Mesial temporal lobe epilepsy: clinical and neuropathologic findings of familial and sporadic forms

Purpose: To evaluate the clinical and hippocampal histological features of patients with mesial temporal lobe epilepsy (MTLE) in both familial (FMTLE) and sporadic (SMTLE) forms.
Methods: Patients with FMTLE (n = 20) and SMTLE (n = 39) who underwent surgical treatment for refractory seizures were studied at the University of São Paulo School of Medicine at Ribeirão Preto. FMTLE was defined when at least two individuals in a family had clinical diagnosis of MTLE. Hippocampi from all patients were processed for Nissl/HE and Timm's stainings. Both groups were compared for clinical variables, hippocampal cell densities, and intensity of supragranular mossy fiber staining.
Results: There were no significant differences between FMTLE and SMTLE groups in the following: age at the surgery, age of first usual epileptic seizure, history of initial precipitating injury (IPI), age of IPI, latent period, ictal and interictal video-EEG patterns, presence of hippocampal atrophy and signal changes at MRI, and postoperative outcome. In addition, no differences were found in cell densities in hippocampal cornu ammonis subfields (CA1, CA2, CA3, CA4), fascia dentata, polymorphic region, subiculum, prosubiculum, and presubiculum. However, patients with SMTLE had greater intensity of mossy fiber Timm's staining in the fascia dentata-inner molecular layer (p< 0.05).
Discussion: Patients with intractable FMTLE present a clinical profile and most histological findings comparable to patients with SMTLE. Interestingly, mossy fiber sprouting was less pronounced in patients with FMTLE, suggesting that, when compared to SMTLE, patients with FMTLE respond differently to plastic changes plausibly induced by cell loss, neuronal deafferentation, or epileptic seizures.     

Cytochrome P450 reaction-phenotyping: an industrial perspective

It is now widely accepted that the fraction of the dose metabolized by a given drug-metabolizing enzyme is one of the major factors governing the magnitude of a drug interaction and the impact of a polymorphism on (total) drug clearance. Therefore, most pharmaceutical companies determine the enzymes involved in the metabolism of a new chemical entity (NCE) in vitro, in conjunction with human data on absorption, distribution, metabolism and excretion. This so called reaction-phenotyping, or isozyme-mapping, usually involves the use of multiple reagents (e.g., recombinant proteins, liver subcellular fractions, enzyme-selective chemical inhibitors and antibodies). For the human CYPs, reagents are readily available and in vitro reaction-phenotyping data are now routinely included in most regulatory documents. Ideally, the various metabolites have been definitively identified, incubation conditions have afforded robust kinetic analyses, and well characterized (high quality) reagents and human tissues have been employed. It is also important that the various in vitro data are consistent (e.g., scaled turnover with recombinant CYP proteins, CYP inhibition and correlation data with human liver microsomes) and enable an integrated in vitro CYP reaction-phenotype. Results of the in vitro CYP reaction-phenotyping are integrated with clinical data (e.g., human radiolabel and drug interaction studies) and a complete package is then submitted for regulatory review. If the NCE receives market approval, information on key routes of clearance and their associated potential for drug-drug interactions are included in the product label. The present review focuses on in vitro CYP reaction-phenotyping and the integration of data. Relatively simple strategies enabling the design and prioritization of follow up clinical studies are also discussed.     

Brazilian plants with possible action on the central nervous system: a study of historical sources from the 16th to 19th century

Brazil is a country rich in biodiversity, endemism, and cultural diversity, inhabited by different types of population. European expeditions and the migratory processes that began in the 16th century greatly contributed both to cultural diversity and to Brazilian popular therapeutics, and produced the first records on medicinal plants in Brazil. This study comprises a bibliographical survey of historic books found in Sao Paulo libraries (16th through 19th centuries) on medicinal plants exerting effects on the central nervous system (CNS). Thirty-four plants native to Brazil were selected from the reading of the books. Of these 34 plants, 13 were also recorded in ethnopharmacological studies among modern Brazilian communities and 16 have been studied phytochemically. Only eight have been the object of pharmacological studies, six of these, recently, with a request for a patent. Results showed that most of the species recorded in this study have been reported as medicinal for centuries, but have never been the object of pharmacological investigation down to the present time. Such results provide ideas for a selection of these species as potentially bioactive to be included in future pharmacological studies.     

Plants of restricted use indicated by three cultures in Brazil (Caboclo-river dweller, Indian and Quilombola)

A detailed record of plants cited during ethnopharmacological surveys, suspected of being toxic or of triggering adverse reactions, may be an auxiliary means to pharmacovigilance of phytomedicines, in that it provides greater knowledge of a “bad side” to plant resources in the Brazilian flora. This study describes 57 plant species of restricted use (abortive, contraceptive, contraindicated for pregnancy, prescribed in lesser doses for children and the elderly, to easy delivery, in addition to poisons to humans and animals) as indicated during ethnopharmacological surveys carried out among three cultures in Brazil (Caboclos-river dwellers, inhabitants of the Amazon forest; the Quilombolas, from the pantanal wetlands; the Krahô Indians, living in the cerrado savannahs). These groups of humans possess notions, to a remarkable extent, of the toxicity, contraindications, and interaction among plants. A bibliographical survey in the Pubmed, Web of Science and Dr. Duke's Phytochemical and Ethnobotanical Databases has shown that 5 out of the 57 species have some toxic properties described up to the present time, they are: Anacardium occidentale L. (Anacardiaceae), Brosimum gaudichaudii Trécul (Moraceae), Senna alata (L.) Roxb. (Fabaceae), Senna occidentalis (L.) Link (Fabaceae), Strychnos pseudoquina A. St.-Hil. (Loganiaceae) and Vernonia brasiliana (L.) Druce (Asteraceae).     

Pulmonary phagocyte depression induced by an acid or alkaline solution in a rat model of peritonitis

BACKGROUND: Peritonitis is a surgical problem with a high mortality rate attributable to various complications, including respiratory infection. This complication is more common under certain conditions reflective of the origin of peritonitis, suggesting that the composition of the peritoneal fluid exerts an influence on the intensity of the macrophage and peritoneal response. To establish a correlation among macrophage function, absorption of bacteria from the peritoneal cavity, and the pH of the peritoneal fluid, we carried out this study. METHODS: Thirty female Wistar rats were divided into three equal groups, all of which received infusions of 0.9% saline by parietal puncture. In group A (control), the saline pH was 7.0; in group B, it was 2.5; and in group C, it was 8.5. After 40 min, 0.25 mL of a suspension containing 10(11) colony-forming units of (99m)Tc-labeled Escherichia coli was infused by the same route. After another 40 min, samples of vena caval blood, spleen, liver, and lung were removed; the radioactivity was counted; bacterial absorption was determined; and the proportional radioactivity/g of tissue was calculated. The values were compared among the groups by the Student t-test, with the level of significance set at p < 0.05. RESULTS: There was significantly greater bacterial absorption in group B than in group C (p = 0.004) but no differences in the numbers of bacteria in the liver and spleen. Bacteria were significantly more numerous in the peripheral blood in group B than in groups A and C (p = 0.04 for both). Pulmonary phagocytosis was significantly reduced in group B compared with group A (p = 0.008) and group C (p = 0.005). CONCLUSION: Peritonitis associated with acidic conditions in the peritoneal cavity is correlated with a reduction in pulmonary phagocytosis and an increase in the numbers of nonphagocytized bacteria in the peripheral blood, possibly representing a direct or indirect cause of the higher incidence of pneumonia and sepsis in these individuals.     

Bioequivalence of two enteric coated formulations of pantoprazole in healthy volunteers under fasting and fed conditions

PURPOSE: To compare the bioavailability of two pantoprazole (CAS 102625-70-7) formulations (40 mg pantoprazole enteric coated tablets) under fasted and fed conditions as well as to evaluate the dissolution profile in biorelevant media. METHODS: The subjects received either 40 mg of the reference or of test formulation in fasting (n = 28) and fed (n=70) condition. The studies were conducted according to a single dose and randomized crossover design. Blood samples were collected up to 12 h after drug administration in fasting condition and up to 48 h in fed condition. Plasma concentrations of pantoprazole were determined by LC-MS/MS. Pharmacokinetic parameters were calculated from the observed plasma concentration-time profiles. Bioequivalence between the formulations in fasting and fed condition was assessed considering 90% confidence intervals for the ratio of means for lnCmax and lnAUC(0-t) within 0.8-1.25. Dissolution profiles were evaluated in biorelevant media [Fasting State Simulating Intestinal Fluid (FaSSIF) and Fed State Simulating Intestinal Fluid (FeSSIF)]. The sameness of the dissolution curves was assessed by f2 values between 50 and 100. RESULTS: Under fasting condition the 90% confidence interval for the ratio of means for the lnCmax, (0.94-1.03) and lnAUC(0-t) (0.89-0.99) was within the guideline range of bioequivalence (0.80-1.25). However, the data for lnCmax (0.51-0.76) and lnAUC(0-t) (0.68-0.90) under fed condition were not within the bioequivalence range. The postprandial study demonstrated a high intra-subject variability and in some subjects pantoprazole could not be detected for up to 24 h, although the dissolution profile of reference and test formulations presented a similar disposition in FaSSIF and FeSSIF as confirmed by the values of f2 higher than 50. CONCLUSION: The results demonstrated that the test formulation was bioequivalent to the reference in fasting condition but not in postprandial state. The dissolution profile in FaSSIF indicates that this biorelevant medium was more adequate to discriminate the in vivo disposition of pantoprazole than FeSSIF. Furthermore, the fed condition study had shown a pronounced influence of food in the absorption of pantoprazole after single oral dose administration.     

DNA repair polymorphisms might contribute differentially on familial and sporadic breast cancer susceptibility: a study on a Portuguese population

The purpose of this study was to evaluate the role of polymorphisms in DNA repair genes as genetic indicators of susceptibility to familial and sporadic breast cancer. We analysed DNA samples from 285 breast cancer patients and 442 control subjects, for XRCC1 Arg399Gln, XPD Lys751Gln, RAD51 G135C and XRCC3 Thr241Met polymorphisms using PCR-RFLP. We observed that women carriers of XRCC1 399Gln genotypes and without family history of breast cancer have a protective effect concerning this disease (OR = 0.54 95% CI 0.35–0.84; p = 0.006). Furthermore, we found that carriers of XRCC3 241Met genotypes without FH have an increased susceptibility of breast cancer (OR = 2.21 95% CI 1.42–3.44; p < 0.001). Additionally, we verified an increased risk of breast cancer in women with FH and carrying RAD51 135C genotypes (OR = 2.17 95% CI 1.19–3.98; p = 0.012). Our results suggest XRCC1 Arg399Gln and XRCC3 Thr241Met DNA repair polymorphisms as important biomarkers to sporadic breast cancer susceptibility, as well as, RAD51 G135C polymorphism as a real risk modifier in familial breast cancer cases.     

Systematic review of baseline low-dose CT lung cancer screening

The purpose of this systematic review was to provide physicians and patients with a synthesis of the available data and an assessment of the operating characteristics associated with baseline LDCT screening for lung cancer. Various databases, meeting abstracts, clinical trials in progress, and major textbooks for relevant data from 1966 to 2006 were searched for relevant studies. The median value of sensitivity, specificity, positive predictive value and negative predictive value were 81%, 81%, 8% and 99%, respectively. Of the studies that compared LDCT with other lung cancer screening maneuvers, it was found that LDCT detected a greater number of cancerous nodules. On average, 80% of lung cancers detected by baseline LDCT screening were categorized as Stage I cancers. Current data demonstrate that both the operating characteristics of baseline LDCT screening and the relatively high proportion of Stage I cancers detected with LDCT may potentially lead to effective screening programs. However, evidence of reduced mortality and morbidity with the use of LDCT is not established. Therefore, LDCT for lung cancer screening should be considered as investigative and needs to be confirmed by well-designed randomized controlled trials prior to community and institutional implementation.