Metformin Tablets Research Articles

P.2.c.011 The effect of carbamazepine co-therapy on the extent of MAO-A inhibition by moclobemide in depressed patients

Type 2 diabetes mellitus is the most common form of diabetes. Metformin is a first-line drug for its treatment. In Mexico, there are 34 generic formulations of metformin, so brand-generic substitutions and generic-generic substitutions are a common practice. Generic products are compared only with their brand-name equivalents and not with the same product made by other manufacturers.Our aim was to establish whether 2 generic formulations of 500 mg metformin available on the Mexican market fulfill the criteria for interchangeability.This single-dose, randomized-sequence, open-label, 3-period crossover study was conducted in 12 healthy subjects in compliance with the Declaration of Helsinki and International Conference on Harmonization guidelines. A validated HPLC procedure coupled with a spectrum mass detector were used to analyze the metformin concentration in plasma samples. All pharmacokinetic analyses were performed using WinNonlin Professional Software version 6.3 (Pharsight Corporation, Sunnyvale, California).Twelve healthy Mexican volunteers were enrolled in the study. Their mean age was 24.33 years and mean weight was 62.54 kg. The mean body mass index was 23.02. The values obtained for the test and reference formulations were: Cmax 1163.5 (295.2) ng/mL for treatment A, 1184.6 (215.0) ng/mL for treatment B, and 1167.8 (176.8) ng/mL for treatment C. AUC0–t was 6240.7 (1629.4) ng/mL/h for treatment A, 6433.7 (1249.8) ng/mL/h for treatment B, and 6567.1 (1145.5) ng/mL/h for treatment C. AUC0–∞ was 6837.3 (1618.5) ng/mL/h for treatment A, 6911.8 (1178.4) ng/mL/h for treatment B, and 7178.6 (1086.8) ng/mL/h for treatment C.The test formulation 500-mg metformin tablets were bioequivalent to the reference formulation and to each other, according to the general laws of health care in Mexico.

Estimation of Metformin in Bulk Drug and in Formulation by HPTLC

A simple and sensitive, HPTLC method has been developed for the quantitative estimation of metformin in its single component tablet formulation. Metformin was chromatographed on silica Gel 60 F 254 TLC plate using ammonium sulfate (0.5%): 2-propanol: methanol in the ratio of 8.0:1.6:1.6 (v/v/v) as mobile phase. Metformin showed R f value of 0.50±0.03 was scanned at 238 nm using Camag TLC Scanner 3. The linear regression data for the calibration plot showed a good relationship with r =0.999. The method was validated for precision and recovery. The limits of detection and quanti fi cation were 95 and 200 ng/spot respectively. The developed method was successfully used for the assay of metformin tablet formulations. The method is simple, sensitive and precise; it can be used for the routine quality control testing of marketed formulations.

Site-specific oral controlled release metformin tablets - development, in vitro, ex vivo and in vivo evaluation

Oral absorption of metformin is confined to the upper part of intestine posing problems in the formulation of extended release tablets. Therefore, the objective of the present study was to develop controlled-release mucoadhesive core tablets and confine the tablets to the specific site in the gastrointestinal tract. A projective coat protects the core tablets from mucoadhesion till the targeted site is reached. Once the tablet reaches the specific site, the coat dissolves exposing the core tablet for mucoadhesion. In vitro coat intactness test and ex vivo tablet bioadhesion test confirmed that the tablets were targeted and contained in the upper intestine. Further, the pharmacokinetic parameters obtained for metformin from the site-specific coated formulation were better (P<0.05) than that of the non-site-specific uncoated formulation in the in vivo studies. Standardized formulation was stable during the stability studies conducted as per ICH Q1C guidelines.

Metformin and the intestine

To the Editor: The antihyperglycaemic effect of metformin is generally attributed to a decrease in hepatic glucose output, with some additional effects that increase peripheral glucose uptake and utilisation [1]. The intestine also makes an important contribution to the glucose-lowering effect of metformin, but this is often overlooked because of a paucity of clinical data [2]. Animal studies indicate that metformin can cause intestinal glucose absorption to be delayed and occur more distally along the tract [3, 4]. However, animal studies have also shown that metformin increases glucose utilisation by the intestine, particularly anaerobic glucose metabolism [5–7], and this contributes to an apparent shortfall in the passage of glucose from the luminal to the serosal side of the intestine [3]. Extra lactate delivered into the portal vein is at least partly converted into glucose, increasing glucose turnover after administration of metformin [5,7,8]. We demonstrate here that metformin increases lactate production in human intestinal mucosa, similar to reports in animal studies. Animal studies have long established that very high concentrations of metformin accumulate in the wall of the intestine [9], which may at least partly explain the increase in anaerobic metabolism. We provide confirmatory evidence herein that similarly high concentrations of metformin accumulate in the human intestinal mucosa. In the present study, eight recently diagnosed, drug-naive, obese type 2 diabetic patients [five men, three women; age 55±3 years (mean±SEM); BMI 33±1 kg/m] attended on three occasions after an overnight fast. Patients gave informed consent, and ethical approval was granted by the research ethics committee. Avenous blood sample was taken for plasma glucose assay (automated glucose oxidase method), and a mucosal biopsy sample (approximately 25 mg) was taken on each occasion from the proximal jejunum, under light midazolam sedation, using an adapted paediatric gastroscope. On the first occasion, tissue was washed, divided into two portions, weighed and then incubated for 2 h at 37°C in 1 ml of Krebs Ringer bicarbonate buffer supplemented with 20 mg/ml serum albumin, 10 mmol/l glucose, 10 mol/l insulin with or without 10 mol/l metformin hydrochloride, and maintained in an atmosphere of 95% O2, 5% CO2 [4, 5]. Lactate production was measured as the concentration of lactate in the medium (manual spectrophotometric method). Metformin therapy was initiated at a dosage of 850 mg once daily and titrated up to twice daily after 2–3 weeks. Two repeat proximal jejunal mucosal biopsies were obtained after 6–8 weeks of therapy. A pre-dose sample was obtained in the morning, 12–16 h after the last metformin tablet (taken the evening before), and a post-dose sample was taken 3 h after the morning tablet. Tissue samples were washed in buffered saline, blotted and weighed, and then metformin was extracted with acetonitrile and assayed by gas chromatography [10]. The results showed that incubation of the jejunal biopsy tissue with 10 mol/l metformin increased lactate producDiabetologia (2008) 51:1552–1553 DOI 10.1007/s00125-008-1053-5

Fixed-Dose Combination Tablet of Repaglinide and Metformin is Bioequivalent to Concomitantly Administered Individual Tablets of Repaglinide and Metformin

Repaglinide and metformin enhance insulin secretion and decrease hepatic gluconeogenesis, respectively, and are commonly coadministered as separate formulations to treat patients with type 2 diabetes mellitus. A single combination therapy tablet offers increased patient convenience and the subsequent potential for increased therapy compliance. The aim of this randomized, single-blind, three-period crossover study was to determine the bioequivalence of a fixed-dose combination (FDC) tablet of repaglinide/metformin 2 mg/500 mg versus repaglinide 2 mg and metformin 500 mg coadministered as separate formulations. Secondary objectives included a comparison of the dose proportionality of an FDC tablet of repaglinide/metformin 1 mg/500 mg and an FDC tablet of repaglinide/metformin 2 mg/500 mg, as well as the safety and tolerability of repaglinide and metformin in combination tablet therapy. Healthy subjects (n = 93, age 18-45 years) were randomized to one of six possible treatment sequences (Williams design) of an FDC tablet of repaglinide/metformin 2 mg/500 mg, repaglinide 2 mg and metformin 500 mg coadministered as separate tablets and an FDC of repaglinide/metformin 1 mg/500 mg. Fifty-five subjects completed the study. Four primary pharmacokinetic endpoints (area under the plasma concentration-time curve [AUC] from time 0 hours to infinity; AUC from time 0 to 24 hours; AUC from time 0 hours to time t [the last time of measurable concentration after dosing]; and the maximum plasma concentration) were used to assess bioequivalence and dose proportionality. The safety and tolerability of repaglinide and metformin in combination tablet therapy were also evaluated. Both repaglinide and metformin in the combination tablet were determined to be bioequivalent to the individual tablets of repaglinide 2 mg and metformin 500 mg, as the limits of the 90% confidence interval of the mean treatment ratio for all pharmacokinetic parameters were contained within the pre-specified interval required for bioequivalence (0.8, 1.25). Additionally, an FDC tablet of repaglinide/metformin 2 mg/500 mg was determined to be dose proportional to an FDC of repaglinide/metformin 1 mg/500 mg for all analysed endpoints. No withdrawals as a result of adverse events occurred during this study. In addition, no clinically relevant abnormalities were found during physical examinations, in vital signs, ECG parameters or clinical laboratory parameters. An FDC tablet of repaglinide/metformin 2 mg/500 mg was bioequivalent to individual tablets of repaglinide 2 mg and metformin 500 mg. Additionally, an FDC tablet of repaglinide/metformin 2 mg/500 mg was dose proportional to an FDC tablet of repaglinide/metformin 1 mg/500 mg. Finally, no unexpected safety concerns were noted with repaglinide/metformin combination tablet therapy. Our results suggest that FDC tablets of repaglinide and metformin would provide safety and efficacy comparable to that of repaglinide and metformin administered as separate formulations.

Formulation, development and evaluation of patient friendly dosage forms of metformin, Part-I: Orally disintegrating tablets

Metformin hydrochloride is an orally administered antihyperglycemic agent, used in the management of non-insulin- dependant (type-2) diabetes mellitus. Difficulty in swallowing (dysphagia) is common among all age groups, especially in elderly and pediatrics. Unfortunately, a high percentage of patients suffering from type-2 diabetes are elderly people showing dysphagia. In this study, orally disintegrating tablets were prepared using direct compression and wet granulation method. First, the tablets of metformin were prepared using starch RX1500 and microcrystalline cellulose by direct compression. The tablets showed erosion behavior rather than disintegration. Then lactose was incorporated which created pores to cause burst release of drug. But these tablets did not give good mouth feel. Thus, Pearlitol SD 200 (spray dried mannitol) was used to prepare tablets by wet granulation (10% polyvinylpyrrolidone in Isopropyl alcohol as binder). The optimized batches of tablets (LMCT3 and MP13) not only exhibited desired mouth feel but also disintegration time, in vitro dispersion time, water absorption ratio, and in vitro drug release. All the batches contained 15% starch 1500 and 4% of croscarmellose sodium. The optimized batches prepared by direct compression and wet granulation showed 85% drug release at 4 min and 8 min, respectively. The strong saline and slight bitter taste of the drug was masked using nonnutritive sweetener and flavor.

Effect of Nigella Sativa oil on various clinical and biochemical parameters of metabolic syndrome

Background: The seeds of Nigella sativa plant have been used to promote health and fight disease for centuries especially in the Middle East and Southeast Asia. This plant has been a great focus of research. This clinical study was undertaken to determine the adjuvant effect of Nigella sativa oil on various clinical and biochemical parameters of the metabolic syndrome. Methodology: This prospective study was conducted at a tertiary health care centre in North India. After final diagnosis and considering inclusion and exclusion criteria, sixty patients were enrolled in this study. Informed and written consent was taken from all the patients enrolled. Approval from institutional ethical committee was obtained. Patients were divided into two groups of thirty. In group I (standard group) patients were given tablet Atorvastatin 10 mg once a day and tablet Metformin 500 mg twice a day for a period of six weeks. In group II (Nigella sativa) group, patients were given tablet Atorvastatin 10 mg once a day, tablet Metformin 500 mg twice a day and Nigella sativa oil 2.5 ml twice daily for a period of six weeks. Blood sugar, both fasting and postprandial, fasting lipid profile, body mass index, body weight and waist circumference were recorded before and after completion of therapy. Result: The above mentioned methodology was followed and it was found that the difference in percentage improvement in group II was significant with reference to total cholesterol, low density lipoprotein (LDL) and fasting blood glucose (p<0.05). Conclusion: Nigella sativa oil is effective as an add-on therapy in patients with metabolic syndrome. Nigella sativa oil has a significant therapeutic activity in diabetic and dyslipidemic patients.

Effect of &lt;i&gt; Nigella sativa&lt;/i&gt; oil on various clinical and biochemical parameters of insulin resistance syndrome

AIM:The seeds of the Nigella sativa plant have been used to promote health and fight disease for centuries, especially in the Middle East and in Southeast Asia. This plant has been a focus of much research. This clinical study was undertaken to know the adjuvant effect of N. sativa oil on various clinical and biochemical parameters of the insulin resistance syndrome.MATERIALS AND METHODS:This prospective study was conducted at a tertiary health care center in North India. After confirmation of diagnosis, 60 patients who fulfilled the inclusion and exclusion criteria were enrolled in this study. Written informed consent was taken from all the patients enrolled. Approval from the institutional ethical committee was also obtained. The patients were divided into two groups of 30 each. In group I (the standard group), patients were advised tablet atorvastatin 10 mg once a day and tablet metformin 500 mg twice a day for a period of 6 weeks. In group II (the N. sativa group), the patients were advised tablet atorvastatin 10 mg once a day, tablet metformin 500 mg twice a day, and N. sativa oil 2.5 ml twice daily for a period of 6 weeks. Fasting and postprandial blood glucose, fasting lipid profile, and waist circumference were recorded before therapy and after completion of therapy.RESULT:The treatment group showed significant (P < 0.05) improvement with reference to total cholesterol, low density lipoprotein cholesterol (LDL-C), and fasting blood glucose (P < 0.05).CONCLUSION:N. sativa oil was found to be effective as an add-on therapy in patients of insulin resistance syndrome. N. sativa oil has a significant activity in diabetic and dyslipidemic patients.

Medication adherence and treatment success in the National Institute of Child Health and Human Development–Reproductive Medicine Network's Pregnancy in Polycystic Ovary Syndrome Trial

We investigated whether poor adherence with metformin tablets may have contributed to the poor success rates seen in the metformin-containing arms of the Pregnancy in Polycystic Ovary Syndrome (PPCOS) Trial. Median adherence for both metformin and clomiphene citrate tablets was within acceptable limits and unrelated to ovulation: thus, failure to comply with physician recommendations for metformin dosing was not the reason for low ovulation and pregnancy rates in the PPCOS Trial.

C-reactive protein levels are unaffected by metformin during pretreatment and an IVF cycle in women with polycystic ovary syndrome

Low-grade chronic inflammation, evaluated by serum C-reactive protein (CRP) levels, has been connected with the polycystic ovary syndrome (PCOS). Effects of metformin on CRP before and during IVF treatment in women with PCOS are unknown. A prospective double-blind placebo-controlled study. Single-center IVF clinic. Sixty-three PCOS women. Treatment with 2000 mg/day metformin or identical placebo tablets for at least 14 weeks before and then during IVF treatment, ending on the day of hCG injection. The CRP levels at five time points ending on the day of ovum collection. At inclusion of infertile untreated PCOS women, body mass index associated with CRP in multivariable regression analysis (r = 0.18). Androgen levels did not associate with CRP levels. Metformin did not influence CRP levels during pretreatment or IVF cycle. After hCG injection, CRP increased in both the metformin and the placebo groups with no significant difference between the groups. In infertile PCOS women, CRP levels are unaffected by metformin treatment. The CRP level increases during IVF treatment, and this increase is unaffected by concomitant metformin. We observed an association between CRP levels and body mass index.

Oral Antidiabetic Drugs: Bioavailability Assessment of Fixed‐Dose Combination Tablets of Pioglitazone and Metformin. Effect of Body Weight, Gender, and Race on Systemic Exposures of Each Drug

Bioavailability of pioglitazone and metformin, in 2 dose strengths, given either as a fixed-dose combination tablet or as coadministration of commercial tablets (coad), was studied in young healthy subjects in 2 separate studies. In study I (n = 63), single oral doses of 15-mg pioglitazone/500-mg metformin fixed-dose combination tablets or equivalent doses of commercial tablets were administered, in a fasting state, in an open-label, randomized, crossover study with a 7-day washout period between treatments. Study II (n = 61) was similar in design to study I, except the 15/850-mg fixed-dose combination tablet and coad treatments were evaluated. Least squares mean (fixed-dose combination/coad) ratios and 90% confidence intervals of the ratios for the 15/500-mg dose strength for the maximum observed serum concentration (Cmax) and area under the serum concentration-time curve from time 0 to infinity (AUC(infinity)) were 0.95 (0.86-1.05) and 1.02 (0.98-1.08), respectively, for pioglitazone and 0.99 (0.95-1.03) and 1.03 (0.98-1.08), respectively, for metformin. Bioequivalency for pioglitazone and metformin between fixed-dose combination tablets and coad treatments was met for both strengths of fixed-dose combination tablets. In a post hoc meta-analysis of combined data from the 2 studies (n = 124), there was considerable overlapping in AUC(infinity) values between gender and race (Caucasians, Blacks, and Hispanics), making neither gender- nor racial-based dosing of pioglitazone or metformin necessary.

The use of metformin for women with PCOS undergoing IVF treatment

Metformin appears to improve reproductive function in some women with polycystic ovary syndrome (PCOS). We wished to explore the effect of metformin in women with PCOS undergoing IVF. A randomized, placebo-controlled, double-blind study was carried out between 2001 and 2004. Patients with PCOS undergoing IVF/ICSI treatment using a long GnRH agonist protocol were randomized to receive metformin (MET), 850 mg, or placebo (PLA) tablets twice daily from the start of the down-regulation process until the day of oocyte collection. The primary outcome was to be an improvement in the overall fertilization rate. One-hundred and one IVF/ICSI cycles were randomized to receive metformin (52) or to receive placebo (49). There was no difference in the total dose of rFSH required per cycle (median dose: MET = 1200 U, PLA = 1300 U; P = 0.937). The median number of oocytes retrieved per cycle (MET = 17.2, PLA = 16.2; P = 0.459) and the overall fertilization rates (MET = 52.9%, PLA = 54.9%; P = 0.641) did not differ. However, both the clinical pregnancy rates beyond 12 weeks gestation per cycle (MET = 38.5%, PLA = 16.3%; P = 0.023) and per embryo transfer (MET = 44.4%, PLA = 19.1%; P = 0.022) were significantly higher in those treated with metformin. Furthermore, a significant decrease in the incidence of severe ovarian hyperstimulation syndrome (OHSS) was observed (MET = 3.8%, PLA = 20.4%; P = 0.023), and this was still significant after adjustment for BMI, total rFSH dose and age (OR = 0.15; 95% CI: 0.03, 0.76; P = 0.022). Short-term co-treatment with metformin for patients with PCOS undergoing IVF/ICSI cycles does not improve the response to stimulation but significantly improves the pregnancy outcome and reduces the risk of OHSS.

In Vitro and In Vivo Evaluation of Two Extended Release Preparations of Combination Metformin and Glipizide

A system that can deliver multi-drugs at a prolonged rate is very important to the treatment of various chronic diseases such as diabetes, asthma, and heart disease. Two controlled-release systems, which exhibited similar release profiles of metformin and glipizide, i.e., elementary osmotic pump tablets (EOP) and bilayer hydrophilic matrix tablet (BT), were designed. The effects of pH and hydrodynamic conditions on drug release from two formulations were investigated. It was found that both drug releases from EOP were not sensitive to dissolution media pH and hydrodynamics change, while the release of glipizide from BT was influenced by the stirring rate. Moreover, in vivo evaluation was performed, relative to the equivalent dose of conventional metformin tablet and glipizide tablet, by a three-crossover study in six Beagle dogs. Cumulative percent input in vivo was compared to in vitro release profiles. The linear correlations of metformin and glipizide between fraction absorbed in vivo and fraction dissolved in vitro were established for EOP—a true zero-order release formula, whereas only nonlinear correlations were obtained for BT. In conclusion, drug release from EOP was both independent of in vitro and in vivo conditions, where the best sustained release effect was achieved, whereas the in vitro dissolution test employed for BT needed to be further optimized to be biorelevant.

Avandamet: combined metformin-rosiglitazone treatment for insulin resistance in type 2 diabetes

Insulin resistance is a major endocrinopathy underlying the development of hyperglycaemia and cardiovascular disease in type 2 diabetes. Metformin (a biguanide) and rosiglitazone (a thiazolidinedione) counter insulin resistance, acting by different cellular mechanisms. The two agents can be used in combination to achieve additive glucose-lowering efficacy in the treatment of type 2 diabetes, without stimulating insulin secretion and without causing hypoglycaemia. Both agents also reduce a range of atherothrombotic factors and markers, indicating a lower cardiovascular risk. Early intervention with metformin is already known to reduce myocardial infarction and increase survival in overweight type 2 patients. Recently, a single-tablet combination of metformin and rosiglitazone, Avandamet, has become available. Avandamet is suitable for type 2 diabetic patients who are inadequately controlled by monotherapy with metformin or rosiglitazone. Patients already receiving separate tablets of metformin and rosiglitazone may switch to the single-tablet combination for convenience. Also, early introduction of the combination before maximal titration of one agent can reduce side effects. Use of Avandamet requires attention to the precautions for both metformin and rosiglitazone, especially renal, cardiac and hepatic competence. In summary, Avandamet is a single-tablet metformin-rosiglitazone combination that doubly targets insulin resistance as therapy for hyperglycaemia and vascular risk in type 2 diabetes.

Gastrointestinal tolerability of extended-release metformin tablets compared to immediate-release metformin tablets: results of a retrospective cohort study

SUMMARYObjective: Metformin, a biguanide antihyperglycemic medication, lowers blood glucose in patients with type 2 diabetes with minimal risk of hypoglycemia. Most common side effects include diarrhea, nausea and vomiting. Extended-release metformin (Glucophage XR)*, a once-daily tablet using the patented GelShield Diffusion System release mechanism, may be better tolerated than immediate-release metformin (Glucophage). This retrospective chart review examined the overall gastrointestinal (GI) tolerability of both formulations.Research design and methods: Patient charts were reviewed and data were collected from October 2001 to May 2002. Adult patients with type 2 diabetes started on extended-release metformin (metformin-XR) or switched from immediate-release metformin to metformin-XR within the previous 2 years were eligible for inclusion in the metformin-XR cohort. Patients started on immediate-release metformin within the previous 2 years were eligible for inclusion in the immediate-release metformin cohort. Previous experience of GI side effects while taking immediate-release metformin did not prevent inclusion in either cohort, though patients with significant underlying GI disease or moderate to severe hepatic or renal impairment were excluded. GI tolerability was assessed during the first year of treatment with immediate-release metformin or metformin-XR. Primary endpoints were overall GI tolerability and frequency of diarrhea during the first year of treatment.Results: A total of 471 patients’ charts were reviewed and data were collected from four diabetes clinics; 310 (metformin-XR) and 158 (immediate-release metformin) eligible patients were included. Patients were, on average, 56 years old, and overweight (mean body mass index 33 kg/m2). The majority of patients were Caucasian (50%), Hispanic (24%) or Black (19%). Mean daily doses were 1258 mg (range 500–2500 mg) for metformin-XR and 1282 mg (range 500–2550 mg) for immediate-release metformin. About 25% of the metformin-XR cohort had been switched from immediate-release metformin due to a history of GI adverse events (AE). Despite this, the frequency of any GI AE was similar between metformin-XR and immediate-release metformin (11.94 vs. 11.39%, p = 0.86). The incidence of individual GI AE also did not differ significantly between cohorts. In a cohort of 205 patients started on immediate-release metformin and switched to metformin-XR, the frequency of any GI AE was 26.34% (while taking immediate-release metformin; n = 205) vs. 11.71% (after switching to metformin-XR; n = 205) ( p = 0.0006) and the frequency of diarrhea was 18.05% (while taking immediate-release metformin) vs. 8.29% (after switching to metformin-XR) ( p = 0.0084).Conclusions: In this retrospective chart review, patients switched from immediate-release metformin to metformin-XR experienced fewer GI side effects on comparable doses of the extended-release metformin.

Tolerability Profile of Metformin/Glibenclamide Combination Tablets (Glucovance??)

It is important to manage blood glucose intensively in patients with type 2 diabetes mellitus in order to reduce the risk of long-term complications. Oral combination therapy that addresses insulin resistance and beta-cell dysfunction is a proven means of improving glycaemic control when monotherapy becomes insufficiently effective. Metformin/glibenclamide (glyburide) combination tablets were developed to provide a means of applying this strategy while minimising polypharmacy. This review examines the tolerability profile of this treatment from four double-blind, randomised clinical trials in a total of 2342 type 2 diabetic patients with hyperglycaemia despite treatment with diet and exercise, a sulphonylurea or metformin. Treatment with combination tablets was associated with markedly superior blood glucose control, at lower doses of metformin and glibenclamide, compared with monotherapies. The incidence of symptoms of hypoglycaemia varied between dosages and trials, though the incidence of severe or biochemically confirmed hypoglycaemia or withdrawals from clinical trials for this reason was consistently low and comparable with glibenclamide alone. No patient required third-party assistance for hypoglycaemia. Significantly fewer diet-failed patients receiving low-dose combination tablets reported gastrointestinal adverse effects compared with metformin alone, with a comparable incidence between metformin and combination tablets in post-monotherapy studies. The incidence of other adverse events, including serious adverse events, was similar for combination tablets and monotherapies. The lower doses of metformin and glibenclamide with the combination tablet approach, and the design of the combination tablets themselves, may underlie the beneficial tolerability profile of this treatment.

굴루코파지 정(염산메트폴민 500 mg)에 대한 그리코민 정의 생물학적 동등성

Metformin is an oral antihyperglycemic agent used in the therapy of noninsulin-dependent diabetes mellitus and does not cause hypoglycemia at the therapeutic dose. Its mechanism of action may involve an increased binding of insulin to its receptors and glucose uptake at the post-receptor level. The purpose of the present study was to evaluate the bioequivalence of two metformin tablets, Glucophage (Daewoong Pharmaceutical Co., Ltd.) and Glycomin (Ilsung Pharmaceuticals Co., Ltd.), according to the guidelines of Korea Food and Drug Administration (KFDA). The metformin release from the two metformin tablets in vitro was tested using KP VII Apparatus II method with various dissolution media (pH 1.2, 4.0, 6.8 buffer solution and water). Twenty four normal male volunteers, years in age and in body weight, were divided into two groups with a randomized cross-over study. After one tablet containing 500 mg as metformin was orally administered, blood was taken at predetermined time intervals and the concentrations of metformin in serum were determined using HPLC with UV detector. Besides, the dissolution profiles of two metformin tablets were very similar at 떠1 dissolution media. The pharmacokinetic parameters such as were calculated. The ANOVA test was performed for the statistical analysis of the logarithmically transformed , untransformed . The results showed that the differences in between two tablets based on the Glucophage were 0.09%, 6.09% and -8.22%, respectively. There were no sequence effects between two tablets in these parameters. The 90% confidence intervals using logarithmically transformed data were within the acceptance range of log(0.8) to log(1.25) , indicating that Glycomin tablet is bioequivalent to Glucophage tablet.

Lipid effects of glyburide/metformin tablets in patients with type 2 diabetes mellitus with poor glycemic control and dyslipidemia in an open-label extension study

Background: Because both type 2 diabetes and elevated plasma lipid levels are important independent risk factors for cardiovascular disease and coronary heart disease, the choice of an antihyperglycemic agent for patients with type 2 diabetes—in whom abnormal plasma lipid levels are often seen—should take into account effects on lipids as well as on markers of glycemic control. Objective: This study assessed the effects on lipid levels of glyburide/metformin tablets in the treatment of type 2 diabetes, particularly in a group of patients who had poor glycemic control and dyslipidemia at baseline. Methods: This 52-week, open-label study was an extension of a 32-week, double-blind, placebo-controlled study. The patient population was drawn from 3 groups: those who completed the double-blind study, those who were discontinued from the double-blind study, and those who were ineligible for the double-blind study based on predefined measures of glycemic control (screening fasting plasma glucose >240 mg/dL and glycosylated hemoglobin [HbA 1c] ≤12%, or HbA 1c 11%–12%) and were directly enrolled in the open-label extension study. Patients with an HbA 1c of <9% received glyburide/ metformin tablets 1.25 mg/250 mg BID; those with an HbA 1c ≥9% received glyburide/ metformin tablets 2.5 mg/500 mg BID. Changes in total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG) levels were assessed for 52 weeks. Results: The study population included 828 patients: 515 who completed the double-blind study, 138 who were discontinued from the double-blind study, and 175 who were enrolled directly. Direct enrollees had poor glycemic control and dyslipidemia at baseline. Improvements in plasma lipid levels were seen as early as week 13. At week 52, the mean change in TC from baseline was −8.0 mg/dL for the total population (95% CI, −10.9 to −5.2; P < 0.05) and −23.2 mg/dL for direct enrollees (95% CI, −30.1 to −16.4; P < 0.05). The mean decrease in LDL-C from baseline for the total population was 2.86 mg/dL (95% CI, −5.3 to −0.4; P < 0.05), compared with a reduction of 13.3 mg/dL for direct enrollees (95% CI, −18.5 to −8.1; P < 0.05). Mean HDL-C levels were minimally affected. Mean TG levels decreased by 27.8 mg/dL for the entire population (95% CI, −42.9 to −12.8; P < 0.05) and by 99.7 mg/dL for direct enrollees (95% CI, −152.5 to −46.8; P < 0.05). Conclusion: In this open-label extension study, treatment with glyburide/metformin tablets for type 2 diabetes had a durable, favorable effect on lipid levels, particularly in those with poor glycemic control and dyslipidemia at baseline.

HIGH ANION GAP METABOLIC ACIDOSIS IN SUICIDE: DON'T FORGET METFORMIN INTOXICATION—TWO PATIENTS' EXPERIENCES

Lactic acidosis is a well-recognized side effect of metformin, especially in patients with renal failure. Only a few cases of deliberate self-poisoning with metformin have been described in the literature. We report two patients who took a large dose of metformin in an attempt to harm themselves and both of them presented with severe lactic acidosis. The first patient was admitted because of taking large amounts of her father's unknown drug for suicide. Arterial blood gas showed severe metabolic acidosis with high anion gap and blood lactate level which metformin intoxication was documented. She died of multiple organ failure although we provided aggressive management including continuous renal replacement therapy. The second case, a type 2 diabetic patient, was sent to the emergency department after taking 110 tablets of metformin (500 mg). Arterial blood gas showed severe metabolic acidosis with high anion gap and blood lactate level. Hypotension and consciousness disturbance occurred later. After one session of hemodialysis, she recovered completely. In our experiences, metformin intoxication should be suspected when patients presented by wide anion gap metabolic acidosis after suicide attempt by taking drugs. Hemodialysis or continuous renal replacement should be initiated as soon as possible in addition to other supportive care.

Review: Optimal dosing strategies for maximising the clinical response to metformin in type 2 diabetes

Recently revised consensus targets for glycaemic management in patients with type 2 diabetes are challenging and require optimisation of dosing strategies for oral antidiabetic therapies. The demonstration of significant cardiovascular outcome benefits in metformin-treated type 2 diabetic patients enrolled in the United Kingdom Prospective Diabetes Study has established this agent as the first line oral therapy after diet failure in newly presenting overweight people with type 2 diabetes mellitus. The antihyperglycaemic efficacy of metformin increases with increasing daily doses between 500 mg and the upper limits of the recommended daily dosage ( ≥ 2000 mg/day). Although metformin is associated with gastrointestinal side-effects in up to 20% of patients, this is not generally dose related. Transient dose reduction, slower titration and taking the dose with meals may ameliorate the problem. Risk of lactic acidosis due to metformin is negligible when this agent is prescribed correctly, and is unrelated to the plasma metformin concentration. Intensification of metformin therapy within the dose range represents a rational and practical therapeutic strategy for optimising glycaemic control in patients who are suitable for, and tolerant of, metformin treatment. The recently introduced 1000 mg metformin tablet should facilitate the use of higher doses and may help treatment compliance.