Using a single tablet daily to treat latent tuberculosis infection in Brazil: bioequivalence of two different isoniazid formulations (300 mg and 100 mg) demonstrated by a sensitive and rapid high-performance liquid chromatography-tandem mass spectrometry method in a randomised, crossover study

The recommended treatment for latent tuberculosis (TB) infection in adults is a daily dose of isoniazid (INH) 300 mg for six months. In Brazil, INH was formulated as 100 mg tablets. The treatment duration and the high pill burden compromised patient adherence to the treatment. The Brazilian National Programme for Tuberculosis requested a new 300 mg INH formulation. The aim of our study was to compare the bioavailability of the new INH 300 mg formulation and three 100 mg tablets of the reference formulation. We conducted a randomised, single dose, open label, two-phase crossover bioequivalence study in 28 healthy human volunteers. The 90% confidence interval for the INH maximum concentration of drug observed in plasma and area under the plasma concentration vs. time curve from time zero to the last measurable concentration “time t” was 89.61-115.92 and 94.82-119.44, respectively. The main limitation of our study was that neither adherence nor the safety profile of multiple doses was evaluated. To determine the level of INH in human plasma, we developed and validated a sensitive, simple and rapid high-performance liquid chromatography-tandem mass spectrometry method. Our results showed that the new formulation was bioequivalent to the 100 mg reference product. This finding supports the use of a single 300 mg tablet daily strategy to treat latent TB. This new formulation may increase patients’ adherence to the treatment and quality of life.

Association Study of Common Genetic Variants and HIV-1 Acquisition in 6,300 Infected Cases and 7,200 Controls.

Multiple genome-wide association studies (GWAS) have been performed in HIV-1 infected individuals, identifying common genetic influences on viral control and disease course. Similarly, common genetic correlates of acquisition of HIV-1 after exposure have been interrogated using GWAS, although in generally small samples. Under the auspices of the International Collaboration for the Genomics of HIV, we have combined the genome-wide single nucleotide polymorphism (SNP) data collected by 25 cohorts, studies, or institutions on HIV-1 infected individuals and compared them to carefully matched population-level data sets (a list of all collaborators appears in Note S1 in Text S1). After imputation using the 1,000 Genomes Project reference panel, we tested approximately 8 million common DNA variants (SNPs and indels) for association with HIV-1 acquisition in 6,334 infected patients and 7,247 population samples of European ancestry. Initial association testing identified the SNP rs4418214, the C allele of which is known to tag the HLA-B*57:01 and B*27:05 alleles, as genome-wide significant (p = 3.6×10(-11)). However, restricting analysis to individuals with a known date of seroconversion suggested that this association was due to the frailty bias in studies of lethal diseases. Further analyses including testing recessive genetic models, testing for bulk effects of non-genome-wide significant variants, stratifying by sexual or parenteral transmission risk and testing previously reported associations showed no evidence for genetic influence on HIV-1 acquisition (with the exception of CCR5Δ32 homozygosity). Thus, these data suggest that genetic influences on HIV acquisition are either rare or have smaller effects than can be detected by this sample size.

The expansion of 300 CTG repeats in myotonic dystrophy transgenic mice does not induce sensory or motor neuropathy.

Although many studies have been carried out to verify the involvement of the peripheral nervous system (PNS) in dystrophia myotonica (DM1) patients, the results remain controversial. The generation of DM1 transgenic mice displaying the human DM1 phenotype provides a useful tool to investigate the type and incidence of structural abnormalities in the PNS. In the present study, the morphological and morphometric analysis of semi-thin sections of sciatic and sural nerves, lumbar dorsal root ganglia (DRG) and lumbar spinal cords revealed that in DM1 transgenic mice carrying 300 CTG repeats, there is no change in the number and diameter of myelinated axons compared to wild type. Only a non-significant reduction in the percentage of thin myelinated axons was detected in electron micrographs of ultra-thin sciatic nerve sections. Analysis of the number of neurons did not reveal a loss in number of either sensory neurons in the lumbar DRG or motor neurons in the lumbar spinal cord in these DM1 mice. Furthermore, in hind limb muscle sections, stained with a neurofilament antibody and alpha-bungarotoxin, the intramuscular axon arborization appeared normal in DM1 mice and undistinguishable from that in wild-type mice. Moreover, in DM1 mice, there was no irregularity in the structure or an increase in the endplate area. Also statistical analysis did not show an increase in endplate density or in the concentration of acetylcholine receptors. Altogether, these results suggest that 300 CTG repeats are not sufficient to induce axonopathy, demyelination or neuronopathies in this transgenic mouse model.

Simultaneous determination of antidementia drugs by HPLC-MS: validation data of the method and plasma level determinations in 300 patients

Aims: A rapid and simple HPLC-MS method was developed for the simultaneousdetermination of antidementia drugs, including donepezil, galantamine, rivastigmineand its major metabolite NAP 226 - 90, and memantine, for TherapeuticDrug Monitoring (TDM). In the elderly population treated with antidementiadrugs, the presence of several comorbidities, drug interactions resulting frompolypharmacy, and variations in drug metabolism and elimination, are possiblefactors leading to the observed high interindividual variability in plasma levels.Although evidence for the benefit of TDM for antidementia drugs still remains tobe demonstrated, an individually adapted dosage through TDM might contributeto minimize the risk of adverse reactions and to increase the probability of efficienttherapeutic response. Methods: A solid-phase extraction procedure with amixed-mode cation exchange sorbent was used to isolate the drugs from 0.5 mL ofplasma. The compounds were analyzed on a reverse-phase column with a gradientelution consisting of an ammonium acetate buffer at pH 9.3 and acetonitrile anddetected by mass spectrometry in the single ion monitoring mode. Isotope-labeledinternal standards were used for quantification where possible. The validatedmethod was used to measure the plasma levels of antidementia drugs in 300patients treated with these drugs. Results: The method was validated accordingto international standards of validation, including the assessment of the trueness(-8 - 11 %), the imprecision (repeatability: 1-5%, intermediate imprecision:2 - 9 %), selectivity and matrix effects variability (less than 6 %). Furthermore,short and long-term stability of the analytes in plasma was ascertained. Themethod proved to be robust in the calibrated ranges of 1 - 300 ng/mL for rivastigmineand memantine and 2 - 300 mg/mL for donepezil, galantamine and NAP226 - 90. We recently published a full description of the method (1). We found ahigh interindividual variability in plasma levels of these drugs in a study populationof 300 patients. The plasma level measurements, with some preliminaryclinical and pharmacogenetic results, will be presented. Conclusion: A simpleLC-MS method was developed for plasma level determination of antidementiadrugs which was successfully used in a clinical study with 300 patients.

Comportamiento de la red de arrastre de fondo 300/160 Poliamida. Crucero BIC Olaya 0305-06

Durante el crucero de evaluación de la merluza peruana en otoño 2003 se evaluó el comportamiento de la red de arrastre de fondo 300/160 Poliamida durante 76 lances de pesca. El monitoreo se llevó a cabo mediante el sistema netsonda Scanmar RX 400, colocada sobre la red empleada a bordo del BIC Olaya. Los parámetros técnicos como abertura horizontal de punta de alas, abertura vertical y profundidad de la red, fueron analizados a través de correlaciones simples para validar las relaciones preestablecidas en anteriores cruceros.

A new technique for simultaneous validation of two manual nonmercury auscultatory sphygmomanometers (A&D UM-101 and Accoson Greenlight 300) based on the International protocol.

INTRODUCTION: Auscultatory nonmercury manual devices seem good alternatives for the mercury sphygmomanometers in the clinic and for research settings, but individual internal validation of each device is time-consuming. The aim of this study was to validate a new technique capable of testing two devices simultaneously, based on the International protocol of the European Society of Hypertension. METHODS: The concept of the new technique is to measure blood pressure alternatively by two observers using a mercury sphygmomanometer and by two observers using the A&D UM-101 and Accoson Greenlight 300 devices, connected by Y-tube to obtain simultaneous readings with both nonmercury devices. Thirty-three participants were enrolled (mean age 47.2±14.0 years). Nine sequential blood pressure measurements were performed for each participant. RESULTS: Both devices passed phase 1 using 15 participants. In phase 2.1 (n=33), on a maximum of 99 measurements, the Accoson device produced 81/95/99 measurements within 5/10/15 mmHg for systolic blood pressure (SBP) and 87/98/99 for diastolic blood pressure (DBP). The A&D device produced 86/96/99 for SBP and 94/99/99 for DBP. In phase 2.2 (n=33), 30 participants had at least 2 out of 3 SBP obtained with Accoson device within 5 mmHg of the mercury device, as compared with 29 of 33 participants with the A&D device. For DBP, this was 33 of 33 participants for both devices. CONCLUSION: Both the nonmercury devices passed the International protocol. The new technique of simultaneous device testing using a Y-tube represents a time saving application of the International protocol.

The effect of two pesticides (Vitavax-300 and Gaucho) on rhizobia and on the nodulation of four legumes

Selostus: Kasvinsuojeluaineiden Vitavax-300 ja Gaucho vaikutus juurinystyräbakteerin kasvuun ja neljän palkokasvin nystyröitymiseen

Iowa Development of Roller Compacted Concrete, HR-300, 1989

Roller compacted concrete (RCC) is a zero slump portland cement concrete mixture that has been used since the early 1970's in massive concrete structures. Iowa Highway Research Board project HR-300 was established to determine if this type mix could be used to pave roads on the Iowa road system. Manatt's Inc. of Brooklyn, Iowa agreed to pave an 800 ft. x 22 ft. x 10 in. section of RCC pavement in their Ames construction yard. This report discusses the construction of the test slab and interprets test results conducted during and after construction. It was observed that RCC can be placed with conventional asphalt paving equipment. However, there are several problems with RCC paving which must be resolved before RCC can become a viable paving alternative on Iowa's roadway system.

Desempenho de clones de seringueira da série IAC 300 selecionados para a região noroeste do Estado de São Paulo

É apresentado o desempenho de 19 novos clones de seringueira [Hevea brasiliensis (Willd. exAdr. de Juss.) Muell. Arg.], resultantes de hibridações conduzidas no Instituto Agronômico e avaliados em experimento de pequena escala, tendo o clone RRIM 600 como testemunha. O experimento em campo obedeceu ao delineamento em blocos ao acaso, com três repetições. Com relação à produção de borracha seca, o clone IAC 40 apresentou a maior média (62,22 g/árvore/sangria) nos três anos de avaliação, seguido pelo IAC 301 (57,67 g/árvore/sangria) e pelo IAC 300 (50,61 g/árvore/sangria), com produções 154%, 138% e 123% superiores em relação ao RRIM 600 (41,04 g/árvore/sangria). Todos os clones selecionados foram vigorosos, com perímetro do caule na abertura do painel variando de 37,81 cm (IAC 317) a 50,90 cm (IAC 315). A porcentagem de plantas aptas a sangria variou de 20,0% (IAC 317) a 100% (IAC 315). Todos os clones apresentaram baixas incidências de quebra pelo vento e de secamento do painel. Não foi detectada nenhuma doença foliar em caráter epidêmico. Dos clones estudados, 15 apresentaram alta resistência à antracnose do painel, e foram superiores ao RRIM 600; os outros cinco apresentaram resistência moderada semelhante ao RRIM 600.

Desempenho de clones de seringueira da série IAC 300 na região do planalto de São Paulo

O objetivo deste trabalho foi selecionar clones de seringueira (Hevea spp.) promissores para a região do planalto do Estado de São Paulo. De uma população de 70 clones, de polinização controlada, integrantes do experimento de avaliação em pequena escala, foram avaliados 16 da série IAC 300. O experimento foi instalado na Estação Experimental de Pindorama, no espaçamento de 7 x 3 m, em delineamento de blocos casualizados, com três repetições, tendo os clones RRIM 600 e GT 1 como testemunhas. Quanto à produção de borracha seca, destacaram-se oito e dez clones superiores ao RRIM 600 e GT 1, respectivamente. Todos os clones avaliados apresentaram-se vigorosos em relação ao perímetro do caule na abertura do painel. Sete deles mostraram alta resistência; sete, resistência moderada, e dois, suscetíveis à antracnose do painel. Sugere-se sua avaliação em experimentos de grande escala, para avaliar, além da produção, os demais caracteres secundários, em diferentes ambientes, para futuras recomendações em larga escala para o Estado de São Paulo.