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The circadian rhythms of preprandial and postprandial blood glucose, free fatty acids, and insulin levels were measured in groups of normal and of diabetic patients controlled by diet alone or by diet with tolbutamide, chlorpropamide, or metformin. All groups showed a greater insulin release after the first meal of the day than after subsequent meals. Diabetic patients controlled for more than two years on diguanide therapy showed the closest resemblance to non-diabetic control subjects. There was no significant difference between the values for diabetic patients on long-term control with diet alone and those on short- or long-acting sulphonylurea. The circadian rhythms disappeared in obese subjects on total starvation.

The efficacy of a delayed release preparation of metformin (‘Obin’)† has been evaluated in 60 diabetic patients either obese and uncontrolled by diet alone or true primary or secondary failures to sulphonylurea treatment. The results show no difference in the therapeutic response between single and twice daily administration of ‘Obin’; likewise there was no difference in frequency of side-effects.

Effect of some antidiabetics on the blood sugar curve after intravenous injection of glucose was investigated with the rabbits pre-treated with priscoline. Since an action of priscoline was found to make the curve type exponential, configuration of glucose tolerance curve could be determined by two constants, e-k and C in a formula yt=ae-kt+C (y, blood sugar level; t, time; a, initial blood sugar).Influences of antidiabetics, insulin, tolbutamide (N-toluyl-sulfonyl-N'-butylurea), metformin (Dimethylbiguanide) and sodium mesoxalate injected intravenously, were as follows:(1)Examinations after single administrationa) After administration of 0.05u./kg of regular insulin, e-k and C became both smaller than those for control. They were influenced in the similar way by subcutaneous injection of 0.1u./kg. b) After injection of 100mg/kg of tolbutamide, C value decreased significantly without change in e-k value. c) 50mg/kg of metformin gave an increasing effect on both of the two constants.(2) Examinations after repeated administrationsAfter the administrations of 100mg/kg of sodium mesoxalate during 5 or 10 days, e-k became smaller but Clarger.(3) There were not any changes in e-k and I values at ter single administration of 100mg/kg of the mesoxalate, or after the repeated administrations of 0.05u./kg of insulin, 100mg/kg of tolbutamide or 31mg/kg of the mesoxalate.Mechanism of these actions was briefly referred to, and a possibility was discussed to apply this glucose tolerance test to the pharmacological screening method for antidiabetics.

The effects of phenformin plus ethylœstrenol and metformin plus ethylœstrenol on serum-cholesterol, platelet stickiness, and fibrinolysis were compared in ten arteriopathic patients in a trial lasting 15 months. Blood fibrinolytic activity was increased by about 50% by both combinations of drugs. Platelet stickiness and serum-cholesterol levels were reduced by the phenformin combination but were increased by the metformin combination. Reduction of platelet stickiness by phenformin plus ethylœstrenol has been maintained in patients of an earlier series who have been followed for 14-24 months. Contrasted with clofibrate and with metformin plus ethylœstrenol, phenformin plus ethylœstrenol has favourable and sustained effects on four factors associated with occlusive vascular disease—fibrinolysis, plasma-fibrinogen, platelet stickiness, and serum-cholesterol—and thus seems suitable for trial as a prophylactic agent in survivors of vascular occlusions.

The present study was investigated the comparative efficacy of extract of Neem (Azadirachta indica) and Metformin hydrochloride (Comet®) in respect of their hypoglycemic activity in Streptozotocin (STZ)-induced diabetic rats. Extract of Neem was administered @ 500 mg/kg body-weight (bwt) and 250 mg/kg bwt. Metformin hydrochloride @ 500 mg/kg bwt and 250 mg/kg daily orally for 21 days. Changes in the blood glucose level and body weight were measured and the results were compared statistically using Anova test. The extract of Neem leaves and Metformin hydrochloride showed significant (p

In an investigation lasting 33 months, the fibrinolytic effects of clofibrate plus androsterone (' Atromid '), phenformin, metformin, and combinations of each diguanide with the anabolic steroid, ethylœstrenol, were compared in two groups of patients with occlusive vascular disease. Atromid was relatively unsatisfactory as a fibrinolytic drug; phenformin and metformin increased fibrinolytic activity, but partial resistance developed to the fibrinolytic effect of both. The addition of ethylœstrenol overcame this resistance; metformin plus ethylœstrenol and phenformin plus ethylœstrenol given twice a day for 12 months produced a sustained increase of fibrinolytic activity in 80% and 89% of the patients treated. When the diguanides were withdrawn, ethylœstrenol alone failed to maintain the full fibrinolytic effect of combined treatment, but this was restored when metformin and phenformin were restituted. Both combinations of drugs reduced plasma-fibrinogen; serum-cholesterol was reduced by phenformin but not by metformin. The findings suggest that phenformin plus ethylœstrenol is suitable for trial as a prophylactic measure in patients with occlusive vascular disease.

An in vivo study has been conducted to observe the effects of caffeine on the hypoglycemic activity of gliclazide and metformin HCI in rats. For this, healthy rats weighing about 250±25 g were used and the blood sugar levels were measured after administration of a drug alone and in combination. Diabetes was induced in rats by administration of alloxan at a dose of 40 mg/kg body weight. Drugs were administered in rats and were observed for four weeks. The blood sugar levels were estimated in two stages; firstly, after two week and secondly, after four week of administration of drug. It was found that the hypoglycemic activities of both gliclazide and metformin HCl were potentiated by concurrent application of caffeine and either of the drugs, but the extent of potentiation was more in case of metformin HCI as evident from the blood sugar level of rats. Key words: Caffeine; Gliclazide; Metformin; Diabetes; Alloxan; Blood sugar; Rats. DOI: 10.3329/dujps.v8i1.5335 Dhaka Univ. J. Pharm. Sci. 8(1): 47-51, 2009 (June)

Based on the clinical observation that biguanide treatment of obese patients may alter insulin levels, the influence of metformin and phenformin on basal and glucose stimulated insulin secretion, as well as on insulin biosynthesis, was studied in isolated islets of rats. — Biguanide concentrations of 100 μg/ml, or higher, significantly reduced glucose stimulated insulin secretion. Both dose dependence and a difference in the intrinsic activities of metformin and phenformin were demonstrated. Incubating the same islets for a second period without biguanides, glucose stimulated insulin secretion was still decreased. Addition of glibenclamide during this second period increased insulin secretion, but did not overcome complete inhibition achieved after incubation at very high biguanide concentrations. Glucose stimulated biosynthesis of proinsulin and insulin was decreased in the presence of biguanides and completely suppressed at very high concentrations. Inhibition of cell respiration in the islet cells effected by high biguanide doses may be the reason for the inhibition of secretion and biosynthesis of insulin. — On the other hand, an insulin release was found at the highest phenformin concentration of 10 mg/ ml and during perfusion of the isolated rat pancreas with higher biguanide doses. — Biguanide concentrations found to be effective in this study are very high compared with therapeutic levels. Moreover, biguanide actions are known to be highly dependent on species, concentration and metabolic situation. — Definite conclusions from these findings regarding clinical significance, therefore, seem unwarranted.

Le coefficient d'assimilation du glucose (kG), les taux seriques d'insuline immunoreactive (IRI) et l'hormone de croissance (GH) ont ete determines a l'occasion d'une charge de glucose par voie intra-veineuse chez 16 malades obeses avant traitement, apres traitement oral d'une semaine au dimethylbiguanide et apres traitement de 10 semaines. -Les malades ont ete groupes selon leurs valeurs kG initiales: groupe 1: 7 malades, kG > 1.3. -groupe 2: 7 malades, kG < 1.3. -groupe 3: 2 malades avec diabete etabli. -Dans le groupe 1, les valeurs kG moyennes n'ont montre aucun changement significatif a la suite du traitement au biguanide, tandis que l'hyperinsulinemie initiale etait reduite de moitie au

Diabetes mellitus is one of the most common medical complications of pregnancy; gestational diabetes mellitus (GDM) accounts for approximately 90-95% of all cases. The incidence of gestational diabetes is increasing. It has been demonstrated that good metabolic control maintained throughout pregnancy can reduce maternal and fetal complications in diabetes Traditionally, insulin therapy has been considered the gold standard for management There has been a traditional reluctance to recommend oral antidiabetic drugs for the management of hyperglycaemia in gestational diabetes mellitus. The medical management of gestational diabetes is still evolving, and recent randomized controlled trials have given a glimse of hope for woman who likes to avoid insulin and prefer oral agents. The current short acting insulin analogs lispro and aspart are safe, but there are only limited data to support the use of long acting insulin analogs. There are randomized controlled trials which have demonstrated efficacy of the oral agents glyburide and metformin. Whilst shortterm data have not demonstrated adverse effects of glyburide and metformin on the fetus, and they are increasingly being used in pregnancy, there remain long-term concerns regarding their potential for harm. This controversy related article gives an overview of the rationale for use of oral antidiabetic agents in the treatment of gestational diabetes. DOI: 10.3329/jdmc.v17i2.6596J Dhaka Med Coll. 2008; 17(2) : 127-130

Bei 21 Patienten wurden vor und 10 Tage nach Biguanidtherapie die Vitamin B12- und Xyloseausscheidung im Urin, sowie die Blutlipide bestimmt. Bei 7 Patienten wurden zusatzlich eine Fettbilanzstudie und ein Fettbelastungstest vor und wahrend Biguanidtherapie durchgefuhrt. Bei 5 Patienten wurde der Schillingtest 2–3 Monate nach Beginn der Biguanidtherapie erneut bestimmt, bei 2 Patienten zur gleichen Zeit nach Absetzen der initialen Therapie. Die Resultate sind folgende: Vitamin B12- und Xyloseabsorption sind wahrend der Biguanidtherapie pathologisch erniedrigt, der Schillingtest kann sich nach der Langzeittherapie normalisieren. Die Blutlipide und das Korpergewicht fallen nach 10-tagiger Therapie ab. Die Resultate lassen auch eine Fettabsorptionsstorung vermuten. Die Ergebnisse berechtigen zur Annahme, das die Blutzuckersenkung nach Biguanidtherapie z.T. ebenfalls die Folge einer Absorptionsstorung ist und sprechen dafur, das das Konzept uber die Wirkungsweise der Biguanide von Sadow, welches in der Einleitung besprochen wird, in diesem Sinne erweitert werden mus. Die sich fur die Klinik ergebenden Konsequenzen dieser biguanidbedingten Absorptionsstorung, insbesondere auch von Vitamin B12 werden diskutiert.

After a brief outline of the factors regulating plasma lactate levels in normal and diabetic subjects, the AA. summarize the history, the possible mechanism of action and the therapeutic applications of the guanidine derivatives. The possibility that these drugs may increase the danger of lactic acidosis is discussed.

Polycystic ovarian syndrome (PCOS) is classically characterized by the clinical triad of androgen excess, anovulation infertility and obesity. Anovulation occurs due to functional ovarian and/or adrenal hyperandrogenism. The etiology and patho physiology of PCOS is unknown .Proposed theories include excess of gonadotropins; the effect of which is amplified by disturbances in intrinsic regulatory peptides, such as inhibin or extrinsic regulatory peptides, such as insulin or insulin like growth factor ( IGF). For over 25 years insulin resistance has been known to be associated with PCOS. Improvement in insulin resistance with the use of insulin sensitizers, such as metformin and thiazoldinediones (TZDs) have been seen to be associated with better ovulation and reduced testosterone levels in patients with PCOS. Aims: The aim of the present review is to discuss the new concepts in the pathogenesis of PCOS and to know usefulness of insulin sensitizers in such patients. Methods: Over 50 articles extending the span of more than 25 years have been reviewed and an attempt has been made to know the etiopathogenesis of PCOS and also to assess the validity for the uses of insulin sensitizers in patients of PCOS. Results: With the advancement of knowledge regarding etiopathogenesis, the management of PCOS has changed in recent years. In view of positive association between hyperinsulinemia and PCOS, improvement in insulin resistance through weight loss and use of insulin sensitizing drugs has been recommended. Conclusions: Besides symptomatic treatment, recent studies recommend use of insulin sensitizers in management in PCOS for better outcome in them. Key words: Polycystic ovarian syndrome (PCOS), Insulin resistance (IR) Insulin sensitizers (IS).doi:10.3126/njog.v3i1.1431 NJOG 2008 May-June; 3(1): 3 - 9

A double-blind trial was undertaken to compare the efficacy of fenfluramine and metformin in promoting weight reduction in thirty-four obese women. Metformin proved to be less effective than fenfluramine and a total daily dose of 3·0 g. produced unacceptable side-effects. The effect of fenfluramine in a total daily dose of 80 mg. was still evident up to 32 weeks on a reducing regimen, and was free of serious side-effects. A further double-blind trial was conducted on eighteen of these obese women after 48 weeks of continuous dietary treatment, to study the effect of fenfluramine in a total daily dosage of 160 mg. and its suitability for long-term maintenance treatment. Fenfluramine in this dosage was found to be effective and safe.

1. A method is described for measuring glucose uptake by pieces of human skeletal muscle removed at surgery. 2. Glucose uptake by this preparation was stimulated by insulin (0.1–10 munits/ml) and inhibited by 2.27 mM-sodium n-butyrate in the presence of insulin (0.1 munit/ml). 3. The antidiabetic drug metformin (60.4 μM) had no effect on glucose uptake in the absence or presence of insulin (0.1 munit/ml), but stimulated uptake in the presence of 2.27 mM-sodium n-butyrate together with insulin (0.1 munit/ml). 4. It is concluded that the metabolic control of glucose uptake in human skeletal muscle is similar to that in rat heart and diaphragm, and that the preparation provides a useful model for biochemical and pharmacological investigations of glucose metabolism in skeletal muscle.

DOI: http://dx.doi.org/10.3126/njog.v5i1.5056 NJOG 2010 Jul-Aug; 5(1): 21-25

In contrast to its effect in animal experiments, biguanide is shown to have no effect on gastric emptying in man. Gastric emptying was assessed by the double sampling test meal 2 h after placebo or 1

24 Std nach oraler Gabe von 100 mg/kg Metformin-14C an Mause lassen sich durchschnittlich 77.2% der applizierten Aktivitat im Urin und 8.4% im Kot nachweisen. Die Ratte eliminiert unter denselben Versuchsbedingungen 66.8% der Dosis mit dem Harn und 18.4% mit dem Kot. In der Galle findet sich weniger als 1% der applizierten Radioaktivitat. Im Urin von Ratten und Mausen tritt als einzige radioaktive Substanz unverandertes Metformin auf. Die vergleichende Untersuchung der Organverteilung von Buformin-14C und Metformin-14C ergibt fur beide Biguanide ein ahnliches Bild. Die hochsten Biguanidkonzentrationen finden sich in Niere, Nebenniere, Pankreas und Leber. Die Serumkonzentrationen betragen nach oraler Gabe von 50 mg/kg Buformin-14C durchschnittlich 1.2 μg/ml und nach 150 mg/kg Metformin-14C 6.2 μg/ml. Gesunde Probanden eliminieren innerhalb von 36 Std durchschnittlich 63% der applizierten Dosis mit dem Harn. Metformin wird auch beim Menschen nicht metabolisiert. Aus der Ausschei-dungsgeschwindigkeit mit dem Urin ergibt sich eine biologische Halbwertzeit des Biguanids von 2.8 Std. Die beim Tier und beim Diabetiker im Vergleich zu anderen Biguaniden schwachere blutzuckersenkende Wirkung von Metformin kann nicht mit einer geringeren Resorption erklart werden. Sie ist auf eine geringere intrinsische Aktivitat dieses Biguanids zuruckzufuhren.

An investigation into B(12) absorption in diabetic patients on long-term phenformin therapy was undertaken and the results were compared to a similar investigation previously reported in diabetics on long-term metformin. Forty-six per cent of patients were found to have B(12) malabsorption as shown by abnormal results of Schilling tests.The mechanism of B(12) malabsorption is unknown but it is suggested that all patients on long-term phenformin therapy should, like the patients on metformin, have annual serum B(12) estimations until the results of a longer follow-up series are known.

The incidence of gestational diabetes is increasing. There has been a traditional reluctance to recommend oral antidiabetic drugs for the management of hyperglycaemia in gestational diabetes mellitus The medical management of gestational diabetes is still evolving, and recent randomized controlled trials have given a glimse of hope for woman who likes to avoid insulin and prefer oral agents.. As insulin therapy is considered the gold standard of pharmacotherapy for gestational diabetes, it becomes a usual recommendation to use it in pregnanacy. The current short acting insulin analogs lispro and aspart are safe, but there are only limited data to support the use of long acting insulin analogs. There are randomized controlled trials which have demonstrated efficacy of the oral agents glyburide and metformin. Whilst short-term data have not demonstrated adverse effects of glyburide and metformin on the fetus, and they are increasingly being used in pregnancy, there remain long-term concerns regarding their potential for harm. This controversy related article gives an overview of the rationale for use of oral antidiabetic agents in the treatment of gestational diabetes. DOI: 10.3329/jbcps.v28i2.5376 J Bangladesh Coll Phys Surg 2010; 28: 129-131

Summary Non-toxic concentrations of phenformin or metformin depress the 14 CO 2 production from palmitic-U- 14 C acid, but not from glucose-U- 14 C, by rat diaphragm homogenate. Moreover, the inhibition of glucose-U- 14 C oxidation by unlabelled palmitic acid is partly removed by biguanides. These data demonstrate that biguanides produce their effects on glucose metabolism through depression of fatty acid oxidation.

Lactic acidosis is a rare but serious complication of the use of biguanides in anti-diabetic therapy. This report details two cases of diabetic lactic acidosis secondary to Metformin, successfully treated by peritoneal dialysis, using sodium acetate as the dialyzing substance. The author emphasizes the use of extra-renal purification, and more specifically peritoneal dialysis, as symptomatic therapy of lactic acidosis in the diabetic patient. Acetate, rather than lactate, as the dialyzing substance, is most justified from a biochemical point of view.

Summary The effect of three sulphonamide derivatives, tolbutamide, acetohexamide and glycodiazine and two of the biguanide derivatives, phenformin and metformin on hepatic glycogenolysis was investigated in the rat. The in vitro studies in both normal and alloxan-diabetic rats reveal that tolbutamide, acetohexamide and glycodiazine inhibited hepatic glucose-6-phosphatase enzyme activity while phenformin and metformin produced no effect. Hepatic phosphorylase enzyme activity was inhibited by tolbutamide and glycodiazine, while acetohexamide, phenformin and metformin failed to produce any effect. The in vivo studies showed that an acute dose of any of the sulphonamide derivatives studied did not affect the two enzyme activities in both normal and alloxan-diabetic rats. However, the two biguanides, phenformin and metformin although not affecting the enzyme activities in normal animals, they produced significant decrease in glucose-6-phosphatase enzyme activity in livers of diabetic rats. The conclusion is reached that sulphonamide derivatives affect the glycogenolytic enzymes directly only in vitro , while a single, moderately big, hypoglycaemic dose produced no effect in vivo . On the other hand, the two biguanides affect glucose-6-phosphatase enzyme activity in diabetic rats by increasing glucose utilization, an effect not related to insulin.