Informe de evaluación científica basada en la evidencia disponible: esclerosis múltiple / Scientific evaluation report based on available evidence: multiple sclerosis

INTRODUCCIÓN: La Esclerosis Múltiple (EM) suele presentarse en cerca del 80% de los casos a través de episodios recurrentes y remitentes, los cuales con el tiempo podrán desarrollar a una forma progresiva y persistente. Un 10 a 15% de los casos, evidencia un cuadro sin remisiones desde su inicio. Durante el año 2010, se incorporó bajo modalidad Garantía Explícita en Salud la Esclerosis Múltiple Remitente Recurrente (EMRR), garantizando en su tratamiento fármacos inmunomoduladores de primera línea, Interferones intramusculares, subcutáneos y el Acetato de Glatiramer. Además, cuentan con cobertura a través de la Ley Ricarte Soto desde el año 2015 aquellos pacientes refractarios a la terapia habitual. TECNOLOGÍAS SANITARIAS ANALIZADAS: Alemtuzumab, Ocrelizumab, Fampridina, Teriflunomida, Dimetilfumarato. EFICACIA DE LOS TRATAMIENTOS: Se extrajo la evidencia de 2 revisiones sistemáticas que reportan 3 Ensayos Controlados Aleatorizados (ECA) para teriflunomida y dimetilfumarato. Adicionalmente, se incluyó información de 1 y 5 ECAs para el tratamiento de alemtuzumab y ocrelizumab, respectivamente. Teriflunomida logra un mayor número de pacientes con ausencia de brotes a los 12 meses. En cuanto a la progresión de la discapacidad asociada a la enfermedad, teriflunomida probablemente no es mejor que placebo para disminuir el número de pacientes libres de progresión de la discapacidad a 2 años. Alemtuzumab probablemente logra un menor número de pacientes con brotes a los 2 años, en comparación a Interferón B, mientras que los pacientes que reciben dimetilfumarato tienen una menor probabilidad de tener brotes que los pacientes tratados con placebo. Ocrelizumab para la Esclerosis Múltiple Primaria Progresiva (EMPP), se compara contra placebo y no se encuentran efectos relevantes en la mayor parte de outcomes (pacientes con confirmación de progresión, SF-36), salvo en indicadores específicos como el número de lesiones activas en T2 ó el volumen cerebral. Para pacientes con EMRR al compararse con Interferón beta-1, se evidencia una reducción de la progresión confirmada a la semana 12, 24 y 96, y reduce la tasa anualizada de brotes a la semana 96. Finalmente, en pacientes con EMRR al comparar ocrelizumab versus placebo, éste podría reducir el número de pacientes con brotes a la semana 24. EVALUACIÓN ECONÓMICA: En cuanto a la discordancia de los estudios revisados se logra establecer que dependiendo de la perspectiva tomada en cuenta para el dimetilfumarato, se establece la efectividad o no del tratamiento, dependiendo ésto también de los tratamientos que se les compare. Donde sí existe consenso es que comparando el dimetilfumarato con acetato de glatiramer, el primero es costoefectivo. En cuanto a ocrelizumab, ambas investigaciones encontradas, desde la perspectiva del pagador, consideran que este tratamiento es costo-efectivo. Por último, teriflunomida fue costoefectivo para una investigación realizada en Finlandia desde la perspectiva del pagador. En cuanto a las recomendaciones de agencias, se aprecia que: alemtuzumab y dimetilfumarato tienden a ser recomendados, no así teriflunomide. Ocrelizumab al momento se encuentra en análisis por las agencias. En cuanto al análisis presupuestal, se encontró que los costos de los mismos para la esclerosis múltiple remitente recurrente, en 1ª línea, serían de un nivel muy alto en relación al fondo disponible. En cuando a la esclerosis múltiple primaria progresiva, el impacto de ocrelizumab para el año 2018 es de MM$4.440. Además, se realizó una comparación de cuál sería el impacto diferencial en esclerosis múltiple remitente recurrente en 2ª línea, en comparación por lo ya cubierto por la ley, de incluir Ocrelizumab o Alemtuzumab. CONCLUSIÓN: Para dar cumplimiento al artículo 28° del Reglamento que establece el proceso destinado a determinar los diagnósticos y tratamientos de alto costo con Sistema de Protección Financiera, según lo establecido en los artículos 7° y 8° de la ley N°20.850, aprobado por el decreto N° 13 del Ministerio de Salud, se concluye que el presente informe de evaluación se considera favorable, de acuerdo a lo establecido en el Título III, de las Evaluaciones Favorables de la Norma Técnica N° 0192 de este mismo Ministerio.

Parecoxib reduces renal injury in an ischemia/reperfusion model in rats

PURPOSE: To evaluate the effect of parecoxib (an NSAID) on renal function by measuring plasma NGAL (serum neutrophil gelatinase-associated lipocalin) levels in an induced-ischemia rat model. METHODS: Forty male Wistar rats were randomly assigned to one of four groups: Ischemia (I), Ischemia/parecoxib (IP), No-ischemia (NI), and No-ischemia/parecoxib (NIP). Body weight, mean arterial pressure, heart rate, body temperature, NGAL levels, and renal histology were compared across groups. RESULTS: The Ischemia (I) group, which did not receive parecoxib, showed the highest NGAL levels (p=0.001), while the IP group, which received the medication, had NGAL levels similar to those of the non-ischemic (NI and NIP) groups. CONCLUSION: Parecoxib resulted in renal protection in this experimental model. .

Informe técnico sobre cobertura de teriflunomida en esclerosis múltiple / Technical report on coverage of teriflunomide in multiple sclerosis

El SIS tiene por objetivo la capacitación y gestión de fondos para el aseguramiento de las prestaciones de salud y la cobertura de riesgos de salud de los asegurados, y que con este fin ha establecido como líneas estratégicas de accón: ser garante del asegurado en la oportunidad, continuidad de las prestaciones de saud financiadas, y promover una gerencia moderna, eficiencia del financiamento y nuevos mecanismos de pago de las prestaciones de salud con énfasis en la atención primaria y salud como derecho. Entre los objetivos generales del SIS destacan fomentar la cultura del aseguramiento en salud de la población, fortalecer los mecanismos de control a las IPRESS en la utilización óptima de los recursos trasnferidos por el SIS y contribuir con el control de enfermedades no transmisibles. El medicamento teriflunomida es una alternativa de tratamiento en pacientes con diagnóstico de esclerosis múltiple remitente-recurrente y formas progresivas que presentan recaídas, de acuerdo a prescripción médica.

Iloperidone – A Newer Antipsychotic.

The optimal treatment of schizophrenia poses a challenge to develop more effective treatments and safer drugs, to overcome poor compliance, discontinuation and frequent switching with available antipsychotics. Iloperidone is a new antipsychotic developed to overcome some of the limitations in the drug treatment of schizophrenia. It has been approved by regulating agencies for use in treatment of adult schizophrenia.

Eficácia terapêutica e segurança de metotrexato + leflunomida em pacientes colombianos com artrite reumatoide ativa refratária ao tratamento convencional / Therapeutic efficacy and safety of methotrexate + leflunomide in Colombian patients with active rheumatoid arthritis refractory to conventional treatment

INTRODUÇÃO: A combinação de metotrexato (MTX) + leflunomida (LFN) demonstrou ser efetiva no tratamento da artrite reumatoide (AR), mas sua segurança tem sido questionada. OBJETIVO: Avaliar a eficácia e a segurança terapêutica da combinação de MTX + LFN em pacientes com AR ativa. MÉTODOS: Estudo multicêntrico com 24 semanas de duração envolvendo 88 pacientes com doença ativa, apesar do tratamento regular com MTX e prednisolona. RESULTADOS: Participaram do estudo 78 mulheres (88%) e 10 homens. A idade foi de 51,3 ± 12,4 anos, e o tempo de evolução da doença, 8,0 ± 6,8 anos. Os pacientes tinham doença ativa evidenciada por IQR média de 10 (7,0-13,0) nas articulações inflamadas e 14,0 (18,0-10,0) nas articulações dolorosas. As respostas ACR obtidas na semana 24 foram: ACR20: 76%; ACR50: 67,1%; e ACR70: 23,9%. Houve melhora na atividade da doença, medida pelo escore DAS-28: 5,8 ± 1,2 no início do estudo vs. 3,8 ± 1,6 na semana 24 (P = 0,000). O evento adverso mais significativo foi elevação das transaminases, ocorrida em oito (26%) pacientes. Oito pacientes descontinuaram o estudo devido a eventos adversos: quatro por elevação das transaminases, um por diabetes insípido, um por erupção cutânea, um por diabetes mellitus e um por dor osteomuscular. CONCLUSÃO: A combinação de MTX + LFN é efetiva para o tratamento de AR em pacientes que não obtiveram sucesso com o tratamento convencional. Há necessidade de rígido controle médico e laboratorial para segurança terapêutica.

INTRODUCTION: The combination of methotrexate (MTX) + leflunomide (LFN) has been shown to be effective in the treatment of RA. Its safety has been questioned. OBJECTIVE: To evaluate the effectiveness and safety of the combination of MTX + LFN in patients with active RA. METHODS: This was a 24-week multicenter study, which included 88 patients with active disease despite consistent treatment with methotrexate and prednisolone. RESULTS: We included 78 women (88%) and 10 men. The age was 51.3 ± 12.4 years, and the evolution of disease was 8 ± 6.8 years. Patients had active disease, which was indicated by a median of IQR of 10.0 (7.0-13.0) for swollen and of 14.0 (18.0-10.0) for tender joints for the whole group. The ACR responses achieved at week 24 were: ACR20: 76.0%; ACR50: 67.1%; ACR70: 23.9%. There was improvement in the activity of disease: DAS-28 score: 5.8 ± 1.2 at baseline vs. 3.8 ± 1.6 at week 24 (P = 0.000). The most significant adverse event was elevation of transaminases in eight patients (26%). Eight patients were withdrawn due to adverse events: four due to the elevation of transaminases, and one each due to diabetes insipidus, rash, diabetes mellitus and osteomuscular pain. CONCLUSION: The combination of MTX + LFN is effective for treating RA in patients for whom conventional treatment has failed. Strict medical and laboratory control is to be enforced for safety.

Efficacy and safety of parecoxib in the treatment of acute renal colic: a randomized clinical trial

PURPOSE: Although nonselective nonsteroidal anti-inflammatory drugs (nsNSAIDs) and opioids are effective treatments for acute renal colic, they are associated with adverse events (AEs). As cyclooxygenase-2 selective NSAIDs may provide a safer alternative, we compared the efficacy and safety of parecoxib versus an nsNSAID in subjects with acute renal colic. MATERIALS AND METHODS: Phase IV., multicenter, double-blind, noninferiority, active-controlled study: 338 subjects with acute renal colic were randomized to parecoxib 40 mg i.v. plus placebo (n = 174) or ketoprofen 100 mg IV plus placebo (n = 164). 338 subjects with acute renal colic were randomized to parecoxib 40 mg IV (n = 174) or ketoprofen 100 mg IV(n = 164) plus placebo. Subjects were evaluated 15, 30, 45, 60, 90 and 120 minutes after treatment start and 24 hours after discharge. Primary endpoint was the mean pain intensity difference (PID) at 30 minutes by visual analog scale (VAS) (per-protocol population). An ANCOVA model was used with treatment group, country, and baseline score as covariates. Non-inferiority of parecoxib to ketoprofen was declared if the lower bound of the 95 percent confidence interval (CI) for the difference between the two groups excluded the pre-established margin of 10 mm for the primary endpoint. RESULTS: Baseline demographics were similar. The mean (SD) mPID30 min was 33.84 (24.61) and 35.16 (26.01) for parecoxib and ketoprofen, respectively. For treatment difference (parecoxib-ketoprofen) the lower bound of the 95 percent CI was 6.53. The mean change from baseline in VAS 30 minutes after study medication was ~43 mm; AEs were comparable between treatments. CONCLUSIONS: Parecoxib is as effective as ketoprofen in the treatment of pain due to acute renal colic, is well tolerated, and has a comparable safety profile.

Toxicidade hepática é rara em pacientes com artrite reumatoide usando terapia combinada de leflunomida e metotrexato / Liver toxicity is rare in rheumatoid arthritis patients using combination therapy with leflunomide and methotrexate

OBJETIVO: De acordo com alguns estudos, a associação de leflunomida (LEF) a pacientes portadores de artrite reumatoide não responsivos a metotrexato (MTX) aumentou a eficácia do tratamento, elevando, porém, o risco de toxicidade hepática. Este estudo objetiva avaliar a incidência de toxicidade hepática no tratamento da artrite reumatoide ativa usando terapia combinada de LEF e MTX em comparação com monoterapia com MTX. MÉTODOS: Entre fevereiro e setembro de 2009, foram arrolados 97 pacientes consecutivos acompanhados pelo Hospital Universitário da Universidade Federal de Santa Catarina, Brasil. Pacientes com artrite reumatoide em uso de MTX somente ou em combinação com LEF tiveram seus prontuários sistematicamente revisados. As enzimas alanino/aspartato aminotransferases foram analisadas retrospectivamente desde o tratamento com MTX ou MTX mais LEF. Hepatotoxicidade foi definida como um aumento das enzimas hepáticas acima de duas vezes o limite superior da normalidade. RESULTADOS: 71 pacientes foram incluídos no estudo: 36,6 por cento usavam 20-25 mg/semana de MTX e 63,4 por cento usavam 20-25 mg/semana de MTX associado a 20 mg/ dia de LEF. Dos pacientes em terapia combinada, 11,1 por cento tinham níveis anormais das enzimas hepáticas versus 11,5 por cento daqueles em monoterapia (P = 1,0). Níveis anormais de aminotransferases têm sido observados em pacientes com artrite reumatoide tanto em monoterapia com MTX quanto com LEF. Em nosso estudo, não encontramos diferença entre as percentagens de elevação das aminotransferases em pacientes tratados somente com MTX ou com terapia combinada. CONCLUSÃO: A combinação de MTX e LEF em pacientes com artrite reumatoide é geralmente segura e bem tolerada.

OBJECTIVE: Some studies have reported that adding leflunomide (LEF) to the treatment of rheumatoid arthritis (RA) in patients who do not respond to methotrexate (MTX) improved efficacy but increased the risk of liver toxicity. This study aimed at assessing the incidence of liver toxicity in patients with active RA using the LEF and MTX combination therapy in comparison with that of patients on MTX monotherapy. METHODS: Between February and September 2009, 97 consecutive patients followed up at the University Hospital of the Universidade Federal de Santa Catarina, Brazil, were enrolled. RA patients on MTX alone or using the LEF and MTX combination had their medical records systematically reviewed. The alanine/aspartate aminotransferase enzymes were retrospectively analyzed since the beginning of treatment with MTX or MTX plus LEF. Hepatotoxicity was defined as an increase of at least two-fold the upper limits of normal of the liver enzymes. RESULTS: 71 RA patients were included in the study: 36.6 percent were using 20-25 mg/week of MTX alone and 63.4 percent were using 20-25 mg/week of MTX plus 20 mg/day of LEF. Of the patients on the combination therapy, 11.1 percent had abnormal levels of liver enzymes versus 11.5 percent of the patients on monotherapy (P = 1.0). Abnormal aminotransferase levels have been seen with both MTX and LEF monotherapies in patients with RA. In our study, no difference was found between the percentages of aminotransferase elevations of patients being treated with MTX alone or in combination with LEF. CONCLUSION: The combination of MTX and LEF in RA patients is generally safe and well tolerated.

Efficacy and safety of atypical antipsychotic drugs (quetiapine, risperidone, aripiprazole and paliperidone) compared with placebo or typical antipsychotic drugs for treating refractory schizophrenia: overview of systematic reviews / Eficácia e segurança dos antipsicóticos atípicos (quetiapina, risperidona, aripiprazol, paliperidona) em comparação com um placebo ou medicamentos antipsicóticos típicos no tratamento da esquizofrenia refratária: overview de revisão sistemática

CONTEXT AND OBJECTIVE: According to some cohort studies, the prevalence of refractory schizophrenia (RS) is 20-40 percent. Our aim was to evaluate the effectiveness and safety of aripiprazole, paliperidone, quetiapine and risperidone for treating RS. METHODS: This was a critical appraisal of Cochrane reviews published in the Cochrane Library, supplemented with reference to more recent randomized controlled trials (RCTs) on RS. The following databases were searched: Medical Literature Analysis and Retrieval System Online (Medline) (1966-2009), Controlled Trials of the Cochrane Collaboration (2009, Issue 2), Embase (Excerpta Medica) (1980-2009), Literatura Latino-Americana e do Caribe em Ciências da Saúde (Lilacs) (1982-2009). There was no language restriction. Randomized controlled trials, systematic reviews and meta-analyses evaluating atypical antipsychotics for treating RS were included. RESULTS: Seven Cochrane systematic reviews and 10 additional RCTs were included in this review. The data generally showed minor differences between the atypical antipsychotics evaluated and typical antipsychotics, regarding improvement in disease symptoms, despite better adherence to treatment with atypical antipsychotics. Risperidone was specifically evaluated in patients with RS in one of the systematic reviews included, with favorable outcomes, but without definitive superiority compared with other drugs of proven efficacy, like amisulpride, clozapine and olanzapine. CONCLUSIONS: The findings underscore the difficulty in treating these patients, with high dropout rates and treatment patterns of modest improvement in assessments of effectiveness. Atypical antipsychotics have advantages over typical antipsychotics mainly through their better safety profile, which leads to better adherence to treatment. A combination of antipsychotics may also be an option for some refractory patients.

CONTEXTO E OBJETIVO: De acordo com alguns estudos de coorte, a prevalência da esquizofrenia refratária (ER) está entre 20-40 por cento. Nosso objetivo foi avaliar a efetividade e segurança de aripiprazol, paliperidona, quetiapina e risperidona no tratamento da esquizofrenia refratária. MÉTODOS: Avaliação crítica das revisões Cochrane publicadas na Biblioteca Cochrane e complementação com referências de ensaios clínicos randomizados (ECRs) mais atualizados sobre ER. As seguintes bases de dados foram pesquisadas: Medline (Medical Literature Analysis and Retrieval System Online) (1966-2009), Ensaios Controlados da Colaboração Cochrane (2009, edição 2), Embase (Excerpta Database) (1980-2009), Lilacs (Literatura Latino-Americana e do Caribe em Ciências da Saúde) (1982-2009). Não houve restrição a idiomas. Ensaios clínicos randomizados, revisões sistemáticas e metanálises que avaliaram antipsicóticos atípicos no tratamento da esquizofrenia refratária foram incluídos. RESULTADOS: Sete revisões sistemáticas Cochrane e 10 ECRs complementares foram incluídos nessa revisão. No geral os dados demonstram pequenas diferenças entre os antipsicóticos atípicos avaliados e os típicos na melhora dos sintomas da doença, apesar da melhor adesão ao tratamento com os atípicos. A risperidona foi avaliada especificamente em pacientes com esquizofrenia refratária em uma das revisões sistemáticas incluídas, a qual demonstrou desfechos favoráveis, porém não definitivos quando comparada a drogas também com eficácia comprovada como amisulprida, clozapina e olanzapina. CONCLUSÕES: Os dados reforçam a dificuldade de tratar esses pacientes, com elevadas taxas de desistência do tratamento e padrões de melhora modestos nas avaliações de eficácia. Os antipsicóticos atípicos têm vantagens sobre os típicos principalmente pelo melhor perfil de segurança, o que leva a melhor adesão ao tratamento. A associação de antipsicóticos também pode ser uma opção em alguns pacientes refratários ao tratamento.

The selective and non-selective cyclooxygenase inhibitors valdecoxib and piroxicam induce the same postoperative analgesia and control of trismus and swelling after lower third molar removal

We compared the clinical efficacy of orally administered valdecoxib and piroxicam for the prevention of pain, trismus and swelling after removal of horizontally and totally intrabony impacted lower third molars. Twenty-five patients were scheduled to undergo removal of symmetrically positioned lower third molars in two separate appointments. Valdecoxib (40 mg) or piroxicam (20 mg) was administered in a double-blind, randomized and crossed manner for 4 days after the surgical procedures. Objective and subjective parameters were recorded for comparison of postoperative courses. Both agents were effective for postoperative pain relief (N = 19). There was a similar mouth opening at suture removal compared with the preoperative values (86.14 ± 4.36 and 93.12 ± 3.70 percent of the initial measure for valdecoxib and piroxicam, respectively; ANOVA). There was no significant difference regarding the total amount of rescue medication taken by the patients treated with valdecoxib or piroxicam (173.08 ± 91.21 and 461.54 ± 199.85 mg, respectively; Wilcoxon test). There were no significant differences concerning the swelling observed on the second postoperative day compared to baseline measures (6.15 ± 1.84 and 8.46 ± 2.04 mm for valdecoxib and piroxicam, respectively; ANOVA) or on the seventh postoperative day (1.69 ± 1.61 and 2.23 ± 2.09 mm for valdecoxib and piroxicam, respectively; ANOVA). The cyclooxygenase-2 selective inhibitor valdecoxib is as effective as the non-selective cyclooxygenase inhibitor piroxicam for pain, trismus and swelling control after removal of horizontally and totally intrabony impacted lower third molars.

Role of cyclooxygenase-2 in lipopolysaccharide-induced hyperalgesia in formalin test.

Lipopolysaccharide (LPS)-induced hyperalgesia and the role of cyclooxygenase (COX) isoforms in acute and chronic nociceptive assays have been well established. However, the role of COX isoforms in LPS-induced hyperalgesia in the formalin test is not clear. Thus, the present study was undertaken to characterize the time course of formalin-induced nociceptive response in LPS-pretreated mice and to investigate possible effects of COX inhibitors to address the potential role of COX isoforms in LPS-induced hyperalgesia in the formalin test. All the animals showed typical biphasic response to formalin challenge. At 0 hr (immediately) and 4 hr after LPS pretreatment, animals did not show any alteration in formalin-induced tonic pain. However, 12 and 16 hr after LPS pretreatment, there was a significant increase in the late phase of formalin-induced nocifensive response as compared to control mice. Treatment with intravenously administered ketorolac (a nonselective COX inhibitor) significantly and dose-dependently inhibited the late phase of formalin-induced nociceptive behaviour in saline and LPS-pretreated mice. In contrast, parecoxib (prodrug of valdecoxib, a selective COX-2 inhibitor) or dexamethasone (COX-2 transcription inhibitor), when administered intravenously or intraperitoneally, respectively, did not show antinociceptive effect in the formalin test in saline-pretreated mice. However, both the agents significantly and dose-dependently decreased the late phase nociceptive behaviour of the formalin test in LPS-pretreated mice to the level of the animals that received saline pretreatment. These results suggest that induction of COX-2 by proinflammatory mediators and subsequent release of prostaglandins could be responsible for LPS enhancement of formalin-induced nocifensive behaviour and supports an important role of COX-2 in LPS-induced hyperalgesia in the formalin test.

Necrolisis tóxica epidérmica: caso clínico / Toxic epidermal necrolysis: clinical case

Toxic epidermal necrolysis is a potentially fatal disease due to allergic reactions to drugs. We report on a 58 years old female, that presented Raynaud sphenomenon during 20 years. During the last year, she developed polyarthritis of hands, shoulders, knees and ankles. Rheumatoid factor (RF), antinuclear antibodies (ANA) and U_ ribonucleoprotein (U1 RNP) were present, and Mixed connective tissue disease was suspected. Because of a poor response to methotrexate the patient received leflunomide. Two weeks later, she began with fever, pruritus and generalized edema. Within days this affected her neck, thorax, eyes and oral mucous. She had bullaes and areas of epidermic detachment. A toxic epidermal necrolysis was diagnosed and treated with IV immunoglobulins. The lesions disappeared successfully. In addition to the dermatological problem, the patient later presented ocular complications that required the transplant of both corneal, with the sub-sequent loss of one of her eyes.

Role of parecoxib in pre-emptive analgesia: comparison of the efficacy and safety of pre- and postoperative parecoxib in patients undergoing general surgery.

Management of acute postoperative pain remains sub-optimal despite the availability of multiple analgesics and improved pain management strategies (with nearly 80 % of patients reporting moderate to extreme pain following surgery). To evaluate the role of parecoxib as a pre-emptive analgesic in patients undergoing general surgery, the present study was undertaken. Eighty patients of either sex, aged 18 to 70 years, requiring elective ambulatory general surgery like hernioplasty, appendicectomy, cholecystectomy, etc, were enrolled in this prospective, randomised, assessor-blind, parallel-group, comparative trial. Eligible patients were randomised to receive a single dose of 40 mg of parecoxib IM/IV either 30-45 minutes prior to induction of anesthesia (pre-emptive analgesia) or in the postoperative period when one reported pain or when the effects of anesthesia were worn off (whichever was earlier). The primary measures of efficacy were pain intensity scores measured on a visual analog scale (VAS) and pain relief before and after therapy. Adverse event monitoring, physical examination and changes in laboratory tests, chest x-ray and ECG were used to evaluate safety. A comparison of the pain intensity scores between the two groups revealed that patients treated with parecoxib preoperatively did not complain of pain in the entire postoperative period up to 12 hours. Mild pain (1.05+/-1.36) was reported by patients in this group only at the 24 hours assessment. On the other hand, patients treated with parecoxib in the postoperative period, experienced severe pain at baseline, which declined gradually up to 12 hours. The difference in the pain intensity scores between the two groups was statistically significant at all the time intervals from 0 hour to 24 hours. All the 40 patients (100%) in the pre-operatively treated group reported total pain relief at 12 hours compared to only 22 patients (55%) in the postoperative period. At 24 hours total pain relief was reported by 70% of the patients in the pre-operatively treated group, compared to only 20% (8) patients in the postoperatively treated group. The difference between the two groups was statistically significant in favour of the pre-operatively treated group (p<0.05). Present results suggested that pre-operative administration of parecoxib was more effective than a postoperative use in providing pain relief in postoperative period in patients undergoing elective general surgical procedures. Both the regimens were well tolerated. Based on the above data, it appears that pre-operative dose of parecoxib 40 mg IV/IM is a useful optionfor pre-emptive analgesia in general surgical practice.

FK778, A Synthetic Malononitrilamide

FK778 is a synthetic malononitrilamide (MNA) that has been demonstrated to have both both immunosuppressive and anti-proliferative activities. The MNAs inhibit both T-cell and B-cell function by blocking de novo pyrimidine synthesis, through blockade of the pivotal mitochondrial enzyme dihyroorotic acid dehydrogenase (DHODH), and the inhibition of tyrosine kinase activity. FK778 has been demonstrated to prevent acute allograft rejection in multiple experimental transplant models in rodents, dogs and primates and to be effective in the rat model of chronic renal allograft rejection. In addition, FK778 has been shown to prevent vascular remodeling after mechanical intimal injury via a mechanism which may be related to tyrosine kinase inhibitory activity in vascular smooth muscle cells. Another intriguing activity of the MNA family is the ability to block replication of members of the Herpes virus family with in vitro evidence that of efficacy against cytomegalovirus (CMV) and polyoma virus, important pathogens in the transplant recipient. FK778 is currently being explored in a number of trials in solid organ transplant recipients.

Evaluation of efficacy, safety and tolerability of valdecoxib in osteo-arthritis patients--an Indian study.

Valdecoxib, a COX-2 inhibitor, has been introduced as a new treatment for osteo-arthritis (OA). The present study was conducted to evaluate the efficacy, safety and tolerability of valdecoxib, in OA patients in an Indian setting. The present 4-week study was a prospective, non-comparative, assessor blind, single group, multicentric trial with OA patients treated with valdecoxib, 10 mg once a day. Efficacy was assessed by analysing the changes in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), visual analogue scale (VAS), patient's and physician's global assessment of arthritis. The incidence of adverse events was monitored throughout the study. There was a clinical and statistical significant improvement in the mean pain score, stiffness score, physical function, composite WOMAC index score and VAS (p<0.05). Patient's and physician's global evaluation of valdecoxib treatment was very good to good in 84.1% and 83.6% of cases respectively. The present study has shown that valdecoxib, in a dose of 10 mg/day given over 4 weeks, is an effective and safe treatment for the signs and symptoms of OA of hip and knee joints.

Risperidone versus haloperidol in the treatment of chronic schizophrenic patients: a parallel group double-blind comparative trial

A parallel group double-blind comparative trial was conducted to study the efficacy and safety of risperidone compared with haloperidol. After a one-week wash-out, 35 chronic schizophrenic patients (17 males, 18 females) were randomly assigned to one of two groups for eight weeks of double-blind treatment. The patients' psychopathology was assessed by means of the Positive and Negative Syndrome Scale for Schizophrenia (PANSS) and the Clinical Global Impression (CGI). Safety assessments included the Extrapyramidal Symptom Rating Scale (ESRS), the UKU Side Effect Rating Scale, vital signs, body weight, ECG and laboratory screening. Thirty-two patients completed the trial: there were 3 dropouts in the risperidone group. The results on the PANSS and CGI indicate that the mean changes from baseline on the total PANSS score and on the total BPRS score were comparable in both treatment groups. The number of patients where a clinical improvement at least 20% reduction in baseline score was also similar in both treatment groups. Risperidone caused less extrapyramidal symptoms and less side effects in UKU scale than haloperidol. No significant ECG changes were induced, no relevant changes in blood pressure or clinical laboratory parameters were observed. This study has demonstrated that the combined serotonin 5-HT2 and dopamine-D2 antagonist risperidone is an antipsychotic as potent as haloperidol. Risperidone causes less extrapyramidal symptoms, and is better tolerated than haloperidol.

Isoxazolynaphthoquinone effects on the growth of Trypanosoma cruzi

Frente a la necessidad de hallar neuveos fármacos contra el agente etiológico de la enfermedad de Chagas y en base a las propiedades biológicas y terapéuticas de naftoquinonas e isoxazoles, se resolvió estudiar el efecto de tres isoxazolilnaftoquinonas (Fig. 1) sobre el desarrollo del Trypanosoma cruzi in-vitro e in-vivo. Para evaluar la acción de las drogas sobre los epimastigotes se realizaron curvas de crecimiento con distintas concentraciones de 2-hidroxi-N-(3,4-dimetil-5-isoxazolil)-1,4-naftoquinina-4-imina (I), N-(3,4-dimetil-5-isoxazolil)-4-amino-1,2 naftoquinona (II), 2-acetil-N-(3,4-dimetil-5-isoxazolil)-1,4-naftoquinona-imina (III) y Nifurtimox como droga de referencia. Los estudios sobre la forma de tripomastigote se realizaron sobre ratones BALB/c de dos meses de edad, evaluado parasistemia en el día 13 post-infección. Los resultados obtenidos con epimastigotes mostraron que todas las drogas indujeron alteraciones consistentes es disminución de movilidad, vacuolización, pérdida de viabilidad y/o lisis de los parásitos (Fig. 2 y 3). En los tratamientos sobre tripomastigotes los resultados más concluyentes se presentaron con I que produjo una reducción de la parasitemia respecto a los controles no tratados (Fig 4)