Process Monitoring of Moisture Content and Mass Transfer Rate in a Fluidised Bed with a Low Cost Inline MEMS NIR Sensor.

PURPOSE: The current trend for continuous drug product manufacturing requires new, affordable process analytical techniques (PAT) to ensure control of processing. This work evaluates whether property models based on spectral data from recent Fabry-Pérot Interferometer based NIR sensors can generate a high-resolution moisture signal suitable for process control. METHODS: Spectral data and offline moisture content were recorded for 14 fluid bed dryer batches of pharmaceutical granules. A PLS moisture model was constructed resulting in a high resolution moisture signal, used to demonstrate (i) endpoint determination and (ii) evaluation of mass transfer performance. RESULTS: The sensors appear robust with respect to vibration and ambient temperature changes, and the accuracy of water content predictions (±13 % ) is similar to those reported for high specification NIR sensors. Fusion of temperature and moisture content signal allowed monitoring of water transport rates in the fluidised bed and highlighted the importance water transport within the solid phase at low moisture levels. The NIR data was also successfully used with PCA-based MSPC models for endpoint detection. CONCLUSIONS: The spectral quality of the small form factor NIR sensor and its robustness is clearly sufficient for the construction and application of PLS models as well as PCA-based MSPC moisture models. The resulting high resolution moisture content signal was successfully used for endpoint detection and monitoring the mass transfer rate.

Data fusion strategies to combine sensor and multivariate model outputs for multivariate statistical process control.

Process analytical technologies (PAT) applied to process monitoring and control generally provide multiple outputs that can come from different sensors or from different model outputs generated from a single multivariate sensor. This paper provides a contribution to current data fusion strategies for the combination of sensor and/or model outputs in the development of multivariate statistical process control (MSPC) models. Data fusion is explored through three real process examples combining output from multivariate models coming from the same sensor uniquely (in the near-infrared (NIR)-based end point detection of a two-stage polyester production process) or the combination of these outputs with other process variable sensors (using NIR-based model outputs and temperature values in the end point detection of a fluidized bed drying process and in the on-line control of a distillation process). The three examples studied show clearly the flexibility in the choice of model outputs (e.g. key properties prediction by multivariate calibration, process profiles issued from a multivariate resolution method) and the benefit of using MSPC models based on fused information including model outputs towards those based on raw single sensor outputs for both process control and diagnostic and interpretation of abnormal process situations. The data fusion strategy proposed is of general applicability for any analytical or bioanalytical process that produces several sensor and/or model outputs. Graphical abstract.

Glycine Receptor Inhibition Differentially Affect Selected Neuronal Populations of the Developing Embryonic Cortex, as Evidenced by the Analysis of Spontaneous Calcium Oscillations.

The embryonic developing cerebral cortex is characterized by the presence of distinctive cell types such as progenitor pools, immature projection neurons and interneurons. Each of these cell types is diverse on itself, but they all take part of the developmental process responding to intrinsic and extrinsic cues that can affect their calcium oscillations. Importantly, calcium activity is crucial for controlling cellular events linked to cell cycle progression, cell fate determination, specification, cell positioning, morphological development and maturation. Therefore, in this work we measured calcium activity in control conditions and in response to neurotransmitter inhibition. Different data analysis methods were applied over the experimental measurements including statistical methods entropy and fractal calculations, and spectral and principal component analyses. We found that developing projection neurons are differentially affected by classic inhibitory neurotransmission as a cell type and at different places compared to migrating interneurons, which are also heterogeneous in their response to neurotransmitter inhibition. This reveals important insights into the developmental role of neurotransmitters and calcium oscillations in the forming brain cortex. Moreover, we present an improved analysis proposing a Gini coefficient-based inequality distribution and principal component analysis as mathematical tools for understanding the earliest patterns of brain activity.

Alisporivir plus ribavirin, interferon free or in combination with pegylated interferon, for hepatitis C virus genotype 2 or 3 infection.

UNLABELLED: Alisporivir is a cyclophilin inhibitor with pan-genotypic anti-hepatitis C virus (HCV) activity and a high barrier to viral resistance. The VITAL-1 study assessed alisporivir as interferon (IFN)-free therapy in treatment-naïve patients infected with HCV genotype 2 or 3. Three hundred forty patients without cirrhosis were randomized to: arm 1, alisporivir (ALV) 1,000 mg once-daily (QD); arm 2, ALV 600 mg QD and ribavirin (RBV); arm 3, ALV 800 mg QD and RBV; arm 4, ALV 600 mg QD and pegylated IFN (Peg-IFN); or arm 5, Peg-IFN and RBV. Patients receiving IFN-free ALV regimens who achieved rapid virological response (RVR) continued the same treatment throughout, whereas those with detectable HCV RNA at week 4 received ALV, RBV, and Peg-IFN from weeks 6 to 24. Overall, 300 patients received ALV-based regimens. In arm 1 to arm 4, the intent-to-treat rates of sustained virological response (SVR) 24 weeks after treatment (SVR24) were from 80% to 85%, compared with 58% (n = 23 of 40) with Peg-IFN/RBV. Per-protocol analysis showed higher SVR24 rates in patients who received ALV/RBV, IFN-free after RVR (92%; n = 56 of 61) than with ALV alone after RVR (72%; n = 13 of 18) or with Peg-IFN/RBV (70%; n = 23 of 33). Both RVRs and SVRs to ALV IFN-free regimens were numerically higher in genotype 3- than in genotype 2-infected patients. Viral breakthrough was infrequent (3%; n = 7 of 258). IFN-free ALV treatment showed markedly better safety/tolerability than IFN-containing regimens. CONCLUSIONS: ALV plus RBV represents an effective IFN-free option for a proportion of patients with HCV genotype 2 or 3 infections, with high SVR rates for patients with early viral clearance. Further investigations of ALV in IFN-free combination regimens with direct-acting antiviral drugs deserve exploration in future trials.

Telbivudine plus pegylated interferon alfa-2a in a randomized study in chronic hepatitis B is associated with an unexpected high rate of peripheral neuropathy.

BACKGROUND & AIMS: This study investigated the antiviral efficacy and safety of telbivudine in combination with pegylated interferon (PegIFN) alpha-2a in chronic hepatitis B (CHB) patients. METHODS: This was a randomized, open-label, multicentre study, in treatment-naïve patients with HBeAg-positive CHB, comparing the efficacy and safety of telbivudine in combination with PegIFN alpha-2a with telbivudine monotherapy and PegIFN alpha-2a monotherapy. The study was terminated early due to increased rates of peripheral neuropathy in the combination-therapy group. RESULTS: Of the 159 patients randomized (from 300 planned) 50 were assigned to combination therapy, 55 to telbivudine, 54 to PegIFN, and 110 (18, 49, and 43, respectively) reached week 24. Peripheral neuropathy occurred in 7/50, 1/54, and 0/54 patients in the three groups of safety populations, respectively. No relationship between the occurrence of peripheral neuropathy and other variables (e.g., pharmacokinetic data, treatment efficacy, ALT levels, creatine kinase elevations) were observed. At week 24, undetectable HBV DNA (<300 copies/ml) was achieved by 71% (12/17), 35% (17/48), and 7% (3/42) of patients, with available data receiving combination therapy, telbivudine monotherapy and PegIFN monotherapy, respectively (p = 0.022 for combination therapy vs. telbivudine; p<0.0001 for combination therapy vs. PegIFN). CONCLUSIONS: Combination therapy carried an increased risk of peripheral neuropathy. Despite the rapid and profound reductions in HBV DNA levels, combination therapy with telbivudine and PegIFN should not be used.

Automated stopped-flow library synthesis for rapid optimisation and machine learning directed experimentation.

For the discovery of new candidate molecules in the pharmaceutical industry, library synthesis is a critical step, in which library size, diversity, and time to synthesise are fundamental. In this work we propose stopped-flow synthesis as an intermediate alternative to traditional batch and flow chemistry approaches, suited for small molecule pharmaceutical discovery. This method exploits the advantages of both techniques enabling automated experimentation with access to high pressures and temperatures; flexibility of reaction times, with minimal use of reagents (µmol scale per reaction). In this study, we integrate a stopped-flow reactor into a high-throughput continuous platform designed for the synthesis of combinatory libraries with at-line reaction analysis. This approach allowed ∼900 reactions to be conducted in an accelerated timeframe (192 hours). The stopped flow approach used ∼10% of the reactants and solvents compared to a fully continuous approach. This methodology demonstrates a significantly improved synthesis success rate of smaller libraries by simplifying the implementation of cross-reaction optimisation strategies. The experimental datasets were used to train a feed-forward neural network (FFNN) model providing a framework to guide further experiments, which showed good model predictability and success when tested against an external set with fewer experiments. As a result, this work demonstrates that combining experimental automation with machine learning strategies can deliver optimised analyses and enhanced predictions, enabling more efficient drug discovery investigations across the design, make, test and analysis (DMTA) cycle.

Efficacy and safety of prolonged 3-year telbivudine treatment in patients with chronic hepatitis B.

BACKGROUND: In the GLOBE trial, telbivudine demonstrated superior efficacy to lamivudine at 2 years in patients with chronic hepatitis B (CHB). AIMS: To investigate the long-term efficacy and safety of telbivudine in the telbivudine-treated cohort from the GLOBE trial. METHODS: Virological and biochemical responses were assessed in 213 HBeAg-positive and 186 HBeAg-negative CHB patients who continued telbivudine treatment for 3 years. RESULTS: Undetectable hepatitis B virus DNA and HBeAg seroconversions were achieved by 77 and 37% of HBeAg-positive patients respectively. Cumulative HBeAg seroconversion rate was 46%. HBeAg seroconversion was sustained at 52 weeks off therapy in 84% of the patients enrolled in the off-treatment follow-up arm of the study. Undetectable viraemia and normal alanine aminotransferase (ALT) levels at 3 years were achieved by 85 and 83% of HBeAg-negative patients respectively. Genotypic resistance rates for the study population who continued therapy during the third year were 11.3 in HBeAg-positive and 6.5% in HBeAg-negative patients. Patients with undetectable viraemia at treatment week 24 had optimal outcomes at 3 years. In the HBeAg-positive population, cumulative HBeAg seroconversion occurred in 58%. Resistance rates for HBeAg-positive and HBeAg-negative patients were 3.6 and 6.2% respectively. The telbivudine safety profile during prolonged therapy was similar to that in the GLOBE trial. CONCLUSIONS: Three years of telbivudine treatment yielded high rates of viral suppression and ALT normalization with a favourable safety profile. High rates of HBeAg seroconversion were achieved with prolonged telbivudine therapy and were sustained in the majority of patients over 52 weeks off therapy.

Acid number, viscosity and end-point detection in a multiphase high temperature polymerisation process using an online miniaturised MEMS Fabry-Pérot interferometer.

Recent advances in the latest generation of MEMS (micro-electro-mechanical system) Fabry-Pérot interferometers (FPI) for near infrared (NIR) wavelengths has led to the development of ultra-fast and low cost NIR sensors with potential to be used by the process industry. One of these miniaturised sensors operating from 1350 to 1650 nm, was integrated into a software platform to monitor a multiphase solid-gas-liquid process, for the production of saturated polyester resins. Twelve batches were run in a 2 L reactor mimicking industrial conditions (24 h process, with temperatures ranging from 220 to 240 °C), using an immersion NIR transmission probe. Because of the multiphase nature of the reaction, strong interference produced by process disturbances such as temperature variations and the presence of solid particles and bubbles in the online spectra required robust pre-processing algorithms and a good long-term stability of the probe. These allowed partial least squares (PLS) regression models to be built for the key analytical parameters acid number and viscosity. In parallel, spectra were also used to build an end-point detection model based on principal component analysis (PCA) for multivariate statistical process control (MSPC). The novel MEMS-FPI sensor combined with robust chemometric analysis proved to be a suitable and affordable alternative for online process monitoring, contributing to sustainability in the process industry.

Telbivudine exhibits no inhibitory activity against HIV-1 clinical isolates in vitro.

Most approved drugs with activity against hepatitis B virus (HBV) have activity against human immunodeficiency virus type 1 (HIV-1), which precludes their use in patients who are coinfected with HBV and HIV-1 and who are not receiving antiretroviral therapy due to the risk of inducing resistance. The activity of telbivudine, a highly selective HBV inhibitor, against temporally and geographically distinct wild-type and multidrug-resistant HIV-1 clinical isolates was evaluated in vitro. No inhibition was observed with up to 600 muM drug, which supports further exploration of telbivudine as a therapeutic option for the treatment of HBV infections in patients coinfected with HIV-1.

Early viral kinetics of telbivudine and entecavir: results of a 12-week randomized exploratory study with patients with HBeAg-positive chronic hepatitis B.

We characterized the early viral kinetic profiles of telbivudine and entecavir and the effects of these potent nucleoside analogs on hepatitis B virus (HBV) DNA and alanine aminotransferase levels in adults with hepatitis B e antigen-positive compensated chronic hepatitis B. Forty-four patients were enrolled in this open-label, parallel-group, multicenter study and randomized to receive telbivudine or entecavir for 12 weeks. Reductions in hepatitis B virus DNA and alanine aminotransferase levels from baseline to weeks 2, 4, 8, and 12 were assessed. Viral kinetic parameters, including viral clearance per day, loss of infected cells per day, and efficiency of inhibition of viral production, were estimated by using a biphasic mathematical model. Statistical analyses were limited to descriptive analyses. The 2 treatment groups achieved similar reductions in HBV DNA and alanine aminotransferase levels. Mean reductions in levels of hepatitis B virus DNA at week 12 were 6.6 +/- 1.6 and 6.5 +/- 1.5 log(10) copies/ml for the telbivudine- and entecavir-treated patients, respectively. There were no significant differences between groups in values for mean viral clearance per day, mean loss of infected cells per day, or efficiency of blocking viral production. The safety profiles for both medications were favorable. During the first 12 weeks of treatment, telbivudine and entecavir demonstrated similar antiviral potencies, resulting in a rapid and profound suppression of serum hepatitis B virus DNA and reduction of alanine aminotransferase levels. No differences in the effects of these 2 agents on early viral kinetics were observed. Both medications were well tolerated.

Telbivudine in combination with adefovir versus adefovir monotherapy in HBeAg-positive, lamivudine-resistant chronic hepatitis B.

PURPOSE: Lamivudine (LAM) resistance is common on lamivudine monotherapy for chronic hepatitis B. This study examined the safety and efficacy of telbivudine (LDT) given with adefovir (ADV) versus ADV monotherapy in patients with chronic, lamivudine-resistant HBV infection. METHODS: An open-label, 96 week study with planned recruitment of 150 HBeAg-positive, lamivudine-experienced Asian patients with a confirmed YMDD resistance mutation, randomized 1:1 to receive ADV alone or with LDT. The study was terminated early due to difficulty in enrolling monotherapy patients. At termination, 42 patients had received study medication for 8-61 weeks. Due to incomplete enrolment, summary statistics only were prepared, without significance testing. RESULTS: A total of 42 patients underwent rescue therapy (switch to ADV or LDT + ADV; n = 21 per group). Median treatment duration was 48 weeks in both groups. HBV DNA changes from baseline were greater in the LDT + ADV arm at all time points (Week 48: -7.4 log10 vs. -4.9 log10 copies/ml), and serum DNA was undetectable (<300 copies/mL) at week 48 in 38.5% (5/13) on LDT + ADV versus 0% (0/9) on ADV monotherapy Two patients (9.6%) on ADV monotherapy experienced virologic breakthrough without evidence of ADV resistance, but none on LDT + ADV; and no confirmed ADV resistance was observed in any on-treatment sample. HBeAg loss occurred in three patients on LDT + ADV and one patient on ADV monotherapy through week 48. Safety profiles were similar between the arms. CONCLUSION: LDT + ADV combination treatment showed better outcomes against lamivudine resistant HBV than ADV alone, with a similar safety profile.

Morphology and reactivity characteristics of char biomass particles.

In this work, 10 different biomasses were selected which included directly grown energy crops, industrial waste material and different wood types. Each biomass was sieved into six different size fractions and pyrolysed in a fixed bed furnace preheated to 1000 °C to produce a char residue. Intrinsic reactivity during burnout was measured using a non-isothermal thermogravimetric method. Scanning electron microscopy and oil immersion microscopy were used to characterise the morphology of the products. Char morphology was summarised in terms of degree of deformation, internal particle structure and wall thickness. Intrinsic reactivity corresponded directly with these morphology groupings showing a significant correlation between char morphotypes, char reactivity and the initial biomass material.

AIDS e miopatia: relato de um caso e revisäo da literatura / AIDS and myopathy: report of a case and review of the literature

É relatado o caso de um paciente com miopatia de apresentaçäo clínica incomum como manifestaçäo inicial da infecçäo por HIV. O paciente apresentava aumento de volume dos membros acompanhado de sinais flogísticos e elevaçäo dos níveis séricos de enzimas musculares. A alteraçäo histopatológica predominante consistia em necrose segmentar de fibrocélulas musculares esqueléticas. Evoluiu com pneumonia por Pneumocytis carini, tratada satisfatoriamente com sulfametaxazol e trimetropim. Apesar do uso sucessivo de indometacina, predinisona e dexametasona, a miopatia continuava a progredir. Após administraçäo de methotrexate, houve regressäo do quadro neurológico

Proteçäo cerebral no tratamento cirúrgico dos aneurismas do arco aórtico: estudo experiemental em cäes / Cerebral protection in the surgical treatment of aortic arch aneurysms: experimental study in dogs

É realizado estudo experimental comparativo entre dois métodos de proteçao cerebral na abordagem cirúrgica dos aneurismas do arco aórtico, avaliando a sua eficácia: hipotermia sistêmica profunda isolada (menor que 2O graus Celsius) com pinçamento arterial braquiocefálico e hipotermia sistêmica profunda associada à perfusao carotídea seletiva. Dois grupos de 15 caes cada foram submetidos, respectivamente, à hipotermia sistêmica profunda com pinçamento arterial braquiocefálico (Grupo I) e à hipotermia sistêmica profunda associada à perfusao seletiva da carótida direita (Grupo II). Foram analisadas amostras seriadas das alteraçoes metabólicas de pH e PaCO2 que ocorreram no retorno venoso cerebral aferidas na veia julgular interna, bem como as alteraçoes histopatológicas encontradas com 45 min., 90 min. e 135 min. de cada procedimento. Os resultados demonstram que, apesar de ambos os métodos de proteçao cerebral serem eficazes por um período de 45 minutos, o método utilizado no Grupo II mostrou ser superior em períodos de até 90 minutos de isquemia cerebral. Em períodos de 135 minutos os métodos tiveram resultados semelhantes, nao oferecendo proteçao cerebral adequada.

Fisiopatologia do complexo demencia-AIDS

Os mecanismos implicados na patogenia das lesoes do Sistema Nervoso Central decorrentes da infeccao pelo HIV ainda nao estao de todo esclarecios. Reconhecem-se alteracoes neurologicas como quadros anatomoclinicos de encefalite aguda, infeccoes assintomaticas, meningite asseptica e o complexo demencia-AIDS(CDA), na vigencia das fases evolutivas desde a penetracao do virus no tecido nervoso provocando infeccao aguda, seguindo-se de uma fase intermediaria e culminando numa fase tardia com aumento da populacao viral e baixa consideravel da reacao imunitaria. Analisam-se as diversas hipoteses patogenicas discutidas na literatura, considerando como mais plausiveis, aquelas que justificam as lesoes do CDA como decorrentes de acao indireta dependente do sistema monocito-macrogafago-microglia infectado pelo hiv como responsavel pela invasao, progressao, infecao persistente e configuracao das lesoes no tecido nervoso. Estas celulas, modificadas em suas funcoes pela presenca do virus, liberariam monocinas, enzimas e radicais O2 livres capazes de produzirem danos estruturais celulares e/ou alteracoes vasculares propiciadoras de edema cronico. Todos esses elementos exerceriam, em conjunto, efeito lesional sobre mielina, axonios e corpo celular de neuronios e glia.

Production of monovalent anti-Bothrops asper antivenom: development of immune response in horses and neutralizing ability

A monovalent antivenom was produced by immunozing two horses with venom of the pit viper Bothrops asper (Ophidia: Viperidae). Although development of the immune response against four toxic and enzymatic activitiesof the venom was similar in both horses during the first two thirds of the immunization schedule, antibody response in one of the horses reached much higher levels in the last part of the immunization. Immunoelectrophoretic analysis indicates that there were precipitating antibodies in the sera of these horses during all the stages of immunization. However, immunoprecipitation did not correlated with the ability of sera to neutralize toxic activities of B. asper venom. Monovalent antivenom was more effective than the commercialy available polyvalent antivenom in the neutralization of Bothrops asper venom. On the other hand, despite the fact that it neutralizes lethal and hemorrhagic activities of the venoms of Lachesia muta and Crotalus durissus, it was less effective than polyvalent antivenom in these neutralizations. Moreover, it does not neutalize defibrinating activity induced by these two venoms, whereas it neutralizes this effect in the case of B. asper venom. It is proposed that monovalent antivenom my be highly effective in the case of envenomations induced by Bothrops asper venom; its use in treating accidentsby L. muta and C. durissus would be indicated only of polyvalent antivenom is not available. Results also demonstrate that it is important to monitor antibody response individually in horses being immunized for antivenom production, due to the conspicuous variability in the response of different animals.

Desarrollo de la respuesta de anticuerpos anti-fosfolipasa A2 en caballos inoculados con veneno para la producción de suero antiofídico polivalente en Costa Rica / Development of antibody anti-phospholipase A2 response in inoculated horses with venom for the productions of polivalent antiofidico serum in Costa Rica

Se estudió el desarrollo de la respuesta inmune y las alteraciones en el estado general en un grupo de ocho caballos adultos sanos utilizados en la producción del suero antiofídico polivalente en el Instituto Clodomiro Picado. Se observó una gran variación individual en la elevación del título de anticuerpos aunque, en términos generales, los máximos títulos se alcanzaron luego de que se inocularon las dosis de 30 mg y 50 mg de la mezcla de venenos. Con respecto a caballos que habían sido previamente utilizados en la producción de suero y que recibieron una dosis de refuerzo, el máximo título se obtuvo entre los 16 y 22 días. Las inoculaciones de la mezcla de venenos indujeron alteraciones leves en el estado general de los cabllos. Sin embargo, la mayoría de ellos desarrollaron abscesos, fístulas y fibrosis en el sitio de inoculación del veneno. Se concluye que, dada la gran variabilidad individual de los caballos en lo que respecta a la respuesta inmune, se hace necesaria su evaluación individual, con el fin de seleccionar los animales que produzcan una respuesta satisfactoria

Malformaçäo vascular gastrointestinal / Gastrointestinal vascular malformation

A doença de Dieulafoy é representada por dilataçäo arterial na submucosa gástrica cuja mucosa suprajacente mostra-se ulcerada e, algumas vezes, pode ser responsável por severa hemorragia gastrointestinal. O diagnóstico endoscópico nem sempre pode ser realizado, tendo em vista a natureza intermitente do sangramento. Säo relatadas e tecidas consideraçöes etipatogênicas sobre dois casos: um no estômago e outro no jejuno

Doença de Thévenard / Thevenard disiase

A doença de Thévenard ou acropatia ulceromutilante familial é uma síndrome autossômica dominante composta de neuropatia sensorial e alteraçoes tróficas dos membros inferiores. A sintomatologia pode iniciar-se em qualquer período da infância. A reduçao da sensibilidade é bilateral e simétrica, enquanto a motricidade permanece intacta. Dois novos casos sao descritos.