Aziz Shaibani

Lacosamide in painful diabetic peripheral neuropathy: a phase 2 double-blind placebo-controlled study.

BackgroundPeripheral diabetic neuropathy affects between 20% and 45% of patients with diabetes. ObjectiveTo ascertain the effect of lacosamide on pain associated with peripheral diabetic neuropathy. MethodsOne hundred nineteen patients with a 1 to 5-year history of pain attributed to diabetic neuropathy and a score of ≥4 on the Likert pain scale entered the multicenter, randomized, double-blind, placebo-controlled trial. Lacosamide (N=60) titrated from 100 to 400 mg/d or maximum tolerated dose and placebo (N=59) were the trial interventions. Primary efficacy criterion was change in pain score on the 11-point Likert pain scale. Secondary assessments included Short-Form McGill Pain and Short-Form-36 Quality of Life Questionnaires, sleep/activity interference, pain intensity, Patient and Clinical Global Impression of Change, and Profile of Mood. Patients receiving at least 1 dose of medication underwent safety evaluation. ResultsNinety-four patients (lacosamide 46; placebo 48) completed the trial. Lacosamide had significantly (P=0.039) better pain relief versus placebo (primary outcome). Improvements were also seen in secondary outcome measures. Adverse events occurred in 52 lacosamide and 44 placebo patients. Common adverse events, occurring in ≥5% of patients, were headache (lacosamide 18%, placebo 22%), dizziness (lacosamide 15%, placebo 8%), and nausea (lacosamide 12%, placebo 7%). Five lacosamide and 3 placebo patients withdrew for adverse events. DiscussionLacosamide seems to attenuate pain in diabetic neuropathy in doses up to 400 mg/d and improves quality of life issues.

Oxcarbazepine in painful diabetic neuropathy : results of a dose-ranging study

Objectives –  To evaluate the efficacy and safety of oxcarbazepine in patients with diabetic neuropathy in a multicenter, double‐blind, placebo‐controlled, dose‐ranging 16‐week study.

Lacosamide in Painful Diabetic Neuropathy: An 18-Week Double-Blind Placebo-Controlled Trial

UNLABELLED The efficacy and tolerability of oral lacosamide (200, 400, and 600 mg/day) was evaluated in patients with painful diabetic neuropathy in a double-blind, randomized, placebo-controlled trial. The primary target dose to be confirmed was lacosamide 400 mg/day. Efficacy was assessed by changes in pain scale scores from baseline, with changes over the last 4 weeks of the 12-week maintenance period regarded as the primary endpoint. Endpoint reductions in mean pain score were higher with all doses of lacosamide, reaching the level of significance with 400 mg/day (P = .05). Over the treatment period (titration + maintenance), pain relief was significantly higher than placebo with lacosamide 400 (P = .02) and 600 mg/day (P = .03). Lacosamide had an early-onset effect with significant reductions over placebo during the titration period. Nonparametric and mixed-model analysis approaches gave similar results, supporting significant efficacy at 400 mg/day. Secondary criteria such as Patients Global Impression of Change, responder rates, and pain-free days provided additional support. Adverse events included dizziness, nausea, and headache. Incidence of cognitive and behavioral adverse events was low. This trial suggests that lacosamide has beneficial effects and may be a suitable treatment option for patients with diabetic neuropathic pain. PERSPECTIVE This study presents efficacy and safety results of a phase 3, double-blind, placebo-controlled trial of the anticonvulsant drug lacosamide in patients with painful diabetic neuropathy. Lacosamide treatment at a dose of 400 mg/day reduced diabetic neuropathic pain with a favorable safety and tolerability profile that may be suitable for patients with diabetes.

Mitochondrial neurogastrointestinal encephalopathy due to mutations in RRM2B.

BACKGROUND Mitochondrial neurogastrointestinal encephalopathy (MNGIE) is a progressive neurodegenerative disorder associated with thymidine phosphorylase deficiency resulting in high levels of plasma thymidine and a characteristic clinical phenotype. OBJECTIVE To investigate the molecular basis of MNGIE in a patient with a normal plasma thymidine level. DESIGN Clinical, neurophysiological, and histopathological examinations as well as molecular and genetic analyses. SETTING Nerve and muscle center and genetic clinic. Patient A 42-year-old woman with clinical findings strongly suggestive for MNGIE. MAIN OUTCOME MEASURES Clinical description of the disease and its novel genetic cause. RESULTS Identification of mitochondrial DNA depletion in muscle samples (approximately 12% of the control mean content) prompted us to look for other causes of our patients condition. Sequencing of genes associated with mitochondrial DNA depletion-POLG, PEO1, ANT1, SUCLG1, and SUCLA2-did not reveal deleterious mutations. Results of sequencing and array comparative genomic hybridization of the mitochondrial DNA for point mutations and deletions in blood and muscle were negative. Sequencing of RRM2B, a gene encoding cytosolic p53-inducible ribonucleoside reductase small subunit (RIR2B), revealed 2 pathogenic mutations, c.329G>A (p.R110H) and c.362G>A (p.R121H). These mutations are predicted to affect the docking interface of the RIR2B homodimer and likely result in impaired enzyme activity. CONCLUSIONS This study expands the clinical spectrum of impaired RIR2B function, challenges the notion of locus homogeneity of MNGIE, and sheds light on the pathogenesis of conditions involved in the homeostasis of the mitochondrial nucleotide pool. Our findings suggest that patients with MNGIE who have normal thymidine levels should be tested for RRM2B mutations.

Long-term oral lacosamide in painful diabetic neuropathy: A two-year open-label extension trial

Objectives: This open‐label follow‐on trial aimed to investigate long‐term safety and efficacy of lacosamide in patients with painful diabetic neuropathy.

Alternative splicing factor ASF/SF2 is down regulated in inflamed muscle

Background: In our recent studies, alternative splicing has been shown to have a major role in inflammation and autoimmune muscle diseases. Aim: To examine the novel hypothesis that the expression of an essential alternative splicing factor, alternative splicing factor 2 (ASF/SF2), is modulated in muscle inflammation. Methods: ASF/SF2 expression in muscle biopsy samples from eight patients with inflammatory myopathy and six non-myositic controls was determined by using western blot with anti-ASF/SF2 antibodies. To further elucidate the mechanism of reduced ASF/SF2 expression in inflamed muscle, differentiated C2C12 myotubes were stimulated with proinflammatory cytokine tumour necrosis factor α (TNFα), followed by western blot analysis of ASF/SF2 expression. Results: ASF/SF2 expression in the muscle biopsy samples from patients with inflammatory myopathy was found to be lower (mean of relative densitometric units 41.1 (2SD 20.7)) than that of the non-myositic controls (mean of relative densitometric units 76.7 (39.6); p<0.05). In addition to this, ASF/SF2 expression was seen to be significantly down regulated (sevenfold) in C2C12 myotubes compared with expression variations in the β-actin control (0.62-fold; mean 1.22 (0.40); p<0.05). Conclusion: Collectively, it is shown, for the first time, that alternative splicing factor ASF/SF2 is down regulated in autoimmune inflammatory myositis—potentially via a TNFα-mediated pathway. The development of (1) novel autoantigen isoform microarrays for disease diagnosis and prognosis; (2) novel autoantigen-tolerising treatments for autoimmune diseases; and (3) novel splicing-redirection treatments can be facilitated by the ongoing study of alternative splicing of autoantigen transcripts.

Efficacy and safety of dextromethorphan/quinidine at two dosage levels for diabetic neuropathic pain: a double-blind, placebo-controlled, multicenter study.

OBJECTIVE To evaluate dextromethorphan coadministered with quinidine as treatment of diabetic peripheral neuropathic pain. DESIGN In a 13-week, phase 3, randomized controlled trial, 379 adults with daily symmetric diabetic peripheral neuropathy (DPN) leg pain for ≥3 months received double-blind placebo, dextromethorphan/quinidine (DMQ) 45/30 mg, or DMQ 30/30 mg, administered once daily for 7 days and twice daily thereafter. Efficacy measures included four pain rating scales applied daily using patient diaries, and another two applied at five clinic visits. RESULTS On all six scales, DMQ 45/30 mg was significantly superior to placebo, including the primary efficacy analysis, which utilized mixed-effects modeling to test all scores on an 11-point numerical Pain Rating Scale (P < 0.0001). Sensitivity analyses gave consistent results. Efficacy vs placebo was also seen for diary ratings of present pain intensity, and pain interference with sleep and with activities (all P < 0.0001). Among clinic visit assessments, DMQ 45/30 mg demonstrated greater leg pain relief (P = 0.0002) and greater reduction of leg pain intensity (P = 0.0286) vs placebo. The efficacy of DMQ 30/30 mg was numerically less than for 45/30 mg but for most outcomes remained significantly greater vs placebo. Adverse events were mostly mild or moderate and of expected types. Discontinuation for adverse events in the DMQ groups was at least twice as common as placebo. CONCLUSIONS Throughout a 13-week trial, DMQ was effective, with an acceptable safety profile, for treatment of DPN pain. Other fixed-dose combinations of DMQ should be studied to improve overall tolerability while maintaining significant efficacy.

Double-blind, placebo-controlled study of HGF gene therapy in diabetic neuropathy.

To evaluate the safety and efficacy of a plasmid (VM202) containing two human hepatocyte growth factor isoforms given by intramuscular injections in patients with painful diabetic neuropathy.

Atypical presentation of VLCAD deficiency associated with a novel ACADVL splicing mutation

Very long chain acyl‐CoA dehydrogenase (VLCAD) deficiency is an autosomal recessive inborn error of metabolism characterized by impaired mitochondrial β‐oxidation of fatty acids with a chain length between 14 and 18 carbons. While expansion of newborn screening has improved our ability to detect VLCAD deficiency in early childhood, the late‐onset form of the disease still presents a significant diagnostic challenge. We report a 20‐year‐old female with VLCAD deficiency who first presented in infancy with hypoketotic hypoglycemia. In childhood the patient developed complex partial seizures that were aggravated by Lamotrigine treatment. The clinical course in early adulthood was complicated by recurrent, often unprovoked, episodes of rhabdomyolysis and myoglobinuria. In addition, she suffered from chronic myalgia, muscle weakness, and diffuse abdominal tenderness. A muscle biopsy revealed accumulation of fat droplets. Her acylcarnitine profile showed significantly elevated C14, C14:1, C16, and C18‐carnitines. Sequence analysis of ACADVL revealed a heterozygous recurrent mutation c.848T>C (p.V283A) and a heterozygous novel splice mutation c.879‐8T>A that results in the inclusion of six nucleotides from intron 9 into the transcript sequence. The molecular characterization of this novel mutation and its correlation with the clinical phenotype are discussed. Muscle Nerve 39: 374–382, 2009

Safety and efficacy of ranirestat in patients with mild-to-moderate diabetic sensorimotor polyneuropathy.

We examined the efficacy and safety of ranirestat in patients with diabetic sensorimotor polyneuropathy (DSPN). Patients (18–75 years) with stable type 1/2 diabetes mellitus and DSPN were eligible for this global, double‐blind, phase II/III study (ClinicalTrials.gov NCT00927914). Patients (n = 800) were randomized 1 : 1 : 1 to placebo, ranirestat 40 mg/day or 80 mg/day (265 : 264 : 271). Change in peroneal motor nerve conduction velocity (PMNCV) from baseline to 24 months was the primary endpoint with a goal improvement vs. placebo ≥1.2 m/s. Other endpoints included symptoms, quality‐of‐life, and safety. Six hundred thirty‐three patients completed the study. The PMNCV difference from placebo was significant at 6, 12, and 18 months in both ranirestat groups, but <1.2 m/s. The mean improvement from baseline at 24 months was +0.49, +0.95, and +0.90 m/s for placebo, ranirestat 40 mg and 80 mg, respectively (NS). The treatment difference vs. placebo reached significance when ranirestat groups were combined in a post hoc analysis (+0.44 m/s; p = 0.0237). There was no effect of ranirestat on safety assessments, secondary or exploratory endpoints vs. placebo. Ranirestat was well tolerated and improved PMNCV, but did not achieve any efficacy endpoints. The absence of PMNCV worsening in the placebo group underscores the challenges of DSPN studies in patients with well‐controlled diabetes.