Intranasal versus intravenous lorazepam for control of acute seizures in children: a randomized open-label study

Purpose: Intravenous lorazepam is considered the drug of first choice for control of acute convulsive seizures. However, resource or personnel constraints necessitate the study of alternative routes and medications. This study compared the efficacy and adverse effects of intranasal versus intravenous lorazepam in children aged 6–14 years who presented with acute seizures. Methods: This was a randomized open‐label study conducted at an Indian hospital from August 2008 to April 2009. One hundred forty‐one consecutive children aged 6–14 years who presented convulsing to the emergency room were included. After stabilization, the children were randomized to receive either intravenous or intranasal lorazepam (0.1 mg/kg, maximum 4 mg). The primary outcome measure was clinical seizure remission within 10 min of drug administration. The study was registered with clinicaltrials.gov (NCT00735527). Key Findings: Seventy patients were randomized to receive intravenous and 71 to receive intranasal lorazepam. The patients in the two groups were comparable at baseline. Clinical seizure remission within 10 min of drug administration was found in 80% of the intravenous group as compared to 83.1% of intranasal group. The lower limit of 95% confidence interval for effect size was approximately −9.7%, with an a priori cutoff for noninferiority of −10%. Significance: Intranasal administration of lorazepam is not found to be inferior to intravenous administration for termination of acute convulsive seizures in children.     

Blood pressure related to age: The India ABPM study

The present paper reports trends in office blood pressure (BP) measurement (OBPM) and ambulatory blood pressure measurement (ABPM) with age in a large multi‐center Indian all comers’ population visiting primary care physicians. ABPM and OBPM data from 27 472 subjects (aged 51 ± 14 years, males 68.2%, treated 45.5%) were analyzed and compared. Individual differences between OBPM and ABPM patterns were compared for patients according to 10‐year age categories. Results showed that systolic (S) BP values started to increase with age from the age of 40, BP variability (SD) increased from the age of 30 years. Diastolic (D) BP values started to decrease from the age of 50 years. Mean OBPM values were higher than daytime ABPM values (all P < .001) in all age‐groups. The prevalence of white coat hypertension (WCH) and masked hypertension (MH) was based on OBPM and daytime, 24‐hour, and nighttime average BPs together. WCH decreased with age from 15.1% and 12.4% in treated and untreated subjects at the youngest age to 7.2% and 6.9% in the oldest age, respectively. MH prevalence was higher for untreated than for treated subjects but remained similar for all age‐groups (range of 18.6%‐21.3%). The prevalence of reverse dippers increased with age from the youngest to oldest group with 7.3%‐34.2% (P < .001 for trend). Dippers prevalence decreased from 42.5% to 17.9% from the youngest to oldest age‐groups, respectively (P < .001 for trend). These findings confirm that BP patterns show clear differences in trends with age, particularly regarding nighttime BP.     

Selective brain cooling in rats ameliorates intracerebral hemorrhage and edema caused by penetrating brain injury: possible involvement of heme oxygenase-1 expression

Brain edema formation associated with trauma-induced intracerebral hemorrhage (ICH) is a clinical complication with high mortality. Studies have shown that heme oxygenase-1 (HO-1) plays an important role in ICH-induced brain edema. In order to understand the role of HO-1 in the protective effect of selective brain cooling (SBC), we investigated the time course of HO-1 changes following penetrating ballistic-like brain injury (PBBI) in rats. Samples were collected from injured and control animals at 6, 24, 48, and 72 h, and 7 days post-injury to evaluate HO-1 expression, heme concentration, brain water content, and immunohistochemistry (IHC). Following a 10% frontal PBBI, HO-1 mRNA and protein was increased at all time points studied, reaching maximum expression levels at 24-48 h post-injury. An increase in the heme concentration and the development of brain edema coincided with the upregulation of HO-1 mRNA and protein during the 7-day post-injury period. SBC significantly decreased PBBI-induced heme concentration, attenuated HO-1 upregulation, and concomitantly reduced brain water content. These results suggest that the neuroprotective effects of SBC may be partially mediated by reducing the heme accumulation, which reduced injury-mediated upregulation of HO-1, and in turn ameliorated edema formation. Collectively, these results suggest a potential value of HO-1 as a diagnostic and/or therapeutic biomarker in hemorrhagic brain injury.     

Disseminated cysticercosis in a child: whole-body MR diagnosis with the use of parallel imaging

Cysticercosis is a parasitic disease caused by infestation with the encysted larval stage of the pork tapeworm, Taenia solium. Disseminated cysticercosis is an exceptional expression of this disease characterized by high morbidity due to massive symptomatic parasite burden in the central nervous system, striated muscles, subcutaneous tissues and other organs. Less than 50 such cases have been reported worldwide, and fewer than 10 children. We report on the whole-body MR diagnosis of extensively disseminated cysticercosis in a child. The critical role of whole-body MR as a stand-alone modality in the diagnosis and management of this pleomorphic disease is highlighted. Whole-body MR diagnosis of an infectious disease is unique.     

Remodeling of tibial fractures in children younger than 12 years

Forty-eight children with an average age of 7.2 years (range: 3-12 years) were examined clinically and radiographically at an average 4-year follow-up (range: 2-10 years), between 1989 and 2000 to analyze correction of deformities following tibial shaft fractures. An inconsistent alteration in the length of the fractured tibia was observed. Anterior angular deformity realigned maximally (52.7%) followed by varus (40.9%) and valgus (23.9%) deformities. Posterior deformity corrected the least (18.5%). In the sagittal plane, acceptable critical anterior and posterior angular deformities that corrected completely were 12 degrees and 6 degrees respectively. In the coronal plane, acceptable critical angular deformities were 10 degrees varus and 8 degrees valgus.     

Split-hand/split-foot malformation 3 (SHFM3) at 10q24, development of rapid diagnostic methods and gene expression from the region

Split-hand/split-foot malformation (SHFM, also called ectrodactyly) is a clinically variable and genetically heterogeneous group of limb malformations. Several SHFM loci have been mapped, including SHFM1 (7q21), SHFM2 (Xq26), SHFM3 (10q24), SHFM4 (3q27) and SHFM5 (2q31). To date, mutations in a gene (TP63) have only been identified for SHFM4. SHFM3 has been shown by pulsed-field gel electrophoresis to be caused by an approximately 500 kb DNA rearrangement at 10q24. This region contains a number of candidate genes for SHFM3, though which gene(s) is (are) involved in the pathogenesis of SHFM3 is not known. Our aim in this study was to improve the diagnosis of SHFM3, and to begin to understand which genes are involved in SHFM3. Here we show, using two different techniques, FISH and quantitative PCR that SHFM3 is caused by a minimal 325 kb duplication containing only two genes (BTRC and POLL). The data presented provide improved methods for diagnosis and begin to elucidate the pathogenic mechanism of SHFM3. Expression analysis of 13 candidate genes within and flanking the duplicated region shows that BTRC (present in three copies) and SUFU (present in two copies) are overexpressed in SHFM3 patients compared to controls. Our data suggest that SHFM3 may be caused by overexpression of BTRC and SUFU, both of which are involved in beta-catenin signalling.     

Diclofenac Sodium-Loaded Eudragit® Microspheres: Optimization Using Statistical Experimental Design

Purpose

In this study, polymeric microspheres containing diclofenac sodium were prepared by single emulsion (oil-in-water) solvent evaporation method and evaluated for their size, morphology, encapsulation efficiency, drug loading, and in vitro drug release.

Methods

Two nonbiodegradable polymers, Eudragit® RS100 and RL100 were used in combination. Microspheres were prepared by varying the amount of polyvinyl alcohol as a surfactant (0.05, 0.125, and 2.0 %, w/v) to the external phase; varying the amount of polymer (1:1, 2:1, and 3:1, w/w) to the drug by employing 3² full factorial design using the Design Expert (Version 8.0.7.1). The drug polymer interactions were investigated by Fourier transform infrared spectroscopy (FTIR) and X-ray powder diffractometry (XRPD). Imaging of particles was performed by field emission scanning electron microscopy.

Results

Graphical and mathematical analysis of the design showed a quadratic model was significant for the responses. Low magnitude of error and significant values of R ² proves the high prognostic ability of the RSM. Encapsulation efficiency of microspheres (41.13 to 65.33 %) increases with an increase in surfactant concentration but decreases with an increase in polymer concentration. The microspheres were found to be discrete, spherical with smooth surface. The absence of drug polymer interactions was confirmed by FTIR spectroscopy. XRPD revealed the dispersion of drug within microspheres formulation. The Perfect pH-independent release profile was achieved from Eudragit® microspheres by anomalous transport mechanism.

Conclusions

In conclusion, Eudragit® microspheres containing diclofenac sodium can be successfully prepared, and seem to be promising for sustained release application.     

Molecular cloning and characterization of Plasmodium falciparum transketolase

The pentose phosphate pathway (PPP) is an important metabolic pathway for yielding reducing power in the form of NADPH and production of pentose sugar needed for nucleic acid synthesis. Transketolase, the key enzyme of non-oxidative arm of PPP, plays a vital role in the survival/replication of the malarial parasite. This enzyme in Plasmodium falciparum is a novel drug target as it has least homology with the human host. In the present study, the P. falciparum transketolase (PfTk) was expressed, localized and biochemically characterized. The recombinant PfTk harboring transketolase activity catalyzed the oxidation of donor substrates, fructose-6-phosphate (F6P) and hydroxypyruvate (HP), with K(m)(app) values of 2.25 and 4.78 mM, respectively. p-Hydroxyphenylpyruvate (HPP) was a potent inhibitor of PfTk, when hydroxypyruvate was used as a substrate, exhibiting a K(i) value of 305 microM. At the same time, noncompetitive inhibition was observed with F6P. The native PfTk is a hexamer with subunit molecular weight of 70kDa, which on treatment with low concentrations of guanidine hydrochloride (GdmCl) dissociated into functionally active dimers. This protein was localized in the cytosol and nucleus of the parasite as studied by confocal microscopy. A model structure of PfTk was constructed based on the crystal structure of the transketolases of Saccharomyces cerevisae, Leishmania mexicana and Escherichia coli to assess the structural homology. Consistent with the homology modeling predictions, CD analysis indicated that PfTk is composed of 39% alpha-helices and 26% beta-sheets. The availability of a structural model of PfTk and the observed differences in its kinetic properties compared to the host enzyme may facilitate designing of novel inhibitors of PfTk with potential anti-malarial activity.