Effects of the administration of pentoxifylline and prednisolone on the evolution of portal fibrogenesis secondary to biliary obstruction-an experimental study in growing animals

Background: Many chronic liver diseases lead to progressive hepatic fibrosis, a condition that can ultimately result in loss of organ function and severe portal hypertension necessitating hepatic transplantation. Within the last few decades, studies have been conducted to demonstrate the possibility of drug modulation of hepatic fibrogenesis. Regarding biliary obstruction, it has been suggested that administration of corticosteroids could promote better late outcomes for children with biliary atresia submitted to Kasai`s portoenterostomy. Models used to test potential antifibrogenic drugs such as pentoxifylline (PTX) have not included growing animals. Methods: In this experimental study, 119 young rats (21st or 22nd days) were submitted to laparotomy and common bile duct ligation (CBDL) or to sham surgery (SHAM). Animals were allocated into 5 groups, according to surgical procedure, and administered the following solutions: (1) CBDL + distilled water, (2) SHAM + distilled water, (3) CBDL + PTX, (4) CBDL + prednisolone (PRED), and (5) CBDL + PTX + PRED (PTX + PRED). Each group was further divided into 2 subgroups according to the length of the experiment (15 or 30 days). At the end of the defined period, animals were weighed, and a hepatic fragment was collected from each one for analyses. Results: The PTX animals exhibited increased weight gain compared to animals in the PRED or PTX + PRED groups. Animals from the 3 therapeutic groups (PTX, PRED, and PTX + PRED) showed diminished collagen-filled area in portal spaces. Total portal space area was increased in the PTX group. Conclusions: Hepatic fibrosis induced by bile duct ligation in young rats could be modulated by pharmacologic interventions. Administration of PTX or PRED, or the combination of both, resulted in diminished collagen-filled areas in portal spaces. (C) 2009 Elsevier Inc. All rights reserved.

A phase II study of UFT with leucovorin administered as a twice daily schedule in the treatment of patients with metastatic colorectal cancer

Prolonged infusions have been shown to be safer and potentially more effective than bolus regimens of 5-fluorouracil (5-FU) as treatment for metastatic colorectal cancer (mCRC). However, infusional 5-FU requires central venous access and costly infusion pumps. Oral fluoropyrimidines enable longer exposures to 5-FU with increased convenience. Tegafur - uracil (UFT) with leucovorin (LV) given thrice daily has improved safety plus comparable survival and response rates to bolus 5-FU/LV. We conducted a phase II clinical study in 98 patients with mCRC to evaluate if UFT with LV given twice daily provided comparable time to progression ( TTP), efficacy and tolerability to that reported for thrice daily in two phase III clinical studies. Secondary objectives included overall response rate ( ORR) and overall survival ( OS). Median TTP was 3.8 months, when compared with 3.5 months for thrice daily. The ORR ( 11%) and median OS ( 12.8 months) with twice daily administration were similar to that of thrice daily administration ( 12% and 12.4 months). The incidence of grade 3/4 treatment-related diarrhoea was 30% on the twice daily and 21% on the thrice daily schedule. These results suggest that twice daily administration has similar efficacy and tolerability to thrice daily administration and is an acceptable alternative for patients who would benefit from UFT with LV therapy.

Effects of intracisternal administration of cannabidiol on the cardiovascular and behavioral responses to acute restraint stress

Systemic administration of cannabidiol (CBD), a non-psychotomimetic compound from Cannabis sativa, attenuates the cardiovascular and behavioral responses to restraint stress. Although the brain structures related to CBD effects are not entirely known, they could involve brainstem structures responsible for cardiovascular control. Therefore, to investigate this possibility the present study verified the effects of CBD (15.30 and 60 nmol) injected into the cisterna magna on the autonomic and behavioral changes induced by acute restraint stress. During exposure to restraint stress (1 h) there was a significant increase in mean arterial pressure (MAP) and heart rate (HR). Also, 24 h later the animals showed a decreased percentage of entries onto the open arms of the elevated plus-maze. These effects were attenuated by CBD (30 nmol). The drug had no effect on MAP and HR baseline values. These results indicate that intracisternal administration of CBD can attenuate autonomic responses to stress. However, since CBD decreased the anxiogenic consequences of restraint stress, it is possible that the drug is also acting on forebrain structures. (C) 2011 Elsevier Inc. All rights reserved.

Intra-dorsal periaqueductal gray administration of cannabidiol blocks panic-like response by activating 5-HT1A receptors

Activation of 5-HT1A receptors in the dorsal periaqueductal gray (dPAG) impairs escape behavior, suggesting a panicolytic-like effect. Cannabidiol (CBD), a major non-psychotomimetic compound present in Cannabis sativa, causes anxiolytic-like effects after intra-dPAG microinjections by activating 5-HT1A receptors. In the present work we tested the hypothesis that CBD could also impair escape responses evoked by two proposed animal models of panic: the elevated T-maze (ETM) and electric stimulation of dPAG. In experiment 1 male Wistar rats with a single cannula implanted in the dPAG received a microinjection of CBD or vehicle and, 10 min later, were submitted to the ETM and open field tests. In experiment 2 escape electrical threshold was measured in rats with chemitrodes implanted in the dPAG before and 10 min after CBD microinjection. In experiment 3 similar to experiment 2 except that the animals received a previous intra-dPAG administration of WAY-100635, a 5-HT1A receptor antagonist, before CBD treatment. In the ETM microinjection of CBD into the dPAG impaired inhibitory avoidance acquisition, an anxiolytic-like effect, and inhibited escape response, a panicolytic-like effect. The drug also increased escape electrical threshold, an effect that was prevented by WAY-100635. Together, the results suggest that CBD causes panicolytic effects in the dPAG by activating 5-HT1A receptors. (C) 2010 Elsevier B.V. All rights reserved.

Chronic administration of harmine elicits antidepressant-like effects and increases BDNF levels in rat hippocampus

A growing body of evidence has pointed to the beta-carboline harmine as a potential therapeutic target for the treatment of major depression. The present study was aimed to evaluate behavioural and molecular effects of the chronic treatment with harmine and imipramine in rats. To this aim, rats were treated for 14 days once a day with harmine (5, 10 and 15 mg/kg) and imipramine (10, 20 and 30 mg/kg) and then subjected to the forced swimming and open-field tests. Harmine and imipramine, at all doses tested, reduced immobility time of rats compared with the saline group. Imipramine increased the swimming time at 20 and 30 mg/kg and harmine increased swimming time at all doses. The climbing time increased in rats treated with imipramine (10 and 30 mg/kg) and harmine (5 and 10 mg/kg), without affecting spontaneous locomotor activity. Brain-derived neurotrophic factor (BDNF) hippocampal levels were assessed in imipramine and harmine-treated rats by ELISA sandwich assay. Interestingly, chronic administration of harmine at the higher doses (10 and 15 mg/kg), but not imipramine, increased BDNF protein levels in rat hippocampus. Finally, these findings further support the hypothesis that harmine could bring about behavior and molecular effects, similar to antidepressants drugs.

Matching prescription claims with medication data for nursing home residents: Implications for prescriber feedback, drug utilisation studies and selection of prescription claims database

Medication data retrieved from Australian Repatriation Pharmaceutical Benefits Scheme (RPBS) claims for 44 veterans residing in nursing homes and Pharmaceutical Benefits Scheme (PBS) claims for 898 nursing home residents were compared with medication data from nursing home records to determine the optimal time interval for retrieving claims data and its validity. Optimal matching was achieved using 12 weeks of RPBS claims data, with 60% of medications in the RPBS claims located in nursing home administration records, and 78% of medications administered to nursing home residents identified in RPBS claims. In comparison, 48% of medications administered to nursing home residents could be found in 12 weeks of PBS data, and 56% of medications present in PBS claims could be matched with nursing home administration records. RPBS claims data was superior to PBS, due to the larger number of scheduled items available to veterans and the veteran's file number, which acts as a unique identifier. These findings should be taken into account when using prescription claims data for medication histories, prescriber feedback, drug utilisation, intervention or epidemiological studies. (C) 2001 Elsevier Science Inc. All rights reserved.

Analytical validation for a series of marker compounds used to assess renal drug elimination processes

Renal drug elimination is determined by glomerular filtration, tubular secretion, and tubular reabsorption. Changes in the integrity of these processes influence renal drug clearance, and these changes may not be detected by conventional measures of renal function such as creatinine clearance. The aim of the current study was to examine the analytic issues needed to develop a cocktail of marker drugs (fluconazole, rac-pindolol, para-aminohippuric acid, sinistrin) to measure simultaneously the mechanisms contributing to renal clearance. High-performance liquid chromatographic methods of analysis for fluconazole, pindolol, para-aminohippuric acid, and creatinine and an enzymatic assay for sinistrin were developed or modified and then validated to allow determination of each of the compounds in both plasma and urine in the presence of all other marker drugs. A pilot clinical study in one volunteer was conducted to ensure that the assays were suitable for quantitating all the marker drugs to the sensitivity and specificity needed to allow accurate determination of individual renal clearances. The performance of all assays (plasma and urine) complied with published validation criteria. All standard curves displayed linearity over the concentration ranges required, with coefficients of correlation greater than 0.99. The precision of the interday and intraday variabilities of quality controls for each marker in plasma and urine were all less than 11.9% for each marker. Recoveries of markers (and internal standards) in plasma and urine were all at least 90%. All markers investigated were shown to be stable when plasma or urine was frozen and thawed. For all the assays developed, there were no interferences from other markers or endogenous substances. In a pilot clinical study, concentrations of all markers could be accurately and reproducibly determined for a sufficient duration of time after administration to calculate accurate renal clearance for each marker. This article presents details of the analytic techniques developed for measuring concentrations of marker drugs for different renal elimination processes administered as a single dose to define the processes contributing to renal drug elimination.

Immunity to malaria after administration of ultra-low doses of red cells infected with Plasmodium falciparum

Background The ability of T cells, acting independently of antibodies, to control malaria parasite growth in people has not been defined. If such cell-mediated immunity was shown to be effective, an additional vaccine strategy could be pursued. Our aim was to ascertain whether or not development of cell-mediated immunity to Plasmodium falciparum blood-stage infection could be induced in human beings by exposure to malaria parasites in very low density. Methods We enrolled five volunteers from the staff at our research institute who had never had malaria. We used a cryopreserved inoculum of red cells infected with P falciparum strain 3D7 to give them repeated subclinical infections of malaria that we then cured early with drugs, to induce cell-mediated immune responses. We tested for development of immunity by measurement of parasite concentrations in the blood of volunteers by PCR of the multicopy gene STEVOR and by following up the volunteers clinically, and by measuring antibody and cellular immune responses to the parasite. Findings After challenge and a extended period without drug cure, volunteers were protected against malaria as indicated by absence of parasites or parasite DNA in the blood, and absence of clinical symptoms. Immunity was characterised by absence of detectable antibodies that bind the parasite or infected red cells, but by the presence of a proliferative T-cell response, involving CD4+ and CD8+ T cells, a cytokine response, consisting of interferon gamma but not interleukin 4 or interleukin 10, induction of high concentrations of nitric oxide synthase activity in peripheral blood mononuclear cells, and a drop in the number of peripheral natural killer T cells. Interpretation People can be protected against the erythrocytic stage of malaria by a strong cell-mediated immune response, in the absence of detectable parasite-specific antibodies, suggesting an additional strategy for development of a malaria vaccine.

Platelet inhibitory effects of the nitric oxide donor drug MAHMA NONOate in vivo in rats

The platelet inhibitory effects of the nitric oxide (NO) donor drug MAHMA NONOate ((Z-1-{N-methyl-N-[6-(N-methylammoniohexyl)amino] diazen-1-ium-1,2-diolate) were examined in anaesthetised rats and compared with those of S-nitrosoglutathione (GSNO; an S-nitrosothiol). Bolus administration of the aggregating agent ADP dose-dependently reduced the number of circulating free platelets. Intravenous infusions of MAHMA NONOate (3-30 nmol/kg/min) dose-dependently inhibited the effect of 0.3 mumol/kg ADP. MAHMA NONOate was approximately 10-fold more potent than GSNO. MAHMA NONOate (0.3-10 nmol/kg/min) also reduced systemic artery pressure and was again 10-fold more potent than GSNO. Thus MAHMA NONOate has both platelet inhibitory and vasodepressor effects in vivo. The dose ranges for these two effects overlapped, although blood pressure was affected at slightly lower doses. The platelet inhibitory effects compared favourably with those of GSNO, even though NONOates generate free radical NO which, in theory, could have been scavenged by haemoglobin. Therefore platelet inhibition may be a useful therapeutic property of NONOates. (C) 2003 Elsevier B.V. All rights reserved.

Can varying the number of teams in a shift schedule constitute a preventive strategy?

OBJECTIVE: The study examines the implications for shiftworkers of applying different numbers of teams in the organization of shiftwork. METHODS: The participating operators came from five different companies applying continuous shift rotation systems. The companies shared the same product organization and a common corporate culture belonging to the same multinational company. Each company had a shift system consisting of four, five or six teams, with the proportion of shifts outside day work decreasing as the number of teams increased. Questionnaire and documentary data were used as data sources. RESULTS: Operators in systems with additional teams had more daywork but also more irregular working hours due to both overtime and schedule changes. Operators using six teams used fewer social compensation strategies. Operators in four teams were most satisfied with their work hours. Satisfaction with the time available for various social activities outside work varied inconsistently between the groups. CONCLUSIONS: In rotating systems the application of more teams reduces the number of shifts outside day work. This apparent improvement for shiftworkers was counteracted by a concomitant irregularity produced by greater organizational requirements for flexibility. The balance of this interaction was found to have a critical impact on employees.

Reduced schedule of human anti rabies immunization with Fuenzalida & Palacios vaccine

The present study evaluates the humoral and cellular immune responses in 35 volunteers submited to short antirabies vaccination schedules with the Fuenzalida & Palacios vaccine based on the administration of doses on non consecutive days. The volunteers were divided into two groups. The first group received a total number of five doses given on days 0, 4, 7, 20 and 35. The other group received four doses, the first one being a double dose given on day 0 and than three other single doses on days 7, 20 and 35. The evaluation of humoral immune response was carried out by serum neutralization (SN) and indirect immunofluorescense (IIF) tests, while the cellular immune response was evaluated by lymphoblastic transformation assay (LTA) and skin test (ST). According to our results these reduced schedules elicited early and effective humoral and cellulafimmune responses to rabies antigen suggesting that new reduced schedules should be extensively studied in order to give the proper bases to the proposition of changes in the current long-term schedule.

Development of cyclodextrin-hydrogel polymeric systems in scCO2 for drug delivery

Thesis for the Degree of Master of Science in Bioorganic Universidade Nova de Lisboa, Faculdade de Ciências e Tecnologia

Hepatitis B vaccine in infants: a randomized controlled trial comparing gluteal versus anterolateral thigh muscle administration

A significantly diminished antibody response to hepatitis B vaccine has been demonstrated in adults when the buttock is used as the injection site. However, in Brazil, the buttock continues to be recommended as site of injection for intramuscular administration of vaccines in infants. In this age group, there are no controlled studies evaluating the immunogenicity of the hepatitis B vaccine when administered at this site. In the present study, 258 infants were randomized to receive the hepatitis B vaccine either in the buttock (n = 123) or in the anterolateral thigh muscle (n = 135). The immunization schedule consisted of three doses of hepatitis B vaccine (Engerix Bâ, 10 mug) at 2, 4 and 9 months of age. There were no significant differences in the proportion of seroconversion (99.3% x 99.2%), or in the geometric mean titer of ELISA anti-HBs (1,862.1 x 1,229.0 mIU/mL) between the two groups. This study demonstrates that a satisfactory serological response can be obtained when the hepatitis B vaccine is administered intramuscularly into the buttock.

Evaluation of long term persistence of Diabetes Mellitus Type II treatment newly diagnosed patients in Lisbon and Tagus health administration region : a three year follow up study

RESUMO: Raional: A persistência à terapêutica é o tempo em qualquer antidiabético oral, desde o seu início até à descontinuação de todas as medicações ou até ao fim do período do estudo. Os objetivos deste estudo foi a análise da persistência à terapêutica no segundo e terceiro anos após início do tratamento em doentes adultos diagnosticados na região de Lisboa e Vale do Tejo e determinar o efeito de determinadas variáveis na persistência a longo prazo. Métodos: Um estudo retrospetivo não interventivo foi desenhado com base nos dados a obter do SIARS (prescrições e aquisições na farmácia) e Pordata. A persistência foi quantificada como a percentagem de doentes que continuam a adquirir pelo menos um antidiabético oral ao segundo e terceiro anos após a compra da primeira receita. A associação entre a persistência e o segundo e terceiro anos com cada uma das co-variáveis foi aferido pelo teste qui-quadrado e os odd ratios foram calculados com recurso a um modelo de regressão logística. Resultados: A persistência à terapêutica obtida foi de 80% e 62% para o segundo e terceiro anos após início da terapêutica. Odd ratios para primeiro e segundo ano: número de grupos farmacoterapêuticos diferentes (OR = 2.167, 1.807 – 2.598, p = 0.000 / OR = 1.863, 1.621 – 2.142, p = 0.000); idade (OR = 0.914, 0.772 – 1.081, p = 0.294 / OR = 0.875, 0.764 – 1.002, p = 0.054); sexo (OR = 1.163, 0.983 – 1.377, p = 0.079); número de diferentes prescritores (OR = 3.594, 3.030 – 4.262, p = 0.000 / OR = 2.167, 1.886 – 2.491, p = 0.000); instituição de prescrição (OR = 0.725, 0.698 – 0.753, p = 0.000 / OR = 0.683, 0.650 – 0.717, p = 0.000); grupo farmacoterapêutico (OR = 1.056, 1.043 – 1.069, p = 0.000 / OR = 1.077, 1.060 – 1.095, p = 0.000); relação com o médico (OR = 0.834, 0.816 – 0.852, p = 0.000 / OR = 0.799, 0.777 – 0.821, p = 0.000) e custo médio mensal por grupo farmacoterapêutico (OR = 0.954, 0.942 – 0.968, p = 0.000 / OR = 0.930, 0.914 – 0.947, p = 0.000). Conclusões: O valor da persistência à terapêutica no segundo ano é ligeiramente acima do que é mencionado na literatura e não existem dados para comparar os resultados do terceiro ano. Relativamente ao efeito das co-variáveis no segundo e terceiro anos após o início do tratamento, os resultados são sobreponíveis, sendo que o sexo não está associado à persistência ao terceiro ano.----------------------------------ABSTRACT: Background: Therapy persistence is the time on any antidiabetic medication, from initiation of therapy to discontinuation of all medications or the end of the study period. The aim of the study was to analyse the therapy persistence in the second and third years after treatment initiation in newly diagnosed adult patients in the Lisbon and Tagus Valley region and to determine the effect of several co-variables in the long term persistence. Methods: A retrospective non-interventional study based on SIARS data (drug prescriptions and acquisitions) and Pordata was designed. Persistence was quantified as the percentage of patients that continued to purchase at least one type of antidiabetic at year 2 and 3 after the date of first prescription acquisition. Association between persistence at second and third years with each of the other co-variables were verified by using the Chi-Square test and odds ratio were calculated using a regression logistic model. Results: Therapy persistence obtained was 80% and 62% for the second and third years after treatment initiation. Odd ratios for second and third years: number of different pharmacotherapeutic groups (OR = 2.167, 1.807 – 2.598, p = 0.000 / OR = 1.863, 1.621 – 2.142, p = 0.000); age (OR = 0.914, 0.772 – 1.081, p = 0.294 / OR = 0.875, 0.764 – 1.002, p = 0.054); gender (OR = 1.163, 0.983 – 1.377, p = 0.079); number of different prescribers (OR = 3.594, 3.030 – 4.262, p = 0.000 / OR = 2.167, 1.886 – 2.491, p = 0.000); institution of prescription (OR = 0.725, 0.698 – 0.753, p = 0.000 / OR = 0.683, 0.650 – 0.717, p = 0.000); pharmacotherapeutic group (OR = 1.056, 1.043 – 1.069, p = 0.000 / OR = 1.077, 1.060 – 1.095, p = 0.000); relationship with the physician (OR = 0.834, 0.816 – 0.852, p = 0.000 / OR = 0.799, 0.777 – 0.821, p = 0.000) and average cost per month and per pharmacotherapeutic group (OR = 0.954, 0.942 – 0.968, p = 0.000 / OR = 0.930, 0.914 – 0.947, p = 0.000). Conclusions: Second year therapy persistence value is slightly above of what is referenced in literature and no data was found to compare the third year value. Regarding the effect of the co-variables analysed at second and third years after treatment initiation, the results were overlapping with gender being not associated with persistence at the third year.