Effect of canagliflozin on serum uric acid in patients with type 2 diabetes mellitus.

Hyperuricaemia is associated with an increased risk of gout, kidney stones and cardiovascular disease. The present post hoc analysis of pooled data from four placebo-controlled phase III studies assessed the effect of canagliflozin, a sodium-glucose co-transporter 2 inhibitor, on serum uric acid levels in patients with type 2 diabetes mellitus (T2DM) and in a subset of patients with hyperuricaemia [defined as baseline serum uric acid ≥475 µmol/l (∼8 mg/dl)]. At week 26, canagliflozin 100 and 300 mg were associated with a ∼13% reduction in serum uric acid compared with placebo. In the subset of patients with hyperuricaemia, placebo-subtracted percent reductions in serum uric acid were similar to those in the overall cohort. More patients in the hyperuricaemic group achieved a serum uric acid level of <360 µmol/l (∼6 mg/dl) with both canagliflozin 100 mg (23.5%) and 300 mg (32.4%) compared with placebo (3.1%). Incidences of gout and kidney stones were low and similar across groups. In conclusion, canagliflozin treatment decreased serum uric acid in patients with T2DM, including those with baseline hyperuricaemia.

Canagliflozin in Asian patients with type 2 diabetes on metformin alone or metformin in combination with sulphonylurea.

AIMS: To evaluate the efficacy and safety of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in Asian patients with type 2 diabetes mellitus (T2DM) inadequately controlled by metformin or metformin in combination with sulphonylurea. METHODS: In this 18-week, randomized, double-blind, placebo-controlled phase III study, patients (N = 676) received canagliflozin 100 or 300 mg or placebo once daily. The primary efficacy endpoint was change in glycated haemoglobin (HbA1c) level from baseline at week 18. Additional endpoints included change in fasting plasma glucose (FPG) and percent change in body weight. Adverse events (AEs) were recorded throughout the study. Efficacy and safety were assessed in the overall population and in two strata based on background therapy. RESULTS: At week 18, canagliflozin 100 and 300 mg provided significant reductions from baseline in HbA1c compared with placebo (-0.97, -1.06 and -0.47%, respectively; p < 0.001). Relative to placebo, canagliflozin 100 and 300 mg also significantly reduced FPG (-1.0 and -1.4 mmol/l) and body weight [-2.2% (-1.5 kg) and -2.3% (-1.6 kg)]. Both canagliflozin doses lowered systolic blood pressure (BP) compared with placebo. The overall incidence of AEs was 38.6, 43.2 and 42.0% with canagliflozin 100 and 300 mg and placebo, respectively. The incidence of genital mycotic infections and urinary tract infections was low and similar across groups. Efficacy and safety findings in the two strata were generally consistent with the overall population. CONCLUSIONS: Canagliflozin provided glycaemic improvements and reductions in body weight and systolic BP, and was generally well tolerated in Asian patients with T2DM on metformin or metformin in combination with sulphonylurea.

Efficacy and safety of canagliflozin over 52 weeks in patients with type 2 diabetes on background metformin and pioglitazone.

AIM: The efficacy and safety of canagliflozin, a sodium glucose co-transporter 2 inhibitor, was evaluated in patients with type 2 diabetes mellitus (T2DM) inadequately controlled with metformin and pioglitazone. METHODS: In this randomized, double-blind, phase 3 study, patients (N = 342) received canagliflozin 100 or 300 mg during a 26-week, placebo-controlled, core period and a 26-week, active-controlled extension in which placebo-treated patients were switched to sitagliptin 100 mg. Efficacy comparisons for canagliflozin versus placebo at week 26 are reported, with no comparisons versus sitagliptin at week 52 (sitagliptin used to maintain double-blind and control for safety). Safety data are reported for canagliflozin and placebo/sitagliptin. RESULTS: Canagliflozin 100 and 300 mg significantly lowered haemoglobin A1c (HbA1c) compared with placebo at week 26 (-0.89%, -1.03% and -0.26%; p < 0.001); reductions with canagliflozin 100 and 300 mg were maintained at week 52 (-0.92% and -1.03%). Relative to placebo, both canagliflozin doses significantly reduced body weight (-2.5 and -3.5 kg), fasting plasma glucose and systolic blood pressure (BP) at week 26 (p < 0.05 for all), with reductions maintained at week 52. Overall adverse event (AE) incidence over 52 weeks was 69.9, 76.3 and 76.5% with canagliflozin 100 and 300 mg and placebo/sitagliptin; AE-related discontinuation and serious AE rates were low. Incidences of genital mycotic infections and AEs related to osmotic diuresis and volume depletion were higher with canagliflozin than placebo/sitagliptin. CONCLUSION: Canagliflozin improved glycaemic control, reduced body weight and systolic BP, and was generally well tolerated in patients with T2DM on metformin and pioglitazone over 52 weeks.

Two mutations of the lutropin/choriogonadotropin receptor that impair signal transduction also interfere with receptor-mediated endocytosis.

The experiments presented herein were designed to probe a potential role for the activation of the LH/CG receptor (LHR) on the receptor-mediated endocytosis of human CG (hCG). Two mutants of the rat LHR (rLHR) that bind the hormone with high affinity but are deficient in signal transduction were prepared by mutating highly conserved residues that have been previously shown to be important in signal transduction in other members of the G protein-coupled receptor family. Mutation of a highly conserved aspartic acid in the second transmembrane domain of the rLHR (designated rLHR-D383N) does not affect hCG binding but impairs signal transduction. When compared with cells expressing an equivalent density of wild type rLHR (rLHR-wt), concentration-response curves for the hCG-stimulated cAMP accumulation in cells expressing rLRH-D383N- are characterized by an 18-fold increase in the EC50 but no change in the maximal response. Cells expressing rLHR-D383N also display a 4- to 5-fold increase in the half-life of internalization of hCG. Mutation of a highly conserved arginine in the second intracellular loop of the rLHR (designated rLHR-R442H) also does not affect hCG binding but impairs signal transduction. When compared with cells expressing an equivalent density of rLHR-wt, concentration-response curves for the hCG-stimulated cAMP accumulation in cells expressing rLHR-R442H are characterized by a 7-fold increase in the EC50 and a 6- to 10-fold decrease in the maximal response. Cells expressing rLHR-R442H also display a 1.5- to 2-fold increase in the half-life of internalization of hCG. These results, together with the finding that an antagonist of hCG is internalized more slowly than hCG, suggest that the activation of the LHR is needed for the efficient endocytosis of the bound hCG.

Cytogenetics and P-glycoprotein (PGP) are independent predictors of treatment outcome in acute myeloid leukemia (AML).

Clinical and biological features have recognized prognostic significance in acute myeloid leukemia (AML). To evaluate the interaction of these variables and weighted effect on treatment outcome, prognostic variables from 96 previously untreated patients were analyzed for association with expression of the MDR1 gene product P-glycoprotein (Pgp), and effect on response to induction chemotherapy, progression-free survival and overall survival. Multivariate relationships were analyzed using six prognostic variables, including age, cytogenetic pattern, gender, CD34+ surface phenotype, AML type (de novo versus secondary) and Pgp. Univariate comparisons indicate that Pgp (P = 0.0001), cytogenetic pattern (P = 0.0004) and a Cd34+ phenotype (P = 0.0005) are predictive of primary treatment failure, whereas Pgp (P = 0.0001) had the greatest predictive value in multivariate analysis. Only cytogenetic pattern retained prognostic significance (P = 0.0143) for response to induction therapy after adjustment for Pgp. Although all variable except gender were associated with Pgp, specimens harboring the favorable karyotypic abnormalities t(15;17), t(8;21) and inv(16) exclusively lacked Pgp expression. In a multivariate model, both Pgp and cytogenetic pattern predicted response and overall survival, whereas secondary AML and cytogenetic pattern influenced remission duration. These findings indicate that cytogenetic has prognostic relevance that is independent of Pgp, and implies the presence of undefined biological mechanisms affecting chemotherapy resistance.

Reciprocal signaling between spiral ganglion neurons and Schwann cells involves neuregulin and neurotrophins.

To investigate the role of neuron-glial cell interactions in the auditory nerve, we asked whether spiral ganglion neurons (SGNs) express neuregulin and whether neuregulin regulates proliferation and/or neurotrophin expression in spiral ganglion Schwann cells (SGSCs). Using immunocytochemistry, we found that type I and type II SGNs express neuregulin in vivo and in vitro. Cultured SGSCs express the neuregulin receptors ErbB2 and ErbB3, but not ErbB4. Neuregulin activates ErbB2 and ErbB3 in cultured SGSCs, evidenced by increased tyrosine phosphorylation of the receptors following neuregulin treatment. Neuregulin treatment increased the proliferation rate of cultured SGSCs by 2.5-fold. Fibroblast growth factor-2 (FGF-2) and transforming growth factor beta (TGF-beta) also increased SGSC proliferation. The mitogenic effect of neuregulin and FGF-2 was blocked by inhibition of mitogen-activated protein kinase signaling but not by inhibition of phosphatidylinositol-3'-OH kinase. Using RT-PCR, we found that cultured SGSCs express neurotrophins, including brain-derived neurotrophic factor and neurotrophin-3 (NT-3), raising the possibility that SGSCs contribute to the trophic support of SGNs. Treatment with neither neuregulin nor TGF-beta increased neurotrophin expression in cultured SGSCs, as had been observed in developing sympathetic ganglia, but appeared to negatively regulate NT-3 expression. Thus, neuregulin and neurotrophins may mediate reciprocal neuron-glial interactions in the auditory nerve.

A 52-week open-label study of the safety and tolerability of paliperidone palmitate in patients with schizophrenia.

The safety and tolerability of paliperidone palmitate, an injectable atypical antipsychotic agent, were assessed in a 1-year open-label extension of a double-blind study in patients with schizophrenia. Patients from the double-blind study who experienced a recurrence, remained recurrence free until study end, or who were in the transition, maintenance or double-blind phases and had received at least one injection of paliperidone palmitate when enrollment was stopped, were eligible for the open-label extension. Patients received gluteal injections of paliperidone palmitate once every 4 weeks: starting dose 50 mg eq. followed by 25, 50, 75, or 100 mg eq. flexible dosing. Of the 388 patients enrolled, 288 completed the open-label extension. During the open-label extension, the median (range) duration of exposure to paliperidone palmitate was 338 days (10; 390), and 74% of patients received all 12 open-label injections of paliperidone palmitate. The most frequent (≥ 5% in total group) adverse events were insomnia (7%); worsening of schizophrenia; nasopharyngitis; headache; and weight increase (6% each). Potentially prolactin-related adverse events occurred in 13 (3%) patients, mostly women, and none resulted in study discontinuation. Extrapyramidal treatment-emergent adverse events were reported in 25 (6%) patients; tremor was the most frequently reported (n = 8, 2%). At open-label extension endpoint, investigator-rated redness at the injection site was observed in ≤ 4% of patients in each group. Injection-site pain was rated by investigators as absent in 82-87% of patients. Schizophrenia symptoms measured by Positive and Negative Syndrome Scale and personal and social performance changes improved during the open-label extension.

Topiramate and physiologic measures of nerve function in polyneuropathy.

OBJECTIVE: To evaluate topiramate treatment on nerve function using electrophysiologic methods and a non-inferiority clinical trial design. METHODS: A double-blind, multicenter, placebo-controlled trial was conducted in patients with painful diabetic polyneuropathy (n = 67). Change in peroneal motor nerve conduction velocity (NCV) was the primary outcome. NCVs of sural sensory and ulnar nerves, and amplitude and latency changes were measured secondarily. Peripheral nerve function was also evaluated in a patient subgroup reporting treatment-emergent paresthesias. RESULT: Least squares mean decrease in NCV was greater for placebo (-0.2 m/s) than for topiramate treatment (-0.1 m/s) (95% CI: -1.30, 1.42). Secondary measures showed no decrease in nerve function for topiramate-treated patients. Neurophysiologic measures were similar in patients with and without paresthesias. The most common adverse events with topiramate were paresthesias, anorexia, weight decrease, and taste perversion. CONCLUSION: This nerve conduction study found no evidence that topiramate is associated with deterioration of nerve function.

Topiramate in painful diabetic polyneuropathy: findings from three double-blind placebo-controlled trials.

OBJECTIVES: To evaluate the efficacy and tolerability of topiramate in patients with painful diabetic polyneuropathy. MATERIALS AND METHODS: Patients with moderate to extreme pain (0-4 Categorical Pain Scale score > or = 2) were randomized to placebo or topiramate (100, 200, or 400 mg/day) in three similar double-blind trials. The primary efficacy analysis was pain reduction from final visit to baseline in the 100-mm Visual Analog Scale (VAS) for the intent-to-treat populations. RESULTS: After 18-22 weeks of double-blind treatment, pain reductions were numerically greater with topiramate in two studies but differences between topiramate and placebo in VAS scores or in the secondary efficacy endpoints did not reach statistical significance in any of the three studies. Across all studies, 24% of topiramate-treated patients and 8% of placebo-treated patients discontinued due to adverse events; groups did not differ in the occurrence of serious adverse events. CONCLUSION: These studies did not find topiramate to be significantly more effective than placebo in reducing pain scores in patients with painful diabetic polyneuropathy. Several design features may have precluded the studies from having sufficient sensitivity to differentiate effective and ineffective treatments. The study design and results are instructive for other investigators designing future clinical studies in neuropathic pain.

Mutation of a Shc binding site tyrosine residue in ErbB3/HER3 blocks heregulin-dependent activation of mitogen-activated protein kinase.

The ErbB2 and ErbB3 proteins together constitute a functional coreceptor for heregulin (neuregulin). Heregulin stimulates the phosphorylation of both coreceptor constituents and initiates a variety of other signaling events, which include phosphorylation of the Shc protein. The role of Shc in heregulin-stimulated signal transduction through the ErbB2.ErbB3 coreceptor was investigated here. Heregulin was found to promote ErbB3/Shc association in NIH-3T3 cells expressing endogenous ErbB2 and recombinant ErbB3. A mutant ErbB3 protein was generated in which Tyr-1325 in a consensus Shc phosphotyrosine-binding domain recognition site was mutated to Phe (ErbB3-Y/F). This mutation abolished the association of Shc with ErbB3 and blocked the activation of mitogen-activated protein kinase by heregulin. Whereas heregulin induced mitogenesis in NIH-3T3 cells transfected with wild-type ErbB3 cDNA, this mitogenic response was markedly attenuated in NIH-3T3 cells transfected with the ErbB3-Y/F cDNA. These results showed a specific interaction of Shc with the ErbB3 receptor protein and demonstrated the importance of this interaction in the activation of mitogenic responses by the ErbB2. ErbB3 heregulin coreceptor complex.

Signal transduction by epidermal growth factor and heregulin via the kinase-deficient ErbB3 protein.

The role of protein tyrosine kinase activity in ErbB3-mediated signal transduction was investigated. ErbB3 was phosphorylated in vivo in response to either heregulin (HRG) in cells expressing both ErbB3 and ErbB2, or epidermal growth factor (EGF) in cells expressing both ErbB3 and EGF receptor. A recombinant receptor protein (ErbB3-K/M, in which K/M stands for Lys-->Met amino acid substitution) containing an inactivating mutation in the putative ATP-binding site was also phosphorylated in response to HRG and EGF. Both the wild-type ErbB3 and mutant ErbB3-K/M proteins transduced signals to phosphatidylinositol 3-kinase, Shc and mitogen-activated protein kinases. Separate kinase-inactivating mutations in the EGF receptor and ErbB2 proteins abolished ErbB3 phosphorylation and signal transduction activated by EGF and HRG respectively. Hence the protein tyrosine kinase activity necessary for growth factor signalling via the ErbB3 protein seems to be provided by coexpressed EGF and ErbB2 receptor proteins.