Ocular and systemic toxicity of high-dose intravitreal topotecan in rabbits: Implications for retinoblastoma treatment.

Although many more eyes of children with retinoblastoma are salvaged now compared to just 10 years ago, the control of vitreous seeding remains a challenge. The introduction of intravitreal injection of melphalan has enabled more eyes to be salvaged safely but with definite retinal toxicity. Intensive treatment with high-dose intravitreal topotecan may be a strategy to control tumor burden because of its cell cycle-dependent cytotoxicity and the proven safety in humans. Therefore, we evaluated the ocular and systemic safety of repeated high-dose intravitreal injections of topotecan in rabbits. Systemic and ocular toxicity was assessed in non-tumor-bearing rabbits after four weekly injections of three doses of topotecan (10 µg, 25 µg, and 50 µg) or vehicle alone. Animals were evaluated weekly for general and ophthalmic clinical status. One week after the last injection, vitreous and plasma samples were collected for drug quantification and the enucleated eyes were subjected to histological assessment. Weight, hair loss, or changes in hematologic values were absent during the study period across all animal groups. Eyes injected with all topotecan doses or vehicle showed no signs of anterior segment inflammation, clinical or histologic evidence of damage to the retina, and ERG parameters remained unaltered throughout the study. Vitreous and plasma topotecan lactone concentrations were undetectable. Four weekly intravitreal injections of topotecan up to 50 µg in the animal model or a 100 µg human equivalent dose were not toxic for the rabbit eye. High doses of topotecan may show promising translation to the clinic for the management of difficult-to-treat retinoblastoma vitreous seeds.

Optimizing the storage of chemotherapeutics for ophthalmic oncology: stability of topotecan solution for intravitreal injection.

BACKGROUND: . Intravitreal administration of topotecan shows activity against tumor vitreous seeding in the conservative treatment of retinoblastoma, a malignant tumor originated in the retina of small children. Adequate storage of the intravitreal topotecan solution would allow immediate availability for patients at health care institutions. The goal of the work was to address the stability of the intravitreal topotecan formulation upon reconstitution. MATERIALS AND METHODS: . Intravitreal topotecan solutions were reconstituted (at a concentration of 0.2 mg topotecan in 1 mL saline solution vehicle, aliquoted in 1 mL plastic syringes) and stored either frozen or at room temperature for different times. Topotecan content was analyzed at time zero and at different conditions using a high performance liquid chromatography method to quantify topotecan lactone (active) and to detect its pH-dependent hydrolysis product, the open carboxylate. RESULTS: . We found that intravitreal topotecan syringes remained stable at room temperature at least for 24 h, at least for 167 days upon stored frozen at -20°C, and up to 8 h after thawing at day 6. The degradation carboxylate product did not appear in the analyzed thawed samples during the whole study. CONCLUSIONS: . This study confirms the stability of frozen intravitreal topotecan syringes and will help optimize the use of this chemotherapy modality at institutions with low resources. Storage of aliquots will also help reduce personnel exposure to chemotherapy at hospital pharmacies.

Farmacovigilancia de inhibidores de calcineurina en trasplante renal y hepático pediátrico / Pharmacovigilance of calcineurin inhibitors in pediatric kidney and liver transplantation

Objetivo: Desarrollar un programa de farmacovigilancia de pacientes pediátricos trasplantados hepáticos y renales centrado en inmunosupresores calcineurínicos del Hospital de Pediatría JP Garrahan de Argentina. Métodos: Se evaluaron las reacciones adversas a medicamentos (RAM) de los pacientes pediátricos trasplantados renales y hepáticos de nuestro hospital tratados con inhibidores de calcineurina (ciclosporina y tacrolimus) por revisión retrospectiva de historias clínicas de pacientes trasplantados en 2010-2011, y análisis prospectivo por farmacovigilancia activa de trasplantados fuera de dicho período, cuyas complicaciones se hayan presentado en los ateneos semanales del Servicio de Trasplante desde marzo de 2011. Las RAM se notificaron a la autoridad sanitaria nacional. Resultados: Se analizaron un total de 59 pacientes, 28 trasplantados renales y 31 hepáticos. Se notificaron, en ambos trasplantes, 60 RAM a ciclosporina destacándose (número de casos) hipertensión arterial (19) y nefrotoxicidad (6). Asimismo, se registraron 46 RAM a tacrolimus, incluyendo hipomagnesemia (25), hipertensión (7) y nefrotoxicidad (5). El 95% y 96% de los eventos adversos a ciclosporina y a tacrolimus, respectivamente, han sido agrupados como probables o definitivos. El 70% y 98% de los eventos adversos a ciclosporina y a tacrolimus respectivamente, han sido de severidad moderada o grave. Conclusiones: Este es el primer proyecto en América Latina que propone y desarrolla el estudio cuali-cuantitativo intensivo de RAM a inhibidores de calcineurina en trasplante pediátrico renal y hepático. Es necesario estimular la notificación espontánea así como continuar el seguimiento de RAM a mediano y largo plazo para mejorar la calidad de vida del paciente trasplantado (AU)

Aim: To develop a pharmacovigilance program of calcineurin inhibitors used in pediatric renal and liver transplant patients at Hospital de Pediatría JP Garrahan, Argentina. Methods: Adverse drug reactions (ADRs) of pediatric patients with kidney and liver transplantation treated with calcineurin inhibitors (cyclosporine and tacrolimus) were evaluated by retrospective review of medical records of patients transplanted between 2010 and 2011. In addition, we carried out active pharmacovigilance since March, 2011. ADRs were reported to the National Health Authority. Results: A total of 59 patients, 28 kidney transplant and 31 liver tarnsplant patients were analyzed. In both transplants, 60 ADRs to cyclosporine were reported including (number of cases), hypertension (19) and nephrotoxicity (6). In addition, 46 ADRs to tacrolimus were registered as hypomagnesemia (25), hypertension (7) and nephrotoxicity (5). A total of 95% and 96% of the adverse events to cyclosporine and tacrolimus, respectively, were defined as probable or definitive. Lastly, 70% and 98% of the events to cyclosporine and tacrolimus respectively, have been moderately severe or severe. Conclusions: This is the first study in Latin America that developed an intensive qualitative and quantitative analysis of the ADRs to calcineruin inhibitors in pediatric kidney and liver transplant patients. Spontaneous reporting should be motivated as well as monitoring ADRs should continue in the medium and long term for improving patient's quality of life (AU)

[Pharmacovigilance of calcineurin inhibitor in peidatric kidney and liver transplantation]. / Farmacovigilancia de inhibidores de calcineurina en trasplante renal y hepático pediátrico.

AIM: To develop a pharmacovigilance program of calcineurin inhibitors used in pediatric renal and liver transplant patients at Hospital de Pediatría JP Garrahan, Argentina. METHODS: Adverse drug reactions (ADRs) of pediatric patients with kidney and liver transplantation treated with calcineurin inhibitors (cyclosporine and tacrolimus) were evaluated by retrospective review of medical records of patients transplanted between 2010 and 2011. In addition, we carried out active pharmacovigilance since March, 2011. ADRs were reported to the National Health Authority. RESULTS: A total of 59 patients, 28 kidney transplant and 31 liver tarnsplant patients were analyzed. In both transplants, 60 ADRs to cyclosporine were reported including (number of cases), hypertension (19) and nephrotoxicity (6). In addition, 46 ADRs to tacrolimus were registered as hypomagnesemia (25), hypertension (7) and nephrotoxicity (5). A total of 95% and 96% of the adverse events to cyclosporine and tacrolimus, respectively, were defined as probable or definitive. Lastly, 70% and 98% of the events to cyclosporine and tacrolimus respectively, have been moderately severe or severe. CONCLUSIONS: This is the first study in Latin America that developed an intensive qualitative and quantitative analysis of the ADRs to calcineruin inhibitors in pediatric kidney and liver transplant patients. Spontaneous reporting should be motivated as well as monitoring ADRs should continue in the medium and long term for improving patient's quality of life.

Objetivo: Desarrollar un programa de farmacovigilancia de pacientes pediátricos trasplantados hepáticos y renales centrado en inmunosupresores calcineurínicos del Hospital de Pediatría JP Garrahan de Argentina. Métodos: Se evaluaron las reacciones adversas a medicamentos (RAM) de los pacientes pediátricos trasplantados renales y hepáticos de nuestro hospital tratados con inhibidores de calcineurina (ciclosporina y tacrolimus) por revisión retrospectiva de historias clínicas de pacientes trasplantados en 2010-2011, y análisis prospectivo por farmacovigilancia activa de trasplantados fuera de dicho período, cuyas complicaciones se hayan presentado en los ateneos semanales del Servicio de Trasplante desde marzo de 2011. Las RAM se notificaron a la autoridad sanitaria nacional. Resultados: Se analizaron un total de 59 pacientes, 28 trasplantados renales y 31 hepáticos. Se notificaron, en ambos trasplantes, 60 RAM a ciclosporina destacándose (número de casos) hipertensión arterial (19) y nefrotoxicidad (6). Asimismo, se registraron 46 RAM a tacrolimus, incluyendo hipomagnesemia (25), hipertensión (7) y nefrotoxicidad (5). El 95% y 96% de los eventos adversos a ciclosporina y a tacrolimus, respectivamente, han sido agrupados como probables o definitivos. El 70% y 98% de los eventos adversos a ciclosporina y a tacrolimus respectivamente, han sido de severidad moderada o grave. Conclusiones: Este es el primer proyecto en América Latina que propone y desarrolla el estudio cuali-cuantitativo intensivo de RAM a inhibidores de calcineurina en trasplante pediátrico renal y hepático. Es necesario estimular la notificación espontánea así como continuar el seguimiento de RAM a mediano y largo plazo para mejorar la calidad de vida del paciente trasplantado.

Multicenter study of hyaluronic acid obtained by biotechnology to evaluate clinical efficacy and safety in knee osteoarthritis.

Viscosuppplementation with intra-articular hyaluronic acid (hyaluronan [HA]) is a relatively new option for improving pain and articular function in patients with symptomatic knee osteoarthritis. An open multi-center study was performed in 365 patients with definite and symptomatic knee osteoarthritis from seven Latin American countries. Five doses of HA were administered once a week. The parameters studied were pain (six items), stiffness (two items) and functional capacity (17 items). The parameters were evaluated 1 week after the corresponding injection. Statistical differences were found when basal determinations of the three parameters were compared with the results of the first and fourth administration (p < 0.05). Intra-articular HA administration was well tolerated. Treatment-related nonserious adverse events were registered in 2.5% of administrations. Based on the results obtained, HA is a useful and well-tolerated symptomatic treatment for knee osteoarthritis with a rapid onset of action.