Formulation and in vitro evaluation of nateglinide microspheres using HPMC and carbopol-940 polymers by ionic gelation method

This study involves the design and characterization of Nateglinide [NAT] microspheres to enhance patient compliance. Ionic gelation technique was used to prepare Nateglinide Microspheres by using rate controlling polymers Carbopol-940 and Hydroxypropylmethyl cellulose [HPMC]. Shape and surface were evaluated with Scanning electron microscopy [SEM]. Percentage Yield, Particle size analysis, Encapsulating Efficiency, Micromeritic analysis, Fourier Transform Infra-Red Spectroscopy [FTIR], Differential Scanning Colorimetry [DSC] were done for characterization of Microspheres. Drug release studies were performed at pH 1.2 and 7.2 using USP dissolution type-2 apparatus and release rates were analyzed by the application of different pharmacokinetic models. The size of microspheres was found to be varied from 781 Micro m to 853 Micro m. Rheological studies proved excellent flow behavior while percentage yield was found to be varied from 72% to 79%. Absence of drug-polymers interactions was confirmed from FTIR and DSC results. The microspheres prepared with sodium alginate showed cracks while microspheres obtained from blend of Carbopol-940 plus sodium alginate were smooth and spherical. Maximum entrapment efficiency [71.4%] was achieved for Microspheres with Carbopol-940. The greater retardation in drug release was observed for microspheres containing Carbopol-940 and release pattern followed Higuchi kinetics model and negligible drug release was observed at pH 1.2

Nuevos fármacos en diabetes tipo 2 / New drugs in diabetes mellitus type 2

La diabetes tipo 2 asociada a obesidad en un 80% es actualmente la enfermedad metabólica de mayor prevalencia y de mayor morbimortalidad causada en un 60% por enfermedad cardiovascular. La podemos controlar en parte, pero no curar. El mayor problema patológico social y económico lo constituyen las complicaciones, si bien las microvasculares responden en parte al control de la glicemia, no lo hacen del mismo modo las cardiovasculares. El tratamiento no está exento de riesgo, la hipoglicemia y el aumento de peso cuando se trata de cumplir metas exigentes, con algunos fármacos disponibles, son los efectos adversos que se observan con mayor frecuencia. Ambos limitan las metas del tratamiento, atemorizando al paciente y provocando inercia médica Por 50 años los fármacos experimentaron pocas modificaciones, insulina, sulfonilureas y biguanidas estuvieron orientados a bajar la glicemia, sin embargo hoy hemos aprendido que la hiperglicemia es la consecuencia de un islote pancreático enfermo y que los fármacos deben apuntar en sentido más amplio, preservado células beta y la función corrigiendo además el problema periférico que constituye la insulinorresistencia, sin aumentar el daño vascular de la diabetes. La visión más amplia ha cambiado el paradigma patogénico y terapéutico, motivando la búsqueda de nuevos fármacos que han motivado esta revisión.

Diabetes mellitus type 2 associated with obesity in a 80% is actually the metabolic disease of major prevalence, and major morbimortality, causing in a 60% cardiovascular disease. These can be partly controlled, but not cure. The great social pathologic and economic problem, are the complications, the microvascular respond to the glycemia control, but with the cardiovascular complications doesn 't respond in the same way. The treatment with some available pharmacos is not free of risk; there are some adverse effects that can be observe with major frequency, like hypoglycemia and weigh in crease. 80th of them restrain the treatment goals, frightening the patient and produce medical inertia. For fifty years pharmacos used in diabetes treatment had experimented few modifications, insulin, sulfonylurea and biguanidins were orientated to reduce glycemia, however today we have learn that hyperglycemia is the consequence of a sick pancreatic islet, and that the medication must be orientated in a more wider sense, preserving beta cells, and its function, modifying also the periphery problem, the insulin resistance component, without increasing the diabetes vascular damage. An amplifying vision had changed the pathogenic and therapeutic paradigm, motivating the search of new pharmacos, goal that motive this revision.

Boron neutron capture therapy in cancer: past, present and future

Undifferentiated thyroid cancer (UTC) is a very aggressive tumor with no effective treatment, since it lacks iodine uptake and does not respond to radio or chemotherapy. The prognosis of these patients is bad, due to the rapid growth of the tumor and the early development of metastasis. Boron neutron capture therapy (BNCT) is based on the selective uptake of certain boron non-radioactive compounds by a tumor, and the subsequent irradiation of the area with an appropriate neutron beam. 10B is then activated to 11B, which will immediately decay releasing alpha particles and 7Li, of high linear energy transfer (LET) and limited reach. Clinical trials are being performed in patients with glioblastoma multiforme and melanoma. We have explored its possible application to UTC. Our results demonstrated that a cell line of human UTC has a selective uptake of borophenylalanine (BPA) both in vitro and after transplantation to nude mice. Treatment of mice by BNCT led to a complete control of growth and cure of 100 percent of the animals. Moreover dogs with spontaneous UTC also have a selective uptake of BPA. At the present we are studying the biodistribution of BPA in patients with UTC before its application in humans.

O câncer indiferenciado de tiróide (CIT) é um tumor muito agressivo sem tratamento efetivo, uma vez que não capta iodo e não responde à radio ou quimioterapia. O prognóstico desses pacientes é ruim, devido ao rápido crescimento do tumor e surgimento precoce de metástases. A terapia por captura de nêutrons de boro (TCNB) é baseada na captação seletiva de certos compostos de boro não-radioativos pelo tumor, e à subsequente irradiação da área com um feixe de nêutrons apropriado. O 10B é então ativado para 11B, cujo decaimento imediato libera partículas alfa e 7Li, de alta transferência linear de energia (TLE) e alcance limitado. Ensaios clínicos estão sendo conduzidos em pacientes com glioblastoma multiforme e melanoma, e nós estamos explorando sua possível aplicação no CIT. Nossos resultados demonstram que uma linhagem celular do CIT humano mostra captação seletiva de borofenilalanina (BPA) tanto in vitro como após transplante em camundongos "nude". O tratamento de camundongos com TCNB leva a um controle completo do crescimento tumoral e à cura em 100 por cento dos animais. Além disso, cães com CIT espontâneo também apresentam captação seletiva de BPA. No momento, estamos estudando a biodistribuição de BPA em pacientes com CIT, antes de sua aplicação em humanos.

Tratamiento del cáncer por captura neutrónica de boro: su aplicación al carcinoma indiferenciado de tiroides / Boron neutron capture therapy applied to undifferentiated thyroid carcinoma

El cáncer indiferenciado de tiroides es un tumor muy agresivo, de muy mal pronóstico y sin tratamiento efectivo. La terapia por captura neutrónica de boro (BNCT) podría ser una alternativa para el tratamiento de esta enfermedad. Se basa en la captación selectiva de boro por el tumor y su activación por un haz de neutrones. El boro activado libera un núcleo de litio-7 y una partícula alfa, las cuales tienen una alta transmisión linear de energía (linear energy transfer, LET) y un alcance de 5-9 µm, destruyendo el tumor. En estudios previos hemos mostrado que la línea celular humana de cáncer indiferenciado de tiroides (ARO) tiene una captación selectiva de borofenilalanina (10BPA) tanto in vitro como después de ser implantada en ratones NIH nude. También demostramos en estos animales inyectados con BPA e irradiados con un haz de neutrones térmicos, un 100% de control sobre el crecimiento tumoral y un 50% de cura histológica. En trabajos posteriores mostramos que la porfirina 10BOPP tetrakis-carborane carboxylate ester de 2,4-bis-(a,b-dihydroxyethyl)-deutero-porphyrin IX) cuando es inyectada 5-7 días antes que el BPA se obtiene una concentración tumoral de boro de aproximadamente el doble que el BPA solo (45-38 ppm vs. 20 ppm). La posterior irradiación con neutrones mostró un 100% de remisión completa en animales con tumores cuyo volumen pre-tratamiento era de 50 mm3 o menor. Los perros padecen CIT espontáneo, con un comportamiento biológico similar al humano, y una captación selectiva de BPA, abriendo la posibilidad de su tratamiento por BNCT

Undifferentiated thyroid carcinoma (UTC) is an aggressive tumor with a poor prognosis due to the lack of an effective treatment. Boron neutron capture therapy (BNCT) is based on the selective uptake of boron by the tumor and its activation by a neutron beam, releasing lithium-7 and an alpha particle that will kill the tumor cells by their high linear energy transfer (LET). In previous studies we have shown a selective uptake of borophenylalanine (10BPA) in a human UTC cell line (ARO) and in NIH nude mice implanted with this cell line. When these animals were injected with BPA and irradiated with an appropriated neutron beam, we observed a 100% of tumor growth control and a 50 % of histological cure when the initial tumor volume was 50 mm3 or less. Further studies with BOPP (tetrakis-carborane carboxylate ester of 2,4-bis-(a, b-dihydroxyethyl)-deutero-porphyrin IX) showed that when this porphyrin was injected 5-7 days before BPA, and the animals were sacrificed 60 min after the i.p. injection of BPA, a significant increase in boron uptake by the tumor was found (45-38 ppm with both compounds vs. 20 ppm with BPA alone). The application of BNCT using the combination of boron compounds showed a 100% of complete remission in tumors with initial volumes under 50 mm3. Dogs suffer spontaneous UTC, with a similar biological behavior to the human tumor, and a selective uptake of BPA. These results open the possibility of applying BNCT to UTC

ATP diphosphohydrolase activity in synaptosomes from cerebral cortex of rats subjected to chemically induced phenylketonuria

ATP diphosphohydrolase (apyrase)(EC3.6.1.5) activity was measured in synaptosomes from cerebral cortex of Wistar rats of both sexes subjected to experimental phenylketonuria, i.e., chemical hyperphenylaninemia induced by subcutaneous administration of 5.2 µmol phenylalanine/g body weight (twice a day) plus 0.9 µmol p-chlorophenylalanine/g body weight (once a day). ATP diphosphohydrolase specific activity (nmol Pi min-1 mg protein-1) of synaptosomes was significantly decreased compared to controls for both ATp (from 147.6 to 129.9) and ADP (from 70.2 to 63.1) hydrolysis one hour after single administration of the drugs to 35-day old rats. Chronic treatment was performed from the 6th to the 28th postpartum day. The enzyme specific activity of synaptosomes was measured one week after the last administration of the drugs and was significantly reduced compared to controls for both ATP (from 164.1 to 150.2) and ADP (from 76.3 to 62.1) hydrolysis. The in vitro effects of the drugs on the synaptosome enzyme specific activity were also investigated. Phenylalnine alone or associated with p-chlorophenylalanine significantly reduced enzyme specific activity for both ATP (from 150.2 to 136.0) and ADP (from 70.5 to 59.3) nucleotides as substrates. Since ATP diphosphohrolase seems to play an important role in neurotransmission, these findings may be related to the neurological dysfunction characteristic of human phenylketonuria