 100 mg/day after 1 week, and then increased up to 200 mg/day if subjects had not remitted. RESULTS: Depressed patients without psychosis responded significantly better than did depressed patients with psychosis using the criteria of remission (HAM-D score - 7; p =.001), response (HAM-D score - 50% of baseline score; p =.011), referral for electroconvulsive therapy (HAM-D score >/= 15; p =.011), or change in HAM-D scores (p =.016). Baseline HAM-D score and psychosis independently predicted response, whereas baseline BPRS scores did not, regardless of whether psychotic status was entered into the analyses. CONCLUSION: Psychotic depression responds more poorly than depression without psychosis to sertraline alone. Psychosis was a predictor of response independent of degree of depression and general psychopathology. Limitations due to an open-label design are discussed, as are differences between this study and others using SSRIs for psychotic depression.

J Clin Psychiatry. 2003 Aug;64(8):875-82.
Probing the safety of medications in the frail elderly: evidence from a randomized clinical trial of sertraline and venlafaxine in depressed nursing home residents.
Oslin DW, Ten Have TR, Streim JE, Datto CJ, Weintraub D, DiFilippo S, Katz IR.
Section of Geriatric Psychiatry, Department of Psychiatry, University of Pennsylvania, Philadelphia, Pa., USA.

BACKGROUND: In nursing home residents and other frail elderly patients, old age and potential drug-drug and drug-disease interactions may affect the relative safety and efficacy of medications. The purpose of this study was to examine the efficacy and tolerability of venlafaxine and sertraline for the treatment of depression among nursing home residents. METHOD: The study was a 10-week randomized, double-blind, controlled trial of venlafaxine (doses up to 150 mg/day) versus sertraline (doses up to 100 mg/day) among 52 elderly nursing home residents with a DSM-IV depressive disorder and, at most, moderate dementia. The primary measure of outcome was the Hamilton Rating Scale for Depression (HAM-D). Adverse events were monitored and recorded systematically during the trial. RESULTS: Twelve subjects were discontinued due to serious adverse events (SAE), 5 were discontinued due to other significant side effects, and 2 withdrew consent. Tolerability estimated by the time to termination was lower for venlafaxine than sertraline for serious adverse events (log rank statistic = 5.28, p =.022), for serious adverse events or side effects (log rank statistic = 8.08, p =.005), or for serious adverse events, side effects, or withdrawal of consent (log rank statistic = 10.04, p =.002). Mean (SD) HAM-D scores at baseline were 20.2 (3.4) for sertraline and 20.3 (3.7) for venlafaxine; intent-to-treat endpoint HAM-D scores were 12.2 (5.1) and 15.7 (6.2) (F = 3.45; p =.069). There were no differences in categorical responses for the intent-to-treat sample or completers. CONCLUSION: In this frail elderly population, venlafaxine was less well tolerated and, possibly, less safe than sertraline without evidence for an increase in efficacy. This unexpected finding demonstrates the need for systematic research on the safety of drugs in the frail elderly.