In vitro and In vivo toxicology evaluation to determine suitable biomedical Polymers for development of a papain-containing drug delivery system

Papain has been known by many decades for wounded tissues repair. However, papain stability is not high enough to be commercialized in a stable pharmaceutical form; therefore its use is limited. The strategy to entrap papain into a polymeric matrix to provide an adequate drug delivery system consists of an alternative to this problem. The purpose of this study was to assess in vitro and in vivo four polymers cytotoxicity and ability to cause cutaneous irritation to be applied as a suitable papain delivery system. A Monocomponent (MSD) and Bicomponent Silicone Dispersions (BSD) and, Natural Rubber Bicentrifuged Latex (NRBL) and an Acrylic Adhesive (AA) were selected. The cytotoxicity was firstly assessed by the Neutral Red Uptake Method. Non-cytotoxic polymers were then submitted to in vivo Cutaneous Irritation Test. Both silicone dispersions were found non-cytotoxic, and NRBL and AA polymers showed cytotoxicity. MSD and BSD polymers did not cause any cutaneous reactions.Colegio de Farmacéuticos de la Provincia de Buenos Aire

Validation Of The Ebmt Risk Score In Chronic Myeloid Leukemia In Brazil And Allogeneic Transplant Outcome.

The management of chronic myeloid leukemia (CML) has changed radically since the introduction of imatinib therapy. The decision of whether to offer a patient a hematopoietic stem cell transplant (HSCT) must be based on the probability of success of the procedure. The aim of this retrospective analysis of 1,084 CML patients who received an allogeneic HSCT in 10 Brazilian Centers between February 1983 and March 2003 was to validate the EBMT risk score. The study population comprised 647 (60%) males and 437 (40%) females, with a median age of 32 years old (range 1 - 59); 898 (83%) were in chronic phase, 146 (13%) were in accelerated phase and 40 (4%) were in blast crisis; 151 (14%) were younger than 20 years old, 620 (57%) were between 20 and 40 and 313 (29%) were older than 40; 1,025 (94%) received an HLA fully matched sibling transplant and only 59 (6%) received an unrelated transplant. In 283 cases (26%) a male recipient received a graft from a female donor. The interval from diagnosis to transplantation was less than 12 months in 223 (21%) cases and greater in 861 (79%). The overall survival, disease-free survival, transplant-related mortality and relapse incidence were 49%, 50%, 45% and 25%, respectively. Of the 1084 patients, 179 (17%) had a risk score of 0 or 1, 397 (37%) had a score of 2, 345 (32%) had a score of 3, 135 (12%) had a score of 4 and 28 (2%) a score of 5 or 6. The overall survival (OS) rate in patients with risk scores 0-1 and 2 was similar (58% and 55%, respectively) but significantly better than that in patients with scores 3 or more (score 3 - 44%, 4 - 36 % and 5-6 - 27%, respectively) pp<0.001). Disease-free survival (DFS) and transplant related mortality (TRM) in a patients with a score of 3 or more were 46% and 49%, respectively and the relapse rate beyond score 5-6 was 77%. Disease status had a negative impact on all outcomes (OS, DFS, TRM, and relapse). The OS rate for male recipients of a graft from a female donor was 40% compared to 52% among the other donor-recipient pairs (p=0.004). DFS and TRM were significant for disease phase and female donor-male recipient (p<0.001 and p<0.003, respectively). In our experience, age and interval between diagnosis and transplant did influence OS, DFS, TRM, and relapse rate. Our results validate the EBMT risk score in the context of a developing country and confirm its usefulness for making point decisions in the imatinib era.90232-

"Development of a polymeric matrix for incorporation and controlled release of papain"

A papaína é uma enzima proteolítica extraída do látex das folhas e frutos do mamão verde adulto. Tem sido amplamente utilizada como agente debridante de escaras e cicatrizante de feridas. No entanto, apresenta baixa estabilidade, o que limita seu uso a formulações de manipulação extemporânea ou de curto prazo de validade. O objetivo deste trabalho foi incorporar a papaína em uma matriz polimérica de modo a obter um sistema de liberação controlada do fármaco. Polímeros de aplicação médica foram selecionados e inicialmente avaliados quanto à sua citotoxicidade. Os polímeros não-citotóxicos foram submetidos ao ensaio de irritação cutânea primária in vivo em animais, para avaliar sua capacidade de causar irritação na pele humana. Diversas membranas foram preparadas com os polímeros considerados adequados para aplicação biomédica para incorporação da papaína. As membranas preparadas com 2% de papaína foram selecionadas para serem submetidas ao ensaio de liberação com células de difusão de Franz. Parte dessas membranas foi irradiada com raios &#947; na dose de 25 kGy para esterilização do material. As membranas irradiadas e não-irradiadas foram testadas simultaneamente a fim de verificar se a radiação &#947; interferiria no perfil de liberação do fármaco. Os resultados do ensaio de liberação indicaram que o fármaco é liberado de maneira constante durante as 12 horas iniciais do experimento. A análise, por Microscopia Eletrônica de Varredura, das membranas irradiadas revelou que as membranas formadas são bastante densas e que seus poros são pequenos.Papain is a proteolytic enzyme extracted from the latex of green papaya leaves and fruits. It has been widely used as debridant for scars and wound healing agent. However, papain presents low stability, which limits its use to extemporaneous or short shelf life formulations. The purpose of this study was to entrap papain into a polymeric matrix in order to obtain a drug delivery system. Polymers of medical application were selected and firstly assessed for cytotoxicity. Non-cytotoxic polymers were evaluated for primary cutaneous irritation test in vivo in animals, in order to verify if they are able to cause irritation to human skin. Many membranes were prepared with the polymers considered suitable for biomedical application for papain entrapment. Membranes containing 2% papain were selected to be evaluated in the releasing test using Fanz diffusion cells. Some of these membranes were irradiated by &#947; rays with 25 kGy dose for material sterilization. Irradiated and non-irradiated membranes were simultaneously assessed in order to verify if &#947; radiation interferes on drug releasing profile. Results obtained from releasing test indicated the drug is released in a constant manner over 12 hours in the beginning of the experiment. Scanning Eletronic Microscopy analysis of the irradiated membranes revealed that membranes are very dense and its pores are small

Influence of gamma radiation onto polymeric matrix with papain

Papain is a proteolytic enzyme that has been widely used as debridement agent for scars and wound healing treatment. However, papain presents low stability, which limits its use to extemporaneous or short shelf-life formulations. The purpose of this study was to entrap papain into a polymeric matrix in order to obtain a drug delivery system that could be used as medical device. Since these systems must be sterile, gamma radiation is an interesting option and presents advantages in relation to conventional agents: no radioactive residues are formed: the product can be sterilized inside the final packaging and has an excellent reliability. The normative reference for the establishment of the sterilizing dose determines 25 kGy as the inactivation dose for viable microorganisms. A silicone dispersion was selected to prepare membranes containing 2% (w/w) papain. Irradiated and non-irradiated membranes were simultaneously assessed in order to verify whether gamma radiation interferes with the drug-releasing profile. Results showed that irradiation does not affect significantly papain release and its activity. Therefore papain shows radioresistance in the irradiation conditions applied. In conclusion, gamma radiation can be easily used as sterilizing agent without affecting the papain release profile and its activity onto the biocompatible device is studied. (C) 2009 Elsevier Ltd. All rights reserved

Cardiovascular risk and cardiovascular events in patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors

We evaluated the incidence of cardiovascular events in 233 consecutive patients with chronic myeloid leukemia, treated with imatinib (116), dasatinib (75), and nilotinib (42). Three events occurred with dasatinib and 6 with nilotinib. Arterial occlusive events occurred more frequently in patients treated with nilotinib (14.2%) rather than dasatinib (2.6%) in patients with high and very high cardiovascular risk factors. This finding may help to guide therapy. Background: Cardiovascular events (CVEs) have been observed in patients with chronic myeloid leukemia treated with second-generation tyrosine kinase inhibitors. Patients and Methods: We retrospectively evaluated the incidence of CVEs on 233 consecutive patients with chronic myeloid leukemia, of which 116 were treated with imatinib, 75 with dasatinib, and 42 with nilotinib. The median follow-up was 2047, 1712, and 1773 days, respectively. Results: The cumulative incidence of CVEs was 4.29%. Three events occurred during dasatinib treatment, 6 during nilotinib treatment, and none during imatinib treatment (P <=.001). Arterial occlusive events occurred in 2 (2.6%) of 75 patients treated with dasatinib and in 6 (14.2%) of 42 patients treated with nilotinib (P <=.001). Furthermore, all of them occurred in patients with high-risk (n = 2) and very high-risk (n = 6) cardiovascular risk, contributing to 4.3% of mortality. Conclusion: CVEs were more frequent in patients treated with second-generation tyrosine kinase inhibitors. Arterial occlusive events were more frequent in patients treated with nilotinib, with high and very high cardiovascular risk.193162166COORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPESSem informaçã

Quality Of Life In Patients Randomized To Receive A Bone Marrow Or A Peripheral Blood Allograft.

Quality of life (QOL) is an important clinical end-point to be considered in the late follow-up of patients treated with allogeneic bone marrow (BM) or peripheral blood progenitor cell (PBPC) transplantation. To assess the QOL in a group of survivors of hematologic malignancies who had been enrolled in a prospective randomized trial comparing allogeneic BM with PBPC. Sixty randomized patients had been enrolled in a study comparing BM with PBPC graft during 1995-99. At the time of this QOL study, 30 were alive and 26 (13 BM and 13 PBPC) were eligible. Clinical and demographic data were collected and psychometric instruments (WHOQOL-100 and the Hospital Anxiety and Depression Scale HAD) were used. Non-parametric and univariate analyses were performed. The PBPC recipients had more chronic graft-versus-host disease (p=0.03) and were on immunosuppressive treatment for a longer period (p=0.02). The WHOQOL-100 analysis demonstrated significant differences between groups with more favorable results in the BM group in the facets of Pain and Discomfort (p=0.03), Mobility (p=0.02) and Daily Living Activities (p=0.03). According to the patients' spontaneous responses, 8 individuals (6 in the PBPC group) believed that their QOL had worsened. With the limitations of a small randomized study, these findings suggest a lower QOL in recipients of allogeneic PBPC than in recipients of BM grafts, probably due to the frequency and severity of chronic graft-versus-host disease. This need to be confirmed in a large international trial.871281-