Of acarbose

Likewise, complete synthesis of acarbose was conveniently accomplished by use of the anhydro derivative 392b prepared from maltotriose. Condensation of 392b with optically active 359 afforded two products, one of which was, after deprotection, shown to be identical to an authentic sample of acarbose. 

Structural mimicry of the substrate is also observed in the complex between PPA and the proteinaceous inhibitor tendamistat [173]. Again, the inhibitor extends into the catalytic site, but contacts only one of the catalytic residues, the glutamate residue. The sequence of three residues of the inhibitor, WRY (Trp-18 to Tyr-20) is positioned in the active site, with the arginine residue forming hydrogen bonds with the catalytic Glu-233. The WRY sequence and residues Thr-55, Gly-59 and Tyr-60 make hydrophobic contacts with the active site which are similar to those of acarbose and of a-All. 

Dosage of acarbose must be individualized while not exceeding the maximum recommended dose of 100 mg 3 times/day for patients more than 60 kg and 50 mg 3 times/day for patients less than 60 kg. 

Because its mechanism of action is different, the effect of acarbose to enhance glycemic control is additive to that of sulfonylureas when used in combination. In contrast to sulfonylureas, acarbose does not enhance insulin secretion. 

Excretion - The fraction of acarbose that is absorbed as intact drug is almost completely excreted by the kidneys. When acarbose was given IV, 89% of the dose was recovered in the urine as active drug within 48 hours. In contrast, less than 2% of an oral dose was recovered in the urine as active (ie, parent compound and active metabolite) drug. The plasma elimination half-life of acarbose activity is about 2 hours in healthy volunteers. 

Diet/Physicai activity The use of acarbose 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. 

Renai function impairment Patients with severe renal impairment (creatinine clearance [Ccr] less than 25 mL/min/1.73 m ) attained about 5 times higher peak plasma concentrations of acarbose and 6 times larger AUCs than volunteers with normal renal function. Treatment of these patients with acarbose is not... 

Agents include acarbose, miglitol and voglibose. Only bacterial breakdown products of acarbose are absorbed which are then rapidly eliminated by the kidneys. Adverse events mainly consist of gastrointestinal complaints which in rare cases can be confused with ileus. Some hepatotoxicity has been reported. 

Acarbose Precose) is an ohgosaccharide derivative that has a higher affinity for the a- glucosidase enzymes than do other dietary oUgosaccharides. Systemic absorption of acarbose is very low ( 2%), with most being broken down in the intestine to several metabolites. About half of the orally administered acarbose is excreted unchanged in the feces, while the remainder, some of which is systemically absorbed, is renally excreted. Acarbose may be associated with hepatotoxicity in rare instances. 

The main synthetic challenge in a synthesis of -acarbose is the attachment of the polyhydroxylated cyclohexene unit, by a nitrogen atom, to the 6"-deoxy trisaccharide. If one accepts that molecular ammonia is not likely to be the ideal reagent to link the cyclohexene and trisaccharide units together, then one also realizes that only two approaches are left either a trisaccharide amine may be attached to a cyclohexene unit or, conversely, a cyclohexenyl amine may be joined to a trisaccharide. 

It would, in principle, be possible to convert the polyol 115 into the 6"-deoxy sugar 118, a direct precursor of /3-acarbose. However, we decided that it would be better to reassess the whole synthesis and reasoned that a 1,6-epithio sugar such as 119 would be an ideal pivot for a synthesis of acarbose the amine 81 could easily be introduced at C-4, the sulfur at C-1 allows for activation to produce a glycosyl donor ready for attachment to the disaccharide alcohol 113 and, finally, desulfurization at C-6 leads to the necessary methyl group. 

The bicyclic sugars 121 and 128-130 should all be capable of some sort of chemical activation to produce glycosyl donors. To date, we have investigated just the related sulfide 133. Treatment of 133 with a range of alcohols, 134-138, in the presence of N-iodosuccinimide and triflic acid, has given rise to intermediate disulfides, e. g. 139 in good yield and capable of reduction (Ra/Ni) to the 6,6 -dideoxy /3-disaccharide 140 [66]. This is truly an excellent result in terms of a direct synthesis of -acarbose. 

In a 2-year study of the tolerability and safety of acarbose in 2035 patients the incidence of adverse effects was 7.5% and of withdrawals 2.5% (11). Of 1907 patients, 444 (23%) reported one or more adverse events. In 143 patients the physician considered that there was a probable or possible relation between the adverse event (all gastrointestinal) and acarbose. There were 77 deaths, but none was considered to be related to acarbose 52 stopped taking acarbose because of an adverse event and 45 were considered to be related to acarbose. Laboratory analyses were all within the reference ranges. HbAlc fell by 1.92%. 

In a post-marketing surveillance study in 27 803 patients with diabetes mellitus (94% type 2), data were reported after 12 weeks. The doses of acarbose were low 4.1% took less than 100 mg/day, 64% 100-250 mg/day, 32% 250-300 mg/day, and 0.1% more than 300 mg/day. Only 2.1% stopped therapy, mainly because of gastrointestinal adverse events. Tolerability appeared to be good and independent of age. Abnormal liver function was reported in 0.01%. The difference between these results and those of many controlled trials may in part be explained by the fact that higher doses have been used in most trials (14). 

In a comparison of voglibose and acarbose in 21 in-patients with type 2 diabetes who took part in a randomized crossover study of acarbose 150 mg/day and voglibose 0.9 mg/day, there was marked interindividual variation in response (18). For both drugs efficacy was better in those with gastrointestinal adverse effects, such as abdominal distention and flatulence. 

In a multicenter, double-blind, placebo-controlled study, 81 patients, in whom treatment with metformin was inadequate, received extra acarbose or placebo during 24 weeks after a 4-week run-in period to establish the optimal dose of acarbose (28). HbAic was reduced by 1.02% and fasting blood glucose by 1.13 mmol/1. Gastrointestinal adverse effects were more common in the acarbose group. 

In a 56-week study there was an association between the use of acarbose and low vitamin B6 concentrations, which occurred in 33% of 240 patients taking acarbose compared with 23% of 119 patients taking placebo (38). Calcium concentrations fell more often in those who took acarbose (28% versus 16%) but returned to normal by the end. These findings have not been reported elsewhere and do not appear to be clinically significant. 

In the STOP-NIDDM trial of acarbose cardiovascular risk and hypertension were reduced however, almost a quarter of the participants withdrew early, and the main cause of early withdrawal was gastrointestinal adverse effects (43). 

The author of a review of the use of acarbose concluded that acarbose is safe in both monotherapy and combination therapy (44). The most common adverse effects are mild to moderate gastrointestinal symptoms, such as flatulence, meteorism, diarrhea, soft stools, abdominal discomfort, and pain. As glucose oxidase increases in the small intestine during therapy, it is advisable to start with a low dose so that the gut can adapt to acarbose. 

In a post-marketing surveillance study of 1142 patients in whom acarbose was added to insulin therapy for type 2 diabetes mellitus, HbAlc improved by 0.9% and there were 108 adverse effects in 6.9% of the patients (45). Most of the complaints were gastrointestinal (flatulence, abdominal pain, diarrhea) and more than half were reported in the first week of acarbose therapy. 

Although the ileus in this case was not clearly related to the use of acarbose, the combination of acarbose, which can cause ileus, with the other drugs that the patient was taking, may have caused it. The anticholinergic effect of promethazine methylene disalicylate may have contributed. 

A 52-year-old man developed watery diarrhea 6-8 times a day 2 weeks after he had started to take acarbose 100 mg. In 3 weeks he lost 3 kg. Duodenal biopsies were normal colon biopsies showed a large increase in intraepithelial lymphocytes. The mononuclear cells expressed CD-25, and HLA-DR antigen was increased in epithelial cells. Within 4 days of acarbose withdrawal the diarrhea had disappeared, and biopsies 4 months later showed that CD-25 expression in the cells of the lamina propria was improved and HLA-DR was no longer expressed by the epithelial cells. On rechallenge the diarrhea recurred within 3 days. Biopsies showed pronounced HLA-DR in the epithelial cells and CD-25 expression in some mononuclear cells in the lamina propria. 

A 74-year-old woman who had used acarbose for 3 months developed progressive weakness and jaundice (60). Her bilirubin was 152 pmol/l (direct bilirubin 96 pmol/1). All of her liver enzymes were substantially raised. All other investigations were normal, except that she was positive for hepatitis C antigen. After withdrawal of acarbose everything became normal within 1 month. 

Comparable reports have prompted a questionnaire investigation of 770 patients with type 2 diabetes at the start of acarbose therapy (62). Patients with one or more susceptibility factors for liver damage underwent ultrasonography and autoantibody assays. There was silent liver disease in 13% and 20 patients had a fatty liver without hepatic disease. In 15% of these patients there were slight reversible changes in transaminase activity after acarbose. 

In a 78-week double-blind single center study 139 patients with type 2 diabetes were randomized to acarbose or placebo in addition to their usual therapy (63). The mean dose of acarbose at the end of the study was 680 mg. Two patients taking 600 mg or more developed raised liver enzymes, to more than three times the upper limit of normal. 

In a 56-week study there was an association between the dose of acarbose in the range 50-300 mg tds and the development of abnormal liver function in 359 patients with type 1 (21%) and type 2 diabetes (38). The patients took the maximum tolerated dose, and 30% took doses of 100 mg or less. Of the patents who were randomized to acarbose (n = 240), 8% developed abnormal liver function tests (alanine transaminase activity more than three times the upper limit of normal) compared with 1% of those who took placebo (n — 119). The dose of acarbose was 200-300 mg tds in those who developed abnormal liver function. Liver function recovered promptly on withdrawal. 

A 43-year-old man developed generalized exanthema pustulosis 48 hours after the start of acarbose therapy (66). The lesions disappeared within 1 week after stopping acarbose. He was not retested. 

In 24 healthy volunteers thioctic acid 600 mg orally had no significant effect on the actions of acarbose 50 mg and acarbose did not alter the pharmacokinetics of thioctic acid (80). 

Sels JP, Verdonk HE, Wolffenbuttel BH. Effects of acarbose (Glucobay) in persons with type 1 diabetes a multicentre study. Diabetes Res Clin Pract 1998 41(2) 139-45. 

Mertes G. Efficacy and safety of acarbose in the treatment of type 2 diabetes data from a 2-year surveillance study. Diabetes Res Clin Pract 1998 40(l) 63-70. 

Scorpiglione N, Belfiglio M, Carinci F, Cavaliere D, De Curtis A, Franciosi M, Mari E, Sacco M, Tognoni G, Nicolucci A. The effectiveness, safety and epidemiology of the use of acarbose in the treatment of patients with type II diabetes mellitus. A model of medicine-based evidence. Eur J Clin Pharmacol 1999 55(4) 239-49. 

Spengler M, Schmitz H, Landen H. Evaluation of the efficacy and tolerability of acarbose in patients with diabetes mellitus. A post marketing surveillance study Clin Drug Invest 2005 25 651-9. 

Salman S, Salman F, Satman I, Yilmaz Y, Ozer E, Sengul A, Demirel HO, Karsidag K, Dinccag N, Yilmaz MT. Comparison of acarbose and gliclazide as first-line agents in patients with type 2 diabetes. Curr Med Res Opin 2001 16(4) 296-306. 

Kelley DE, Bidot P, Freedman Z, Haag B, Podlecki D, Rendell M, Schimel D, Weiss S, Taylor T, Krol A, Magner J. Efficacy and safety of acarbose in insulin-treated patients with type 2 diabetes. Diabetes Care 1998 21(12) 2056-61. 

Holman RR, Cull CA, Turner RC. A randomized doubleblind trial of acarbose in type 2 diabetes shows improved glycemic control over 3 years (U.K. Prospective Diabetes Study 44) Diabetes Care 1999 22(6) 960-4. 

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