Efficacy and safety of perampanel in generalized and focal to bilateral tonic‐clonic seizures: A comparative study of Asian and non‐Asian populations

Perampanel is an approved adjunctive treatment for focal seizures with or without focal to bilateral tonic‐clonic (FBTC) seizures and generalized tonic‐clonic (GTC) seizures. We compared efficacy and safety of perampanel vs placebo in Asian and non‐Asian populations in a post hoc analysis of pooled data from 5 randomized phase 3 studies. Patients (≥12 years old) with focal + FBTC seizures received perampanel 2, 4, 8, or 12 mg or placebo; patients with GTC seizures received perampanel 8 mg or placebo (titration: 4‐6 weeks; maintenance: 13 weeks). Efficacy endpoints included median percentage change in FBTC or GTC seizure frequency per 28 days and 50% responder rate relative to baseline. Median percentage change in FBTC seizure frequency was significantly greater for perampanel 8 and 12 mg than placebo in the Asian population (median difference from placebo: ?30.32%, P = 0.0017; ?30.06%, P = 0.0008, respectively) and perampanel 4, 8, and 12 mg in the non‐Asian population (?35.07%, P = 0.0001; ?37.78%, P < 0.0001; ?34.53%, P < 0.0001, respectively). In both populations, median percentage change in GTC seizure frequency was significantly greater for perampanel 8 mg than placebo (median difference from placebo: Asian, ?37.37%, P = 0.0139; non‐Asian, ?27.04%, P = 0.0006). The 50% responder rates were significantly greater than placebo for perampanel 8 and 12 mg for FBTC seizures (Asian: 58.0%, P = 0.0017 and 58.6%, P = 0.0013, respectively; non‐Asian: 59.3%, P < 0.0001 and 54.3%, P = 0.0050, respectively) and perampanel 8 mg for GTC seizures (Asian: 57.6%, P = 0.0209; non‐Asian: 68.8%, P = 0.0329). Pooled FBTC/GTC seizure data showed generally similar patterns of response to perampanel in both populations. The most frequent treatment‐related adverse events were fatigue, irritability, dizziness, somnolence, and headache. Perampanel was effective, well tolerated, and can be considered a therapeutic option for FBTC/GTC seizures in Asian populations.     

Effect of surfaces on fluid-phase prekallikrein activation

The activation of prekallikrein by factor XII fragments (XIIf), during incubation in plastic tubes was previously noted to be increased by high molecular weight (HMW) kininogen as well as other plasma proteins. In this report, we investigated the mechanism responsible for this increase. Although we confirmed that HMW kininogen, bovine serum albumin, fibrinogen, cold insoluble globulin, and mixed phospholipids apparently increased prekallikrein activation, we found that the product of prekallikrein activation (kallikrein) lost substantial activity in less than 0.5 min after exposure to a variety of fresh surfaces. This loss was partially prevented by the presence of various proteins and phospholipids. Similar protection against inactivation of XIIf, the enzyme in this reaction, was also found. In contrast, no loss of the substrate, prekallikrein, was observed during incubation. The loss of kallikrein activity was found to be proportional to the surface area of the incubation vessel as well as the concentration of kallikrein. Further loss of kallikrein activity could also be prevented by pretreating the vessel with kallikrein. We therefore conclude that various substances apparently affect prekallikrein activation in a purified system by preventing the enzyme and product in the reaction mixture from losing activity due to adsorption to a surface.     

Effects of correction of metabolic acidosis on blood urea and bone metabolism in patients with mild to moderate chronic kidney disease: a prospective randomized single blind controlled trial

BACKGROUND: There are no controlled trials on the efficacy of oral bicarbonate therapy in patients with mild to moderate chronic kidney disease (CKD). This prospective randomized controlled study was done to evaluate the effects of correction of metabolic acidosis on renal functions and bone metabolism in this group of patients. PATIENTS AND METHODS: Forty patients were randomized to treatment with oral bicarbonate or placebo for a period of 3 months. Investigations at baseline included venous pH, bicarbonate, renal functions, serum iPTH, and bone radiology. The treatment group (Group B) received daily oral sodium bicarbonate therapy at a dose of 1.2 mEq/kg of body weight. Their venous blood pH and bicarbonate levels were estimated weekly to keep blood pH near 7.36 and bicarbonate at 22-26 mEq/L by adjusting the dose of sodium bicarbonate. At the end of 3 months, all the tests were repeated in both groups. RESULTS: After oral bicarbonate therapy (OBT), there was a significant decline in the rise of blood urea level in Group B associated with a sense of well-being in 50% patients. The rise in parathormone (PTH) was six times the baseline value in Group A and only 1.5 times baseline value in Group B, although not statistically significant. There was no significant change in total calcium, phosphorus, alkaline phosphatase, creatinine, total protein, or albumin levels. CONCLUSION: Correction of metabolic acidosis in patients with moderate CKD attenuates the rise in blood urea and PTH, which might prevent the deleterious long-term consequences of secondary hyperparathyroidism.     

Anatase titanium dioxide nanoparticles in mice: evidence for induced structural and functional sperm defects after short-, but not long-, term exposure

Titanium dioxide (TiO₂) nanoparticles (TNPs) are widely used commercially and exist in a variety of products. To determine if anatase TNPs (ATNPs) in doses smaller than previously used reach the scrotum after entry in the body at a distant location and induce sperm defects, 100% ATNP (2.5 or 5 mg kg⁻¹ body weight) was administered intraperitoneally to adult males for three consecutive days, followed by sacrifice 1, 2, 3, or 5 weeks later (long-) or 24, 48 or 120 h (short-term exposure). Transmission electron microscopy revealed the presence of ANTP in scrotal adipose tissues collected 120 h postinjection when cytokine evaluation showed an inflammatory response in epididymal tissues and fluid. At 120 h and up to 3 weeks postinjection, testicular histology revealed enlarged interstitial spaces. Significantly increased numbers of terminal deoxyribonucleotidyl transferase-mediated dUTP nick-end labeling-positive (apoptotic) germ (P = 0.002) and interstitial space cells (P = 0.04) were detected in treated males. Caudal epididymal sperm from the short-term, but not a long-term, arm showed significantly (P < 0.001) increased frequencies of flagellar abnormalities, excess residual cytoplasm (ERC), and unreacted acrosomes in treated versus controls (dose-response relationship). A novel correlation between ERC and unreacted acrosomes was uncovered. At 120 h, there were significant decreases in hyperactivated motility (P < 0.001) and mitochondrial membrane potential (P < 0.05), and increased reactive oxygen species levels (P < 0.00001) in treated versus control sperm. These results indicate that at 4–8 days postinjection, ANTP induce structural and functional sperm defects associated with infertility, and DNA damage via oxidative stress. Sperm defects were transient as they were not detected 10 days to 5 weeks postinjection.     

A review of perioperative complications during frameless stereotactic surgery: our institutional experience

Purpose  Frameless stereotactic neurosurgery is increasingly being used for the biopsy of intracranial tumors and the resection of deep-seated lesions where reliance on surface anatomic landmarks can be misleading, as well as in movement disorders, psychiatric disorders, seizure disorders, and chronic refractory pain. Nascent biological approaches, including gene therapy and stem-cell and tissue transplants for movement disorders, also utilize neuronavigational techniques. These procedures are complex and involve understanding of the basic principles and factors affecting neuronavigation. The procedure may appear to be simple, but serious complications may occur. Methods  The purpose of this study was to review the intraoperative and postoperative complications occurring during frameless stereotaxy at our institution from January 2003 to July 2007. Results  Seventy-eight patients underwent various neurosurgical procedures under general anesthesia. Intraoperative complications seen were intraoperative brain bulge (n = 3), seizures (n = 3), failure to extubate (n = 4), and fresh neurodeficits (n = 6). No hemodynamic disturbances such as hypertension or hypotension or bradycardia or tachycardia requiring active intervention were observed. Conclusion  Awareness and vigilance can help in the early identification and better management of the above intraoperative complications.     

Management of zygomatic complex fracture in armed forces

Introduction: The Armed Forces personnel are exposed to various kinds of injuries due to the nature of their duties. Increase in motorized population without taking protective measures and rise in violence has contributed towards maxillofacial injuries. The aim of this study was to determine the incidence, aetiology and management of injuries resulting in fracture of the Zygomatic complex in Armed Forces personnel and their families.     

The pharmacokinetic diversity of two von Willebrand factor (VWF)/ factor VIII (FVIII) concentrates in subjects with congenital von Willebrand disease. Results from a prospective, randomised crossover study

The pharmacokinetic (PK) profiles of von Willebrand factor (VWF) /factor VIII (FVIII) concentrates are important for treatment efficacy and safety of von Willebrand disease (VWD) patients. This prospective, head-to-head, randomised crossover study compared the PK profile of a new, high purity, human plasma-derived (pd)VWF/FVIII concentrate, Wilate, with the PK profile of an intermediate purity (pd)VWF/FVIII concentrate, Humate-P, in VWD patients. Subjects with inherited VWD were randomised to a single intravenous dose (40 IU/kg VWF ristocetin cofactor activity [VWF:RCo]) of Wilate or Humate-P in Period 1, and switched to the other study drug in Period 2. Each period was preceded by a washout time of ≥ 7 days. Coagulation factor parameters were analysed at multiple time-points. Of 22 randomised subjects, 20 had evaluable PK profiles, which indicated comparability for VWF antigen and VWF:RCo between Wilate and Humate-P. The reported VWF:RCo average and terminal t1/2 of 10.4 and 15.8 hours (h), respectively, for Wilate and 9.3 h and 12.8 h for Humate-P, were not statistically different. Also, the mean VWF:RCo in vivo recoveries (Wilate 1.89, Humate-P 1.99 IU/dl per IU/kg) were similar between the two replacement therapies. Wilate showed parallel decay curves for VWF:RCo and FVIII clotting activity (FVIII:C) over time, while FVIII:C of Humate-P displayed a plateau between 0 and 12-24 h. This study demonstrated bioequivalent PK properties for VWF between Wilate and Humate-P. The PK profile of Wilate, combined with the 1:1 VWF/FVIII ratio, theoretically should facilitate dosing and laboratory monitoring of VWF replacement to prevent bleeding in individuals with VWD.