Simultaneous determination of pioglitazone and candesartan in human plasma by LC-MS/MS and its application to a human pharmacokinetic study

A simple and rapid liquid chromatography-tandem mass spectrometric(LC-MS/MS) assay method has been developed and fully validated for simultaneous quantification of pioglitazone and candesartan in human plasma.Irbesartan was used as an internal standard.The analytes were extracted from human plasma samples by solid-phase extraction technique using a Strata-X 33 mm polymeric sorbent.The reconstituted samples were chromatographed on a C18 column by using a 80:20(v/v) mixture of acetonitrile and 0.1% formic acid as the mobile phase at a flow rate of 0.8 mL/min.The calibration curves obtained were linear(rZ0.99) over the concentration range of 15-3000 ng/mL for pioglitazone and 5-608 ng/mL for candesartan.The results of the intra-and inter-day precision and accuracy studies were well within the acceptable limits.A run time of 2.7 min for each sample made it possible to analyze more than 300 plasma samples per day.The proposed method was found to be applicable to clinical studies.

Research on the protection effect of pioglitazone for non-alcoholic fatty liver disease (NAFLD)in rats

Objective： The prevalence of non-alcoholic fatty liver disease （NAFLD） has markedly increased. Insulin resistance has been implicated in the pathogenesis of NAFLD. This study was aimed at observing the relationship between insulin resistance and NAFLD, and evaluating the role of pioglitazone （PGZ） acting as insulin-sensitizing agents in the prevention and treatment of rat fatty liver induced by high fat feeding. Methods： The rats were separated randomly into 6 groups： model group Ⅰ were fed high fat diet for 8 weeks, PGZ prevention group were given PGZ 4 mg/（kg.d） simultaneously, while control group Ⅰ were fed normal food for 8 weeks; model group Ⅱ were fed high fat diet for 16 weeks, PGZ treatment group were given PGZ 4 mg/（kg.d） orally simultaneous with high fat diet for 8 weeks after high fat feeding for 8 weeks, control group Ⅱ were fed normal food for 16 weeks. The rats were sacrificed after 8 weeks and 16 weeks respectively. Liver weight, body weight, serum activities of alanine aminotransferase （ALT）, aspartate aminotransferase （AST）, alkaline phosphatase （ALP）, tumor necrosis factor alpha （TNF-α）, fasting blood glucose （FBG）, fasting plasma insulin （FINS）, HOMA （homeostasis model assessment） insulin resistance index （HOMA-IR）, and the liver histology of rats of all groups were assayed. Results： After 8 weeks, the liver in model group Ⅰ showed typical steatosis, accompanied with mild to moderate lobular inflammatory cell infiltration, liver indexes and serum levels of ALT, AST, ALP, TNF-α were significantly increased （P〈0.05） compared with control group Ⅰ. Whereas, the degree of hepatic injury was attenuated in PGZ prevention group, liver indexes and serum levels of ALT, ALP were significantly decreased （P〈0.05） compared with model group Ⅰ. After 16 weeks, notable steatosis, and lobular inflammation were observed in model group Ⅱ rat liver, while the degree of hepatic injury was attenuated in the PGZ treatment group. Liver index, serum levels ofALT, AST, ALP, FINS and HOMA-IR were significantly increased （P〈0.05） in model group Ⅱ compared with control group Ⅱ. Whereas, in PGZ treatment group, serum levels of AST and FINS showed decreasing tendency, liver indexes, serum levels of ALT, ALP, TNF-α and HOMA-IR were significantly decreased compared with model group Ⅱ. Conclusion： Insulin resistance plays a role in the pathogenesis of NAFLD in rats. Pioglitazone can attenuate insulin resistance and biochemical and histological injury in high fat-induced fatty liver in rats.

Effect of pioglitazone on nerve conduction velocity of the median nerve in the carpal tunnel in type 2 diabetes patients

AIM To evaluate the impact of pioglitazone pharmacotherapy in median nerve electrophysiology in the carpal tunnel among type 2 diabetes patients.METHODS The study was executed in patients with type 2 diabetes, treated with oral drugs, categorized under pioglitazone or non-pioglitazone group(14 in each group), and who received electrophysiological evaluation by nerve conduction velocity at baseline and 3 mo.RESULTS At 3 mo, pioglitazone-category had inferior amplitude in sensory median nerve [8.5 interquartile range(IQR) = 6.5 to 11.5) vs non-pioglitazone 14.5(IQR 10.5 to 18.75)](P = 0.002). Non-pioglitazone category displayed amelioration in amplitude in the sensory median nerve [baseline 13(IQR = 9 to 16.25) vs 3 mo 8.5(IQR = 6.5 to 11.5)](P = 0.01) and amplitude in motor median nerve [baseline 9(IQR = 4.75 to 11) vs 3 mo 6.75(IQR = 4.75 to 10.25)](P = 0.049); and deterioration of terminal latency of in motor ulnar nerve [baseline 2.07(IQR = 1.92 to 2.25) vs 3 mo 2.16(IQR = 1.97 to 2.325)](P = 0.043). There was amelioration of terminal latency in sensory ulnar nerve [baseline 2.45(IQR = 2.315 to 2.88) vs 3 mo 2.37(IQR = 2.275 to 2.445) for pioglitazone group(P = 0.038).CONCLUSION Treatment with pioglitazone accentuates probability of compressive neuropathy. In spite of comparable glycemic control over 3 mo, patients treated with pioglitazone showed superior electrophysiological parameters for the ulnar nerve. Pioglitazone has favourable outcome in nerve electrophysiology which was repealed when the nerve was subjected to compressive neuropathy.

Pioglitazone:A review of analytical methods

Pioglitazone is an oral anti-hyperglycemic agent. It is used for the treatment of diabetes mellitus type 2. It selectively stimulates nuclear receptor peroxisome proliferator-activated receptor gamma （PPAR-gamma）. It was the tenth-best-selling drug in the U.S. in 2008. This article examines published analytical methods reported so far in the literature for the determination of pioglitazone in biological samples and pharmaceutical formulations. They include various techniques like electrochemical methods, spectrophotometry, capillary electrophoresis, high-performance liquid chromatography, liquid chromatography-electrospray ionization-tandem mass spectrometry and high-performance thin layer chromatography.

Efficacy and safety of vildagliptin/pioglitazone combination therapy in Korean patients with diabetes

AIM:To assess the efficacy and safety of vildagliptin/pioglitazone combination therapy in Korean patients with type 2 diabetes mellitus(T2DM).METHODS:This was a post hoc analysis in Korean patients,from a 24-wk,randomized,active-controlled,double-blind,parallel-group,multicenter study.Eligible patients were aged between 18 and 80 years,drug naive,and had been diagnosed with T2DM [hemoglobin A1c(HbA1c):7.5-11.0 and fasting plasma glucose(FPG):【 270 mg/dL(【 15 mmol/L)].Patients were randomized(1:1:1:1) to receive the vildagliptin/pioglitazone comb ination at 100/30 mg q.d.(high-dose) or 50/15 mg q.d.(low-dose),vildagliptin 100 mg q.d.,or pioglitazone 30 mg q.d.monotherapies.The primary outcome measure was change in HbA1c from baseline to endpoint.RESULTS:The distribution of baseline demographic and clinical parameters was well balanced between treatment groups.The overall mean age,body mass index,HbA1c,FPG,and duration of disease were 50.8 years,24.6 kg/m2,8.6,10.1 mmol/L,and 2.2 years,respectively.Adjusted mean changes(± standard error) in HbA1c from baseline(~8.7) to week 24 endpoint were-2.03 ± 0.16(high-dose,N = 34),-1.88 ± 0.15(low-dose,N = 34),-1.31 ± 0.21(vildagliptin,N = 36),and-1.52 ± 0.16(pioglitazone,N = 36).The high-dose combination therapy demonstrated greater efficacy than monotherapies [vildagliptin(P = 0.029) and pioglitazone(P = 0.027)].Percentage of patients achieving HbA1c 【 7 and ≤ 6.5 was the highest in the high-dose group(76 and 68) followed by low-dose(58 and 47),vildagliptin(59 and 37),and pioglitazone(53 and 28) groups.The overall incidence of adverse events was comparable.CONCLUSION:In Korean patients,first-line treatment with high-dose combination therapy improved glycemic control compared to pioglitazone and vildagliptin monotherapies,consistent with results published for the overall study population.

An experimental study of pioglitazone in treating vascular dementia

Objective To compare the therapeutic effects of different doses of pioglitazone,a kind of peroxisome proliferator-activated receptor γ(PPARγ)agonist,on vascular dementia and explore how pioglitazone affects cerebral ischemia.Methods Modified Pulsinelli’s vessel ligation was used to establish a vascular dementia model in rats.Recognition,learning and memory were evaluated by Morris’s water maze test.Immunoenzyme staining was used to determine the number of nerve cells.Immunofluorescence double-staining was used to examine the expression of PPARγ/nerve cells and PPARγ/astrocytes in different groups.Results Both in pioglitazone groups and sham-operation group,the latency was reduced significantly compared to that in control group(P<0.01).Sham-operation group had the largest number of neurons in the cortex,followed by low-dose pioglitazone group and high-dose pioglitazone group,and control group came last.Compared with control group,pioglitazone groups had more PPARγ expression in nerve cells,and the fluorescence intensity of PPARγ was stronger.Conclusion Pioglitazone can induce the expression of PPARγ in neuron endochylema and astrocyte endochylema to protect nerve cells,and then to improve spatial learning and memory function in VD rats.

Effects of pioglitazone on proliferation and differentiation of human preadipocytes

Objective： To explore the effects of thiazolidinediones （TZDs） pioglitazone on proliferation and differentiation of human preadipocytes. Methods：Omental adipose tissue biopsies were obtained from 15 patients who were undergoing elective open-abdominal surgery. The primary culture and differentiated induction of human preadipocytes were performed, and the human preadipo-cytes were treated with pioglitazone at different concentrations at proper moments. Dynamic morphological changes of the human preadipocytes were observed, and their proliferation and differentiation were assessed with Colorimetric MTT Assay and Oil Red O Staining. Results：After 24 hours and 72 hours with pioglitazone, 0.1 μmol/L （μmol/ml） pioglitazone increased the MTT values of the human preadipocytes by 25.3% and 34.8%,respectively（P 〈 0.05）, while 1 μmol/L pioglitazone by 27.4% and 26.6%（P 〈 0.05）, compared with the control group without pioglitazone. The human preadipocytes with pioglitazone cumulated more adipose in the endochylema than those without pioglitazone obviously. 0.1 μmol/L pioglitazone increased the differentiation degree of the human preadipocytes differentiated for 8-10 days by 44.81% and 1 μmol/L pioglitazone by 53.76%（P 〈 0.05）. Conclusion：Thi- azolidinediones pioglitazone may significantly promote the proliferation and differentiation of the human omental preadipocytes.

Rapid LC-ESI-MS-MS Method for the Simultaneous Determination of Sitagliptin and Pioglitazone in Rat Plasma and Its Application to Pharmacokinetic Study

A liquid chromatography tandem mass spectrometry (LC-MS/MS) based method was developed for the simultaneous monitoring plasma levels of Sitagliptin (STG) and Pioglitazone (PIO) for applicability to pharmacokinetic studies. The method was based on HPLC separation on the reversed phase Phenomenex Synergy C18 column (30 mm length, 4.6 mm internal diameter, and 4.0 μm particle size) at a temperature of 40?C using a binary gradient mobile phase consisting of methanol and 2 mM ammonium acetate buffer pH adjusted to 4.5 with acetic acid, at a flow rate of 1 mL?min?1. Tolbutamide was used as an internal standard. Detection of analytes was achieved with LC-MS/MS system in Multiple Reaction Monitoring (MRM) mode. The method was validated over concentration range of 10.98 - 2091.77 ng?mL?1 for SIT and 8.25 - 1571.63 ng?mL?1 for PIO and lower limit of quantification was 10.98 ng?mL?1 and 8.25 ng?mL?1 for STG and PIO respectively. Recoveries from spiked controls were within acceptance criteria for all the analytes and internal standard at all QC levels. Within batch and between batch accuracy for STG was found within 96.9% - 100.3% and for PIO was found within 100.0% - 104.3%. Within batch and between batch precision for STG was less than 3.1% CV (coefficient of variation) and for PIO was less than 5.3% CV at all concentrations levels. This method was successfully applied to monitor pharmacokinetics profile of both STG and PIO on simultaneous oral administration to rats. This method can be applicable for pharmacokinetic drug-drug interaction studies.

Comparison of the Hypoglycemic, Hypolipidemic and Hepatoprotective Effects of<i>Asparagus racemosus</i>Linn. in Combination with Gliclazide and Pioglitazone on Alloxan-Induced Diabetic Rats

In recent years, the popularity of medicinal plants as a remedy has been increased manifold due to having minimal adverse effects. The current study aimed to compare the hypoglycemic, hypolipidemic and hepatoprotective effects of the ethanolic extract of Asparagus racemosus (EEAR) Linn. alone and combinedly with conventional antidiabetic agents (gliclazide and pioglitazone) in alloxan-induced diabetic rats. Diabetes was induced in male Wister albino rats by the administration of single intra-peritoneal injection of alloxan monohydrate (120 mg/kg b.w.). Effect of oral administration of two different doses of EEAR (200 and 400 mg/kg b.w.), gliclazide (10 mg/kg b.w.) and pioglitazone (10 mg/70kg/b.w.) alone for 2 weeks and a combination of EEAR (200 mg/kg b.w.) with either gliclazide (10 mg/kg b.w.) or pioglitazone (10 mg/70kg/b.w.) for 2 weeks were examined on hypoglycemic activity on 0th, 5th, 10th and 14th day of treatment. After 2 weeks of treatment, hypolipidemic and hepatoprotective effects were estimated by serum biochemical markers such as total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL), very low density lipoprotein (VLDL), high density lipoprotein (HDL), serum glutamate oxaloacetate transaminases (SGOT), serum glutamate pyruvate trans-aminases (SGPT) and total protein (TP) with the help of commercially available kits. The survival rate, body weight and organ weight were also measured. Alloxan treatment resulted in persistent hyperglycemia, hyperlipidemia and liver dysfunction in rats. Treatment with EEAR at different doses improved hyperglycemia significantly (p th and 14th day of treatment in a dose-dependent mood when compared to the disease control rats, gliclazide treated rats and pioglitazone treated rats. The combination therapy significantly (p th, 10th and 14th day of treatment as compared to that of disease control rats, gliclazide treated rats and pioglitazone treated rats. Proposed adjunct therapy also markedly (p < 0.001;p < 0.01, p < 0.001) improved serum TG, HDL and LDL level with insignificant change in VLDL and TC level while comparing with groups receiving gliclazide treated rats and pioglitazone treated rats. Administration of different doses of EEAR markedly (p < 0.05, p < 0.01, p < 0.001;p < 0.05, p < 0.01;p < 0.05) reduced the activity of TC, TG, LDL, VLDL and HDL cholesterol levels in a dose-dependent approach with respect to that of gliclazide treated rats and pioglitazone treated rats. The effect of combination therapy significantly (p < 0.001;p < 0.001;p < 0.01, p < 0.001) decreased the SGOT, SGPT and TP hepatic enzyme levels when compared to disease control rats, gliclazide treated rats and pioglitazone treated rats indicated improvement in liver dysfunctions. Administration of different doses of EEAR noticeably (p < 0.05, p < 0.01, p < 0.001;p < 0.05, p < 0.01;p < 0.05, p < 0.01) reduced the liver enzymes level including SGOT, SGPT and TP in a dose-dependent manner as compared to the disease control rats, gliclazide treated rats and pioglitazone treated rats. The maximum survival rate (100%) was observed in rats of combination treated rats. No significant changes in the body weight and organ weight to body weight ratio were observed except the groups that were given combined therapy showed improvement in the liver and pancreas weight. Our study suggests that the EEAR potentiates the activity of gliclazide and pioglitazone in controlling blood glucose levels, modifies the lipid profile and improves in liver dysfunction on alloxan-induced diabetic rats.

Protective effect of pioglitazone on kidney injury in diabetic rats

Objective:To investigate the protective effect of pioglitazone on kidney injury in diabetic rat model and its mechanisms.Methods:Forty healthy Sprague Dawley rats were selected and randomly divided into five groups,with 8 rats in each group.Group A served as control group and were administered with sterile citrate buffer(i.p.)as placebo.Groups B.C,D and E rats were injected(i.p.)with streptozotocin to induce type I diabetes,Diabetic rats in Group B were intragastrically administered with sterile saline solution alone.Groups C,D and E rats were iutragastrically given pioglitazone hydrochloride suspension at doses of 10,20,30 mg/kg per day.respectively.After eight weeks of treatment,all rats were anesthetized and blood was withdrawn from the abdominal aortic ofr detection of hemoglobin A_(1c),serum creatinine(SCr)and blood ures nitrogen(BUN)levels.Rats were then sacrificed and the left kidney was excised for calculation of kidney hypertrophy index(KHI),observation of renal pathological changes using light microscope and electron microscope.Mean glomerular cross-sectional areas(MGA).mean glomerular volume(MGV).glomerular basement membrane thickness and foot process fusion ratio were ealculated.RT-PCR was employed for detection of podocalyxin(PCX)protein expression.Results:Results showed that levels of hemoglobin A_(1c),BUN.SCr in Groups B,C.D and E rats were significantly higher than those in Group A(P<0.05),while BUN aud SCr levels in rats of Groups C,D and E were significantly lower than those in Group B(P<0.05).KHI,MGA and MGV levels were significantly higher in Groups B.C,D and E rats than those in Group A(P<0.05);KHI and MGA levels in Group B rats were significantly higher than those in Groups C.D and E(P<0.05)and MGV in Groups D and E was significantly lower than that in Gtoups B and C(P<0.05).Histology study showed normal glomerulus structure,morphology,volume,endothelial cells and mesangial cells as well as clear glomerular eapillary in Group A rats.Renal mesangial matrx proliferation and expansion of glomerulus cavities in Groups B.C.D and E were observed.However.damage degree in Groups C.D and E were more moderate than that iu Group B.Conclusions:Pioglitazone can reduce kidney damage in diabetic rats.which may be attributed to its role in increasing glomerular PCX protein expression and inhibiting urinary excretion of PCX,and its effect is dose dependent.

Development and validation of a high throughput LC–MS/MS method for simultaneous quantitation of pioglitazone and telmisartan in rat plasma and its application to a pharmacokinetic study

Management of cardiovascular risk factors in diabetes demands special attention due to their co-existence. Pioglitazone （PIO） and telmisartan （TLM） combination can be beneficial in effective control of cardiovascular complication in diabetes. In this research, we developed and validated a high throughput LC-MS/MS method for simultaneous quantitation of PIO and TLM in rat plasma. This developed method is more sensitive and can quantitate the analytes in relatively shorter period of time compared to the previously reported methods for their individual quantification. Moreover, till date, there is no bioanalytical method available to simultaneously quantitate PIO and TLM in a single run. The method was validated according to the USFDA guidelines for bioanalytical method validation. A linear response of the analytes was observed over the range of 0.005-10 pg/mL with satisfactory precision and accuracy. Accuracy at four quality control levels was within 94.27%-106.10%. The inlxa- and inter-day precision ranged from 2.32% to 10.14% and 5.02% to 8.12%, respectively. The method was reproducible and sensitive enough to quantitate PIO and TLM in rat plasma samples of a preclinical pharmacokinetic study. Due to the potential of PIO-TLM combination to be therapeutically explored, this method is expected to have significant usefulness in future.

Effects of pioglitazone on serum leptin and adiponectin in polycystic ovary syndrome patients with insulin resistance

Objective To investigate the effects of pioglitazone on serum leptin and adiponectin in polycystic ovary syndrome(PCOS)patients with insulin resistance(IR).Methods Thirty-five PCOS patients with IR were treated with pioglitazone 15mg/d for 12 weeks.The results of ovulation induction were observed.The changes of fasting plasma glucose(FPG),fasting serum insulin(FINS),serum levels of leptin,adiponectin,follicle-stimulating hormone(FSH),luteinizing hormone(LH),testosterone(T)and blood fat were examined at the baseline and after the therapy by enzyme-linked immunosorbent assay(ELISA)and radioimmunoassay(RIA).Results After the treatment,the rate of ovulation per cycle was improved in 31(88.5%)out of the 35 patients.After treatment,the level of serum leptin was decreased(P<0.05)while the level of serum adiponectin was increased(P<0.05).After 12 weeks’ treatment,waist-to-hip ratio and F-G score were significantly decreased(P<0.05),BMI declined but without significant difference(P>0.05).The levels of LH,T,FINS,Homa-IR,total cholesterol,triglyceride and low density lipoprotein-cholesterol were significantly decreased(P<0.01,P<0.05),whereas the level of high density lipoprotein-cholesterol was significantly increased(P<0.01).No significant difference was seen in FSH and FPG following treatment(P>0.05).Conclusion Pioglitazone treatment can effectively improve PCOS with IR patients’ clinical syndromes,insulin sensitivity,glucose and lipid metabolism at least partly through improving the profiles of leptin and adiponectin.

Effect of Pioglitazone on Transdifferentiation of Preosteoblasts from Rat Bone Mesenchymal Stem Cells into Adipocytes

We aimed to examine the effect of pioglitazone on transdifferentiation of preosteoblasts from rat bone marrow mesenchymal stem cells(BMSCs) into adipocytes and investigate its effect on bone metabolism.BMSCs were harvested from the femurs and tibias of a rat,then separated,purified,proliferated for 3 generations and differentiated into preosteoblasts for 5 days and 14 days respectively in the presence of osteogenic medium.Thereafter,the preosteoblasts were cultured for 21 days in the presence of adipogenic medium with and without pioglitazone(1 μg/mL).Partially-differentiated osteoblasts were identified by mineralized nodules with Alizarin red S staining.Transdifferentiated adipocytes were identified by Oil Red O staining.Reverse transcription PCR(RT-PCR) was performed to assay the expression levels of osteogenic markers Runx2 and ALP,and an adipogenic marker PPARγ.Those cells cultured for 5 days did not show mineralized nodules as detected by staining of Alizarin red S,while those cultured for 14 days showed dispersed mineralized centers in the form of brown spots,although without obvious red mineralized nodules.After adipogenic transdifferentiation for 21 days,adipose-drops were found in cells of 5CG and 5EG earlier than those of 14CG and 14EG,and the former showed much more adipocytes separately as detected by Oil Red O staining.Whatever the time was 5 days or 14 days of BMSCs osteogenic differentiation,the cells cultured with pioglitazone showed much more adipocytes than those without pioglitazone.Our experiment showed that the less time it took for BMSCs osteogenic differentiation,a stronger ability remained for BMSCs to transdifferentiate into adipocytes.The mRNA expression levels of Runx2 and ALP were decreased by 1.79 and 1.90 times respectively in 5EG(P< 0.05) as compared with 5CG,and that of PPARγ was increased by 1.31 times in 5EG(P<0.05) as compared with 5CG.The mRNA expression levels of Runx2 and ALP were decreased by 1.45 and 1.54 times respectively in 14EG(P<0.05) as compared with 14CG,and that of PPARγ was increased by 1.39 times in 14EG(P<0.05) as compared with 14CG.It was concluded that pioglitazone stimulated the transdifferentiation of BMSCs into adipocytes.These observations provided a potential mechanism of imbalance in thiazolidinedione induced bone metabolism.

Effects of Pioglitazone on Renal Mitochondrial calcium and cytochrome C levels in Early Diabetic Nephropathy Rats

Objective: To study the effect of pioglitazone on mitochondrial Ca2+ and cytochrome c (cyt c) in early diabetic rats, and to explore its mechanism of protecting kidney. Methods: 72 DM rats were randomly divided into negative control group (NC group), negative control+ pioglitazone intervention group (NCP group), diabetes group (DM group) and diabetes +pioglitazone intervention group (DMP group). In NCP and DMP groups, pioglitazone was administered to the stomach, blood glucose, renal mass index, 24-h urine protein, glomerular morphologic indice, glomerular base-membrane thickness and other indexes were measured, and the contents of Ca2+ and Cyt C in renal tissue were measured. Results: (1) the renal metabolism index, glomerular morphologic indice, glomerular base-membrane thickness of DM group was significantly higher than that of NC group (P < 0.01). The renal metabolism index, glomerular morphologic indice, glomerular base-membrane thickness of DMP group was significantly lower than that of DM group, the difference between the two groups was significant(P<0.05). (2) in DM group, mitochondrial Ca2+ and cytoplasmic cytc were higher than those in NC group, while mitochondrial cytc was lower than that in control group. There was significant difference between the two groups (P < 0.05). In DMP group, mitochondrial Ca2+ and cytoplasmic cytc were lower than those in DM group, while mitochondrial cytc was higher than that in control group. There was significant difference between the two groups (P <0.05). Conclusion: Pioglitazone treatment can reduce the release of mitochondrial cytochrome C and maintain mitochondrial calcium homeostasis.

Combined Therapy of Pioglitazone and Atorvastatin Alleviate Diabetes in Rats More Effectively than That of Mono Therapy

Present research was designated to investigate the hypoglycemic, hypolipidemic and antioxidant activity of the combination of pioglitazone and atorvastatin on long-term alloxan-induced diabetes rats (AIDRs). The experiments were carried out to determine blood glucose level, lipid profile, free radial scavenging activities, superoxide dismutase (SOD) and catalase in liver tissue. In addition, left ventricular (LV) hypertrophy and cardiomyocyte size were also determined by histological analysis. It was found that in short-term induction, pioglitazone significantly reduced the blood glucose level without having any considerable effect on lipid profile and antioxidant enzymes (SOD and catalase) in rats. On the other hand, atorvastatin significantly reduced total cholesterol (TC), triglyceride (TG) and low density lipoprotein cholesterol (LDL-C) with marked increase in the level of high density lipoprotein cholesterol (HDL-C) and improved activity of SOD and catalase enzymes. However, pathological changes of heart and pancreas were not observed after short-term exposure to alloxan in rats. Long-term diabetes induction resulted in LV hypertrophy and prominent shrinkage of islets of Langerhans cells. Treatment with atorvastatin in combination with pioglitazone significantly reduced the LV hypertrophy, TC, TG and LDL level whereas they noticeably increased HDL level, DPPH (1,1-Diphenyl-2-picryl-hydrazyl) free radical scavenging activity, SOD and catalase activity with satisfactory recovery of Langerhans cells. The result demonstrated that combination therapy was more effective than that of mono-therapy for preventing diabetes with cardiovascular diseases (CVD) in rats.

Decreased bone mineral density in young male veterans on Pioglitazone

Background and objective: Epidemiological and observational studies indicate that thiazolidinedione (TZD) therapy with rosiglitazone and pioglitazone is associated with an increased risk of fractures. The effect of TZDs on bone mineral density (BMD) in men with type 2 diabetes is still in debate. The objective of the study was to investigate changes in BMD and bone turnover markers (BTM) associated with Pioglitazone use in men. Design and Methods: This prospective cross sectional comparative study evaluated the changes in BMD and BTM in male veterans aged less than 55 years, with diabetes with or without use of pioglitazone. In a 6 month follow up study, main outcome measures included BMD at AP spine, femur and wrist;and BTM (osteocalcin and CTx) at a referral center, with no interventions. Results: Pioglitazone use was associated with significant decrease in BMD (annualized %change of >3%) at femoral neck, total hip and 1/3rd radius;increase in CTx by 29% and decrease in osteocalin by 20% at 6months. Conclusions: Even in young men pioglitazone use was associated with bone loss. The changes in BTM suggest effect of pioglitazone on both osteoblast and osteoclast activity.

Effect of metformin and Pioglitazone on insulin dose reduction in type 2 diabetes mellitus patients: An open level comparative prospective study

Insulin therapy cause weight gain and may increase its own requirement. Type 2 diabetes mellitus is associated with insulin resistance and affect both endogenous and exogenous insulin effect. Metformin and Pioglitazone, commonly used insulin sensitizers, have the potentiality of reducing the insulin dose, in Type-2 diabetes mellitus (T2DM) patients. This study was held to assess and compare such potentiality. 40 T2DM patients not controlled by diet, exercise and oral antidiabetic agents were selected for this study. Study had observed that Pioglitazone and metformin both significantly had reduced the dose of insulin. But metformin reduce the dose of insulin significantly more than that of Pioglitazone. Metformin had reduced the triglyceride, LDL-c, waist hip ratio significantly but modestly increased serum lactic acid and HDL-c. It can be concluded that co-administration of metformin with insulin is more beneficial in relation to the dose of insulin, waist hip ratio, and lipid modification when compare to Pioglitazone.

Pioglitazone does not modify ANP levels of type 2 diabetic patients

Background: The atrial natriuretic peptide (ANP) regulates fluid volume redistribution between heart and the pulmonary vessels. In diabetic patients the physiological action of ANP appears to be seriously altered. Methods: 12 subjects (gender 6M/6F, age 47 ± 2 years, BMI 29.1 ± 0.1 kg/m2), with type 2 diabetes and under stable conditions, were studied after one month of pioglitazione treatment (30 mg/die) by means of isotonic blood volume expansion. Results: After one month of pioglitazone treatment the meta- bolic profile of the subjects improved (decrease dia- stolic blood pressure: p = 0.05, total cholesterol: p = 0.01, triglycerides: p = 0.03 and blood glucose: p = 0.01) as the expansion of their plasma volume was found associated with the decrease of hematocrit (p < 0.05). The statistical comparison before versus after pioglitazone showed a significant decrease in the ba- sal aldosterone levels post-treatment (p < 0.04). Nonetheless ANP plasma levels were similar before and after therapy. Conclusions: The inappropriately high concentrations of ANP induced by hyperglyce-mia and the abnormal responses to a physiological sti- mulus like an isotonic blood volume expansion are not reverted by one month of pioglitazone. This is in contrast with the brisk improvement of the metabolic profile seen for the same period of treatment. ANP secretion is modified by fluid load in diabetic patients. This anomaly is not reverted by pioglitazone.

Effects of Metformin and Pioglitazone on impaired glucose tolerance patients—An open level prospective study

Introduction: impaired glucose tolerance (IGT) often leads to type 2 diabetes (T2DM) and macro vascular disease;and usually associated with insulin resistance. Pioglitazone and metformin are commonly used insulin sensitizers (IS);and can prevent or delay the development T2DM and macro vascular disease. This study was deployed to search the better IS between these two in relation to plasma glucose and lipid control;and physical parameter altering effect. Materials and methods: 100 IGT patients selected randomly from outpatients department following prefixed inclusion and exclusion criteria. Pioglitazone and metformin were administered sequentially. Washout period was 2 weeks. Total follow up period was 24 weeks. Results: 70 IGT patients had completed the study. Metformin had reduced plasma glucose (fasting & postprandial), lipids and physical parameters significantly (p < 0.05) more than Pioglitazone. Discussion: Metformin, a hepatic insulin sensitizer, is more effective than PPAR-□ agonist Pioglitazone in the treatment of IGT;and this is due to the expression of PPAR-□ is more in adipose tissue but postprandial utilization of plasma glucose is more in muscle tissue.