Rabdomiólisis grave secundaria a deshidratación hipernatrémica / Severe rhabdomyolysis secondary to severe hypernatraemic dehydration

Introducción: La rabdomiólisis es una enfermedad poco frecuente en pediatría. El objetivo es presentar un paciente en el que se desarrolló secundario a una deshidratación hipernatrémica grave tras una diarrea aguda. Caso clínico: Lactante de 11 meses que consultó por fiebre, vómitos, diarrea y anuria. Presentó convulsión tónico-clónica autolimitada. Ingresó en mal estado general, severamente deshidratado, con escasa reactividad. En las pruebas complementarias destacó acidosis metabólica grave, hipernatremia e insuficiencia renal prerrenal. Al tercer día apreció leve hipotonía axial y elevación de creatín fosfokinasa 75.076 UI/l, interpretado como rabdomiólisis. Se inició hiperhidratación y alcalinización sistémica, con buena respuesta clínica y bioquímica, siendo dado de alta sin secuelas motoras. Conclusiones: La hipernatremia grave está descrita como causa rara de rabdomiólisis e insuficiencia renal. En pacientes críticos es importante un alto índice de sospecha de rabdomiólisis y determinación seriada de la creatín fosfokinasa para su detección y tratamiento precoz.

Introduction: Rhabdomyolysis is a rare paediatric condition. The case is presented of a patient in whom this developed secondary to severe hypernatraemic dehydration following acute diarrhoea. Case report: Infant 11 months of age who presented with vomiting, fever, diarrhoea and anuria for 15 hours. Parents reported adequate preparation of artificial formula and oral rehydration solution. He was admitted with malaise, severe dehydration signs and symptoms, cyanosis, and low reactivity. The laboratory tests highlighted severe metabolic acidosis, hypernatraemia and pre-renal kidney failure (Sodium [Na] plasma 181 mEq/L, urine density> 1030). He was managed in Intensive Care Unit with gradual clinical and renal function improvement. On the third day, slight axial hypotonia and elevated cell lysis enzymes (creatine phosphokinase 75,076 IU/L) were observed, interpreted as rhabdomyolysis. He was treated with intravenous rehydration up to 1.5 times the basal requirements, and he showed a good clinical and biochemical response, being discharged 12 days after admission without motor sequelae. Conclusions: Severe hypernatraemia is described as a rare cause of rhabdomyolysis and renal failure. In critically ill patients, it is important to have a high index of suspicion for rhabdomyolysis and performing serial determinations of creatine phosphokinase for early detection and treatment.

Influence of Sodium CMC and HPMC on the Physical Characteristics of Ofloxacin Floating Matrix Tablets.

Aims: Sustained release floating drug delivery systems or gastro retentive drug delivery systems enables prolonged and continuous input of drug to the upper part of gastrointestinal tract and improves the bioavailability of medication. A new strategy is proposed for the development of floating drug delivery systems of Fluoroquinolone antibiotic, Ofloxacin, a potent moiety for treating UTI’s. Methodology: Various rate retarding polymers like HPMC K4M, HPMC 5 cps and swelling agent as Sodium carboxymethyl cellulose in different proportions were tried and optimized to achieve the drug release for 8 hr. All the formulations were evaluated for floating properties, swelling characteristics and in vitro drug release studies. The in vitro drug release was found to be matrix diffusion controlled. Optimized formulation was subjected to intermediate stability studies at various combinations of temperature and humidity according to ICH guidelines. Results: Lower hardness and higher thickness decreased the floating lag time and increased floating duration. Based on drug release studies, formulation F5 was optimized as the best formulation because it released about 89.27 ±2.6% of the drug at the end of 8 hr while other formulations released not more than 80 ±2.2%. This may be due to high NaCMC content which might have caused excessive channeling, thereby giving a burst release. Optimized formulation F5 was found to follow zero order kinetics with r2 value of 0.993. Conclusion: In conclusion we have been proved that HPMC K4M has retarded the drug release, while HPMC 5cps has facilitated high buoyancy time for the tablets. NaCMC has influenced as channeling agent. Formulation F5 was optimized for its long buoyancy time, prolonged duration of drug release, zero order and diffusion controlled drug release kinetics which can assure 100% bioavailability.

Effect of quaternary ammonium carboxymethylchitosan on release rate in-vitro of aspirin sustained-release matrix tablets

The aim of this study was to develop a derivative of chitosan as pharmaceutical excipient used in sustained-release matrix tablets of poorly soluble drugs. A water-soluble quaternary ammonium carboxymethylchitosan was synthesized by a two-step reaction with carboxymethylchitosan [CMCTS], decylalkyl dimethyl ammonium and epichlorohydrin. The elemental analysis showed that the target product with 10.27% of the maximum grafting degree was obtained. To assess the preliminary safety of this biopolymer, cell toxicity assay was employed. In order to further investigate quaternary ammonium carboxymethylchitosan application as pharmaceutical excipient, aspirin was chosen as model drug. The effect of quaternary ammonium CMCTS on aspirin release rate from sustained-release matrix tablets was examined by in-vitrodissolution experiments. The results showed that this biopolymer had a great potential in increasing the dissolution of poorly soluble drug. With the addition of CMCTS-CEDA, the final cumulative release rate of drug rose up to 90%. After 12 h, at the grade of 10, 20 and 50 cps, the drug release rate increased from 58.1 to 90.7%, from 64.1 to 93.9%, from 69.3 to 96.1%, respectively. At the same time, aspirin release rate from sustained-release model was found to be related to the amount of quaternary ammonium CMCTS employed. With the increase of CMCTS-CEDA content, the accumulated release rate increased from 69.1% to 86.7%. The mechanism of aspirin release from sustained-release matrix tablets was also preliminary studied to be Fick diffusion. These data demonstrated that the chitosan derivative has positive effect on drug release from sustained-release matrix tablets

Estudos de síntese de fármacos dirigidos formadores de micelas de hidroximetilnitrofural e helenalina potencialmente antichagásicos e leishmanicidas / Synthesis studies of micelle-forming targeted drugs of hidroximetilnitrofural and helenalin potentially antichagasic and leishmanicide

A doença de Chagas e as leishmanioses são doenças endêmicas tropicais, que afetam milhões de pessoas, especialmente em países subdesenvolvidos, e são responsáveis por série de implicações médicas, sociais e econômicas. Seus agentes etiológicos são protozoários pertencentes à ordem Kinetoplastida, os quais provocam várias manifestações clínicas, dependendo do tipo de protozoário infectante, da imunidade do hospedeiro e da progressão destas infecções. Atualmente, os principais problemas relacionados a estas parasitoses são a carência de fármacos eficazes, a elevada toxicidade dos fármacos disponíveis na terapêutica, bem como o crescente número de casos de resistência. Neste contexto, a busca por novos e melhores quimioterápicos contra essas doenças é urgente. A latenciação é um dos processos que podem ser utilizados com vistas a esse objetivo. Por meio desse processo, o uso de micelas poliméricas como transportadoras de fármacos com a finalidade de prolongar a ação e, consequentemente, diminuir a toxicidade do fármaco, tem sido crescente. Ademais, é possível dirigir a ação dessas formas de transporte por meio de fármacos dirigidos. Face ao exposto, o presente trabalho teve por objetivo a síntese fármacos dirigidos formadores de micelas dos compostos bioativos helenalina e hidroximetilnitrofural, os quais apresentam atividade tripanomicida e leishmanicida. Pretende-se, assim, promover a liberação controlada e a consequente diminuição da toxicidade destes compostos, bem como melhorar suas características físico-químicas. A ação destes compostos será dirigida para macrófagos, no interior dos quais se encontram os parasitos, através da ligação do tiomanosídio como grupo diretor das micelas.

Chagas disease and leishmaniasis are endemic tropical diseases affecting millions of people, especially in underdeveloped countries, being responsible and they are responsible for relevant medical, social and economic matters. Etiological agents for both diseases are protozoa belonging to the Kinetoplastidae order, which cause various clinical manifestations depending on the type of protozoa infecting, the host immunity and the progression of the infection. Currently, the main problems with these parasitic diseases are the lack of effective drugs, the high toxicity of available drugs for their treatment and the growing number of cases of resistance. In this context, the search for new and better chemotherapeutic agents against those diseases is urgent. Latentiation is one of the molecular modification processes that can be used with the aim of achieving this objective. Through this process, the use of micelles as drug carriers with the objective of prolonging its action and, consequently, diminishing its toxicity has been increasing. Besides, it is possible to direct the action of those carriers thourhg the targetd drugs. This said, in this work we studied the synthesis of micelle-forming targeted drugs of the bioactive compounds helenaline and hydroxymethylnitrofurazone, which showed to be trypanomicide and leishmanicide. Thus, promoting the controlled release and the consequent decreasing of the toxicity of those compounds, besides improving their physic-chemical properties are our goal. The action of those compounds will be directed to macrophages, where the parasites, mainly leishmanias, live, by covalent binding of the directed group thiomanoside to the micelles.

Development and evaluation of a chronotherapeutic drug delivery system of torsemide / Desenvolvimento e avaliação de um sistema de entrega de drogas cronoterapêuticas de torsemida

The objective of this study was to prepare and evaluate chronotherapeutic drug delivery systems (ChrDDs) of torsemide. Compression coated tablets (CCT) containing torsemide in the core tablet were prepared by the compression coating technique with different grades of polyethylene oxide (PEO WSR 301 & 1105). The optimized formulations were characterised for tabletting parameters and drug polymer interaction by Fourier-Transform Infrared Spectroscopy (FTIR).The hardness of all the CCT using PEO WSR 301 & PEO WSR 1105 were in the range 6-8 kg/cm² & 5.5 to 7 kg/cm² respectively. Their friability values were <0.3 percent. All the CCT showed a clear lag time but finalized as per the predetermined lag time. As the amount of PEO was increased in the outer layer the drug released was delayed. The drug content of all the CCT was >99 percent. The FTIR studies showed no interaction throughout the process of development. Formulations of F7 and of P7 were considered optimized formulations since they yielded a predetermined lag time of 6h before burst release. Hence, these formulations can be exploited to achieve chronotherapeutic drug delivery systems of Torsemide for the treatment of hypertension at the time the patient needs it.

O objetivo deste estudo foi preparar e avaliar sistemas cronoterapêuticos de liberação de fármacos (ChrDDs) de torsemida. Comprimidos revestidos por compressão (CCT) contendo torsemida no (núcleo) foram preparados pela técnica de revestimento por compressão, com diferentes categorias de óxido de polietileno (PEO WSR 301 & 1105). As formulações otimizadas foram caracterizadas por parâmetros de compressão e interação fármaco polímero por Infravermelho com Transformada de Fourier (FTIR). A dureza dos CCT utilizando PEO WSR 301 e PEO WSR 1105 foi entre 6-8 kg/cm² e 5,5 a 7 kg/cm², respectivamente. Os valores de friabilidade foram <0,3 por cento. Todos os CCT mostraram claro tempo de retardo, mas finalizaram de acordo com o tempo de retardo pré-determinado. À medida que a quantidade de PEO aumentava na camada mais externa, a liberação do fármaco era retardada. O teor de fármaco em todos os CCT foi >99 por cento. Os estudos de FTIR mostraram que não h[a interação durante o processo de desenvolvimento. As formulações F7 e P7 foram consideradas otimizadas, uma vez que resultaram em tempo de retardo pré-determinado de 6 h antes da liberação por meio de explosão. Dessa forma, estas formulações podem ser exploradas para se obter sistemas de liberação.

Development of a controlled release formulation of an indigenous insect growth regulator, DPE-28, a substituted diphenylether, for controlling the breeding of Culex quinquefasciatus.

Background & objectives: DPE-28, a substituted diphenyl ether (2,6-ditertiarybutyl phenyl-2’,4’-dinitro phenyl ether) was reported to exhibit promising insect growth regulating activity against Culex quinquefasciatus, the vector of lymphatic filariasis. A controlled release formulation (CRF) of DPE-28 has been developed to control Cx. quinquefasciatus in its breeding habitats. Toxicity of DPE-28, safety to non-target mosquito predators and the release profile of the CRF of DPE-28 are studied and discussed. Methods: The acute oral and dermal toxicity was tested in male and female Wistar rats as per the Organization for Economic Cooperation and Development (OECD) guidelines 425 and 402 respectively. The toxicity of DPE-28 to non-target predators was tested as per the reported procedure from this laboratory. The CRF of DPE-28 was prepared by following the reported procedure developed at this laboratory earlier. The concentration of DPE-28 released from the CRF was monitored by HPLC by constructing a calibration graph by plotting the peak area in the Y-axis and the concentration of DPE-28 in the X-axis. Results: DPE-28 has been tested for acute oral toxicity and found to be moderately toxic with LD50 value of 1098 mg/kg body weight (b.w). The results of the acute dermal toxicity and skin irritation studies reveal that DPE-28 is safe and non-irritant. DPE-28 when tested at 0.4 mg/litre against non-target mosquito predators did not produce any mortality. The release profile of the active ingredient DPE-28 from the CRF by HPLC technique showed that the average daily release (ADR) of DPE-28 ranged from 0.07 to 5.0 mg/litre during first four weeks. Thereafter the matrix started eroding and the ADR ranged from 5 to 11 mg/litre during the remaining 5 wk. The cumulative release of active ingredient showed that > 90 per cent of the active ingredient was released from the matrix. Interpretation & conclusions: The controlled release matrix of DPE-28 was thus found to inhibit the adult emergence (>80%) of Cx. quinquefasciatus for a period of nine weeks. The CRF of DPE-28 may play a useful role in field and may be recommended for mosquito control programme after evaluating the same under field conditions.

Formulation and evaluation of xanthan gum based aceclofenac tablets for colon targeted drug delivery / Formulação e avaliação de goma xantana baseados comprimidos Aceclofenac por câncer de cólon de entrega de drogas alvo

The objective of the present study is to develop a colon targeted drug delivery systems for Aceclofenac using xanthan gum as a carrier. In this study, multilayer coated system that is resistant to gastric and small intestinal conditions but can be easily degraded by colonic bacterial enzymes was designed to achieve effective colon delivery of Aceclofenac. The xanthan gum, the drug and the physical mixture were characterized by Fourier transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC). All the formulations were evaluated for hardness, drug content uniformity and other physical properties. Release aspects of Aceclofenac in simulated gastrointestinal fluid and colonic fluid with enzymes were investigated. From these results, Eudragit coated system exhibited gastric and small intestinal resistance to the release of Aceclofenac. The rapid increase in release of Aceclofenac in SCF was revealed as due to the degradation of the xanthan gum membrane by bacterial enzymes. The designed system could be used potentially as a carrier for colon delivery of Aceclofenac by regulating drug release in stomach and the small intestine.

O presente estudo teve como objetivo o desenvolvimento de sistema de liberação cólon-alvo de aceclofenaco empregando goma xantana. Nesse trabalho, o revestimento de múltiplas camadas com característica de resistência às condições do intestino delgado além de gastrorresistência oferece como vantagem a rápida degradação desse sistema por enzimas bacterianas colônicas. Dessa forma, o planejamento de tal sistema possibilitou a liberação específica do aceclofenaco no cólon. A goma xantana e o fármaco, além da mistura física desses dois componentes, foram caracterizados por espectroscopia no infravermelho com transformada de Fourier (FTIR) e calorimetria diferencial exploratória (DSC). Todas as formulações foram avaliadas no que se refere à dureza, à uniformidade de conteúdo do fármaco além de outras propriedades físicas. Os perfis de liberação do aceclofenaco no fluido gástrico simulado e fluido colônico simulado contendo enzimas foram investigados. Os resultados revelaram que o sistema revestido com Eudragit® exibiu resistência gástrica e intestinal à liberação de aceclofenaco. O rápido aumento na liberação de aceclofenaco no fluido colônico simulado foi atribuido à degradação da goma xantana por enzimas bacterianas. O sistema apresenta aplicação potencial no desenvolvimento de produtos para a liberação cólon-alvo de aceclofenaco.

Preparation and in-vitro in-vivo evaluation of sustained release matrix diclofenac sodium tablets using PVP-k90 and natural gums

Conventional dosage form is nowadays mostly replaced by sustained release formulation in order to increase drug efficacy and patient compliance. The sustained release properties of the PVP K90 alone and in combination with guar gum, xanthan gum and gum tragacanth were evaluated using diclofenac sodium [100 mg/tablet] as a model drug. Tablets were processed using wet granulation method and evaluated for sustained drug release properties. The drug release from the formulations was studied in relationship with Commercially available Diclofenac Sodium SR, used as a reference tablets and results were expressed as similarity [f1] and differential factor [f2]. The tablets prepared using PVP K90 160 mg/tablet sustained the release of diclofenac sodium for 12 hours. Formulations where the PVP K90 was partially replaced with different gums also sustained the release of drug for 12 hours. The release of the drug from these formulations mainly followed Higuchi model and super case-II and Non-Fickian diffusion. The in-vivo drug release was studied in healthy human volunteers using non-blinded cross over, two period design using Diclofenac Sodium SR Tablets as a reference drug. The relative bioavailability of the formulation containing PVP K90 and gum tragacanth was 0.91. The studies showed that the use of the PVP K90 in combination with gum tragacanth both in-vitro and in-vivo sustained the release of the drug

Comparison of antibacterial activity of three fluorides- and zinc-releasing commercial glass ionomer cements on strains of mutans streptococci: an in vitro study.

The purpose of present study was to investigate the antibacterial activity of three commercially available fluoride- and zinc-releasing glass ionomer cements on strains of mutans streptococci. Three glass ionomers (Fuji II Conventional, Fuji II Light Cure, and Fuji IX) were used. The antibacterial effect of glass ionomer cements were estimated by anaerobically growing mutans streptococci on a selective medium by inoculating human saliva and measuring the inhibition zones around the glass ionomer discs on the medium. Fluoride and zinc release were measured and compared with the antibacterial activity. The results, when statistically analyzed, showed a direct correlation between fluoride release and antibacterial activity, but there was no correlation between zinc release and antibacterial activity.

Preliminary evaluation of glipizide spheres and compacts from spheres prepared by cross-linking technique

The objective of this research was to use the natural polymer Carrageenan to obtain controlled release spheres loaded with glipizide using the cross-linking technique. The effect of polymer level and drug load were investigated. The drug was dispersed in Carrageenan solution and the dispersion was dropped by a device containing 3 disposable syringes into cross-linking solution containing 3 calcium chloride. After 15 minutes residence time, the spheres were collected by decantation and dried in hot air oven at 38 degrees C +/- 2 degrees C for 24 hours. The dried spheres were successfully compacted into tablets using rotary Manesty B-3B machine equipped with 12/32 inches round flat face punches, target tablet weight was 400 mg +/- 5. As the polymer level was increased in the sphere formulation, the drug release rate was increased. However, as the drug level was increased in the sphere formulation, the release rate was decreased. This trend was also true for tablets compacted from spheres. The scanning electron microscope photographs supported the dissolution data. More cracks and rough surface were observed in tablets compacted from spheres containing high polymer level and low drug level.

Formación de complejos fármaco-resina usados en preparados de liberación prolongada / Formation of drug-resine complexes used in delayed-action preparations

Se estudiaron los tiempos para alcanzar el equilibrio en reacciones de intercambio iónico durante la formación de sales complejas poliestireno divinil-benceno sulfonato, con los fármacos dexanfetamina, metilhomatropina y salbutamol. Se hicieron reaccionar sales de los fármacos en solución con la resina en su forma "sodio", cuantificándose a intervalos la concentración en el sobrenadante, siguiendo el avance de la reacción y determinando el punto de equilibrio. Se propone un estadístico simple que permite seleccionar el tiempo para dar por terminada la reacción, y se encuentran valores inferiores a los informados en la literatura. Se comenta la relación entre dimensión molecular y nivel de saturación del complejo