Our library of drug research abstracts drawn from the medical literature is updated on a regular schedule, and you can be assured that new actos research articles will be listed here shortly after becoming available to us.
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Medical research on actos
Microglia and Astrocyte Activation by Toll-Like Receptor Ligands: Modulation by PPAR-gamma Agonists.
PPAR Res. 2008; 2008: 453120
Gurley C, Nichols J, Liu S, Phulwani NK, Esen N, Kielian T
Microglia and astrocytes express numerous members of the Toll-like receptor (TLR) family that are pivotal for recognizing conserved microbial motifs expressed by a wide array of pathogens. Despite the critical role for TLRs in pathogen recognition, when dysregulated these pathways can also exacerbate CNS tissue destruction. Therefore, a critical balance must be achieved to elicit sufficient immunity to combat CNS infectious insults and downregulate these responses to avoid pathological tissue damage. We performed a comprehensive survey on the efficacy of various PPAR-gamma agonists to modulate proinflammatory mediator release from primary microglia and astrocytes in response to numerous TLR ligands relevant to CNS infectious diseases. The results demonstrated differential abilities of select PPAR-gamma agonists to modulate glial activation. For example, 15d-PGJ(2) and pioglitazone were both effective at reducing IL-12 p40 release by TLR ligand-activated glia, whereas CXCL2 expression was either augmented or inhibited by 15d-PGJ(2), effects that were dependent on the TLR ligand examined. Pioglitazone and troglitazone demonstrated opposing actions on microglial CCL2 production that were TLR ligand-dependent. Collectively, this information may be exploited to modulate the host immune response during CNS infections to maximize host immunity while minimizing inappropriate bystander tissue damage that is often characteristic of such diseases.
Treating Hispanic patients for type 2 diabetes mellitus: special considerations.
J Am Osteopath Assoc. 2008 May; 108(5 Suppl 3): S5-13
Freeman JS
The number of Hispanic people in the United States with diagnosed diabetes mellitus is projected to increase by 107% by 2020. The author presents the case of a 62-year-old obese Hispanic man, with newly diagnosed type 2 diabetes mellitus (T2DM), diabetic peripheral neuropathy, background retinopathy, and diabetic nephropathy. The patient also had diagnosed hypertension, peripheral vascular disease, and hyperlipidemia. The treatment plan for this patient included the following medications: pioglitazone hydrochloride (a thiazolidinedione, 30 mg/d); irbesartan (an angiotensin receptor blocker, 150 mg/d titrated to 300 mg/d); hydrochlorothiazide (an antikaliuretic agent, 12.5 mg/d); and aspirin (325 mg/d). Sitagliptin phosphate (a dipeptidyl peptidase IV inhibitor, 50 mg/d) was added to the treatment regimen to improve glycemic control. Simvastatin (20 mg/d) and niacin (1 g/d) were used for lipid management. Therapy also included a low-protein diet and walking program. At 6-month follow-up, the patient showed substantial improvement in his glycosylated hemoglobin level, lipid profile, blood pressure, creatinine clearance rate, and urine albumin level. There were also improvements in his peripheral vascular disease and diabetic peripheral neuropathy. Furthermore, the patient demonstrated encouraging progress in diet and lifestyle modification and in mental attitude.
Aggressively managing type 2 diabetes mellitus, hyperlipidemia, and bone loss.
J Am Osteopath Assoc. 2008 May; 108(5 Suppl 3): S20-7
Spellman CW
Physicians have many options available for treating patients with type 2 diabetes mellitus (T2DM). Making decisions on types of pharmaceuticals to use and when to introduce them into the treatment regimen can be a complex process. In addition, nutrition and exercise must be considered in any comprehensive treatment plan. The author describes the case of an African American woman with uncontrolled T2DM, obesity, hyperlipidemia, low bone mass, menopausal symptoms, stage 3 chronic kidney disease, distal sensory neuropathy, and background retinopathy. An aggressive, comprehensive treatment plan developed for this patient included pharmaceuticals (triple oral therapy: metformin, pioglitazone hydrochloride, and sitagliptin phosphate), nutrition counseling (with a registered, licensed dietician), and exercise. Treatment led to substantial improvements in the patient's daytime glucose level, glycosylated hemoglobin level, and body weight at 3-month follow-up. Further interventions were needed to address the patient's hyperlipidemia and low bone mass. The author offers physician guidelines for making decisions on glycemic control for patients with T2DM and for managing hyperlipidemia. He also strongly recommends incorporating nutrition counseling by registered, licensed dietitians and exercise (preferably of a weight-bearing nature) into treatment plans for patients with T2DM, hyperlipidemia, and low bone mass.
Reducing global cardiovascular risk in patients with type 2 diabetes mellitus.
J Am Osteopath Assoc. 2008 May; 108(5 Suppl 3): S14-9
Gavin JR
Type 2 diabetes mellitus (T2DM) and its complications must be managed by using a comprehensive, or global, approach to treatment. The author describes the case of a white man, aged 51 years, with T2DM that was diagnosed 3 years earlier. The patient was obese and had a history of chronic low back pain. He also had diagnosed hypertension, decreased vibratory sensation in the feet, an S4 atrial gallop, trace ankle edema, degenerative joint disease in the knees, and decreased range of motion in the lumbar spine. Other findings at the patient's initial visit included hyperglycemia, microalbuminuria, and lipid abnormalities. Initial treatment included metformin; a nonsteroidal anti-inflammatory drug (naproxen); a thiazolidinedione (rosiglitazone maleate); a thiazide diuretic (hydrochlorothiazide); an angiotensin-converting enzyme inhibitor (enalapril); and low-dose aspirin. At 6-month follow-up, the patient continued to have elevated glycosylated hemoglobin, hypertension, dyslipidemia, and excess weight. Additional treatment strategies consisted of pioglitazone hydrochloride; metformin in combination with the dipeptidyl peptidase IV inhibitor sitagliptin phosphate; a statin (atorvastatin hydrochloride); and enrollment in a diet and exercise program. Results at 12-month follow-up included a substantial decrease in glycosylated hemoglobin and improved hypertension and dyslipidemia. The patient was successfully treated across the full range of global cardiovascular risk reduction.
Pioglitazone increases adiponectin levels in nondiabetic patients with coronary artery disease.
Coron Artery Dis. 2008 Jun 17;
Patel SR, Mailloux LM, Coppola JT, Mindrescu C, Staniloae CS
OBJECTIVES: Hypoadiponectinemia is associated with coronary artery disease (CAD). Pioglitazone has been shown to increase levels of adiponectin in diabetic patients. We sought to assess whether administration of pioglitazone to patients with CAD and without diabetes would affect plasma adiponectin levels and endothelial function. METHODS: Seventeen patients with stable CAD and without evidence of diabetes were treated for 12 weeks with pioglitazone hydrochloride 30 mg daily. Adiponectin levels and endothelium-dependent flow-mediated vasodilation (ED-FMD) measurements were obtained pretreatment, posttreatment, and after a 12-week washout period. RESULTS: Treatment with pioglitazone increased adiponectin levels from an average of 10.6 to 21.1 mug/ml (P=0.001) and improved ED-FMD from 4.45 to 8.43% (P=0.001). CONCLUSION: Treatment with pioglitazone increased plasma adiponectin levels and improved ED-FMD in patients with stable CAD and no evidence of diabetes or insulin resistance.
J Biol Chem. 2008 Jun 25;
Pagel-Langenickel I, Bao J, Joseph JJ, Schwartz DR, Mantell BS, Xu X, Raghavachari N, Sack MN
The pathophysiology underlying mitochondrial dysfunction in insulin resistant skeletal muscle is incompletely characterized. To further delineate this we investigated the interaction between insulin signaling, mitochondrial regulation and function in C2C12 myotubes and in skeletal muscle. In myotubes elevated insulin and glucose disrupt insulin signaling, mitochondrial biogenesis and mitochondrial bioenergetics. The insulin sensitizing thiazolidinedione pioglitazone restores these perturbations in parallel with induction of the mitochondrial biogenesis regulator PGC-1alpha. Overexpression of PGC-1alpha rescues insulin signaling and mitochondrial bioenergetics and its silencing concordantly disrupts insulin signaling and mitochondrial bioenergetics. In primary skeletal myoblasts pioglitazone also upregulates PGC-1alpha expression and restores the insulin-resistant mitochondrial bioenergetic profile. In parallel, pioglitazone upregulates PGC-1alpha in db/db mouse skeletal muscle. Interestingly, the siRNA knockdown of the insulin receptor in C2C12 myotubes downregulates PGC-1alpha and attenuates mitochondrial bioenergetics. Concordantly, mitochondrial biogenergetics are blunted in insulin receptor knockout mouse derived skeletal myoblasts. Taken together these data demonstrate that elevated glucose and insulin impairs and pioglitazone restores skeletal myotube insulin signaling, mitochondrial regulation and bioenergetics. Pioglitazone functions, in part, via the induction of PGC-1alpha. Moreover, PGC-1alpha is identified as a bidirectional regulatory link integrating insulin-signaling and mitochondrial homeostasis in skeletal muscle.
Circ J. 2008 Jul; 72(7): 1193-7
Sugamura K, Sugiyama S, Matsuzawa Y, Nozaki T, Horibata Y, Ogawa H
Background Pioglitazone added to successful statin therapy may be beneficial for coronary artery disease (CAD) patients without diabetes mellitus. Methods and Results Fourteen individuals optimally treated with statin for >6 months were randomized to a pioglitazone or control group. Pioglitazone significantly improved insulin resistance, reduced high-sensitivity C-reactive protein, increased high-molecular-weight adiponectin and high-density lipoprotein cholesterol levels. Ultrasound echogenicity of carotid atheroma assessed by integrated backscatter was significantly increased by pioglitazone and correlated with adiponectin levels. Conclusion Adding pioglitazone to successful statin therapy may be an effective therapeutic strategy for patients with CAD. (Circ J 2008; 72: 1193 - 1197).
PERISCOPE: pioglitazone offers the right cluster of effects to confer benefit in type 2 diabetes.
Cardiovasc J Afr. 2008 May-Jun; 19(3): 159-62
J Immunol. 2008 Jul 1; 181(1): 235-42
Bonfield TL, Thomassen MJ, Farver CF, Abraham S, Koloze MT, Zhang X, Mosser DM, Culver DA
Macrophage CSF (M-CSF) regulates monocyte differentiation, activation, and foam cell formation. We have observed that it is elevated in human pulmonary alveolar proteinosis (PAP) and in the GM-CSF knockout mouse, a murine model for PAP. A potential regulator of M-CSF, peroxisome proliferator-activated receptor-gamma (PPARgamma), is severely deficient in both human PAP and the GM-CSF knockout mouse. To investigate the role of PPARgamma in alveolar macrophage homeostasis, we generated myeloid-specific PPARgamma knockout mice using the Lys-Cre method to knock out the floxed PPARgamma gene. Similar to the GM-CSF-deficient mouse, absence of alveolar macrophage PPARgamma resulted in development of lung pathology resembling PAP in 16-wk-old mice, along with excess M-CSF gene expression and secretion. In ex vivo wild-type alveolar macrophages, we observed that M-CSF itself is capable of inducing foam cell formation similar to that seen in PAP. Overexpression of PPARgamma prevented LPS-stimulated M-CSF production in RAW 264.7 cells, an effect that was abrogated by a specific PPARgamma antagonist, GW9662. Use of proteasome inhibitor, MG-132 or a PPARgamma agonist, pioglitazone, prevented LPS-mediated M-CSF induction. Using chromatin immunoprecipitation, we found that PPARgamma is capable of regulating M-CSF through transrepression of NF-kappaB binding at the promoter. Gel-shift assay experiments confirmed that pioglitazone is capable of blocking NF-kappaB binding. Taken together, these data suggest that M-CSF is an important mediator of alveolar macrophage homeostasis, and that transcriptional control of M-CSF production is regulated by NF-kappaB and PPARgamma.
J Gastroenterol Hepatol. 2008 Jun; 23(6): 930-7
Yamamoto Y, Ono T, Dhar DK, Yamanoi A, Tachibana M, Tanaka T, Nagasue N
BACKGROUND AND AIM: Peroxisome proliferator-activated receptor-gamma (PPARgamma), a member of the nuclear receptor superfamily, is widely expressed in adipocytes and other tissues, including the liver. Several reports have shown that PPARgamma activation induced cell-cycle arrest and apoptosis in tumor cells. We investigated the role of the PPARgamma/ligand system and the effect of the PPARgamma agonist during liver regeneration. METHODS: Expression of PPARgamma and serum levels of 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) by enzyme immunoassay were evaluated in rats following partial hepatectomy (PH group). Further, the effect of the PPARgamma agonist, pioglitazone, on liver regeneration (PH + PGZ group) was evaluated by proliferating cell nuclear antigen labeling index, relative liver weight, and expression of cell-cycle regulators. RESULTS: The number of PPARgamma-stained hepatocytes decreased at 24 h (PH, 15.8 +/- 2.2%; sham, 35.5 +/- 2.4%; P < 0.001) and increased in the late phase of liver regeneration compared to the sham-operated group (P < 0.001 at 48-120 h). The peaks of serum 15d-PGJ2 (627.0 +/- 91.1 pg/ml) and PPARgamma expression (90.6 +/- 3.1%) coincided in the late phase of liver regeneration. Also, oral administration of pioglitazone inhibited hepatocyte proliferation, in terms of the proliferating cell nuclear antigen (PCNA) labeling index and p27 expression during the late phase of liver regeneration, and caused a transient reduction in liver mass when compared to the PH group. CONCLUSIONS: These results indicate that the PPARgamma/ligand system may be one of the key negative regulators of hepatocyte proliferation and may be responsible for the inhibition of liver growth in the late phase of liver regeneration.