Desarrollo de nuevos sistemas de liberación modificada y administración oral para el tratamiento de la tuberculosis / Development of new oral drug delivery systems for tuberculosis treatment

INTRODUCCIÓN: Rifampicina es inestable en medio ácido, y su descomposición es acelerada por isoniazida. El desarrollo de una formulación que permita la iberación secuencial de rifampicina (en estómago) e isoniazida (en intestino) podría superar este inconveniente. OBJETIVO: Obtener materiales portadores de rifampicina e isoniazida mediante acomplejamiento con polielectrolitos y caracterizarlos para determinar su utilidad en el desarrollo de sistemas de liberación sitio-específica, en combinación a dosisfija. MÉTODOS: Se utilizaron carboximetilcelulosa (CMC) y ácidoalgínico (AA) como polielectrolitos modelo. Se obtuvieron series de complejos CMC-rifampicina y AA-isoniazida. Se caracterizó el tipo de interacción, la capacidad de carga y las características reológicas de los materiales sólidos que, tras ser compactados bajo la forma de matrices simples o mixtas, fueron sometidos a ensayos de liberación en medios biorrelevantes. RESULTADOS: La interacción entre los grupos involucrados fue iónica, con una capacidad de carga del 100%. Los materiales presentaron propiedades de flujo desfavorables, con mejora por granulación. Las matrices liberaron rápidamente rifampicina en medio ácido con mínimos niveles concomitantes de isoniazida. La matriz seleccionada presentó liberación modulada de isoniazida, completada al cabo de 3 horas en un medio que simulaba el contenido intestinal. CONCLUSIONES: Los nuevos materiales pueden ser utilizados en el desarrollo de una formulación oral de liberación sitio-específica, capaz de mejorar la efectividad, reducir efectos adversos e incrementar la estabilidad de rifampicina.

INTRODUCTION: Rifampicin is unstable in acidic medium and its decomposition is accelerated by isoniazid. The development of a formulation to allow the sequential release of rifampicin (in stomach) and isoniazid (in gut) could overcome this problem. OBJECTIVE: To obtain materials with rifampicin and isoniazid, loaded in polyelectrolyte polymers and characterize them in order to determine their utility in the development of oral delivery systems for site-specific fixeddose combination. METHODS: Carboxymethyl cellulose (CMC) and alginic acid (AA) were used as polyelectrolytes. Series of complexes CMC-rifampicin and AA-isoniazid were obtained. The type of interaction, loading capacity and rheological properties were characterized in solid materials, which after compaction under simple or combined matrixes were testedin biorrelevant media. RESULTS: The interaction between components was ionic, and loading capacity was 100%.The powders showed unfavorable flow properties, improving by granulation. Release of rifampicin in acidic medium was fast, with minimal concomitant levels of isoniazid. The selected matrix showed a controlled release of isoniazid, which was completed after 3 hours in simulated intestinal media. CONCLUSIONS: The new materials can be used for the development of site specific oral formulations of rifampicin and isoniazid. They may lead to improved effectiveness, reduced side effects and higher rifampicin stability.

Intestinal barrier function and serum concentrations of rifampin, isoniazid and pyrazinamide in patients with pulmonary tuberculosis

Intestinal barrier function and serum concentrations of rifampin, isoniazid and pyrazinamide were studied in healthy controls and patients with active pulmonary tuberculosis. A case-control study of 29 controls and 30 cases attending at the Health Center, July, 2004 to December, 2005 was conducted. The body mass index was significantly reduced in cases compared to controls (p < 0.001). The intestinal paracellular transport of lactulose was significantly (p = 0.019) reduced in cases compared to controls. The transcellular transport of mannitol and the lactulose:mannitol ratio were not significantly (p = 0.0698) reduced in cases compared to controls. Low serum concentrations of rifampin, isoniazid and pyrazinamide were observed in 81 percent (48/59), 92 percent (54/59) and 28 percent (12/59), respectively, in all individuals. The results demonstrated a marked decrease on intestinal paracellular transport in patients with active pulmonary tuberculosis and reduced serum concentrations of rifampin and isoniazid in both groups.

effect of vehicles on spray drying of rifampicin inhalable microparticles: in vitro and in vivo evaluation

The aim of this study was to evaluate the effect of solvents used in the spray drying and the aerodynamic properties of the rifampicin microparticles and pulmonary absorption of the microparticles. Different mixtures of dichloromethane and water were used as solvents for spray drying of rifampicin microparticles. The water to dichloromethane ratios were 25:75, 50:50, 75:25, 80:20, 90: 10 and 100:0. The solutions were dried at inlet temperature of 70 °C. The powder properties of the samples were examined by laser diffraction, scanning electron microscopy [SEM], helium densitometer and infrared spectroscopy [IR]. The aerosolization performance of these formulations was investigated using an Andersen cascade impactor. Pulmonary absorptions of formulations were examined by the in situ pulmonary absorption described by Enna and Schanker method. The plasma concentration time profiles of rifampicin were constructed 8 hours following the intravenous and the intrapulmonary administrations. The pharmacokinetics parameters, C[max], T[max], t[1/2] AUC, mean residence time [MRT], K[a] and K[e] were determined for each formulations. The T[max] values for the samples decreased by increase in the amount of water in the initial feed. The T[max] values for the spray dried samples from the different mixtures of dichloromethane and water were 60 [min] and 30 [min] respectively. The solvent mixture as the spray drying vehicle played an important role in the in vitro and in vivo lung deposition. The type of spray drying vehicle showed significant effect on the aerodynamic behavior and pharmacokinetic parameters of the particles. The pulmonary absorption of drug revealed the possibility of achieving the minimal inhibitory concentration [MIC] of the antibiotics. The spray drying vehicle only affected absorption patterns of the formulations and it did not have any effect on the elimination rat of particle

Intestinal permeability and malabsorption of rifampin and isoniazid in active pulmonary tuberculosis

Low antimycobacterial drug concentrations have been observed in tuberculosis (TB) patients under treatment. The lactulose/mannitol urinary excretion test (L/M), normally used to measure intestinal permeability, may be useful to assess drug absorption. The objective of this research was to study intestinal absorptive function and bioavailability of rifampin and isoniazid in TB patients. A cross sectional study was done with 41 patients and 28 healthy controls, using the L/M test. The bioavailabilities of rifampin (R) and isoniazid (H) were evaluated in 18 patients receiving full doses. Urinary excretion of mannitol and lactulose, measured by HPLC, was significantly lower in TB patients. The serum concentrations of the drugs were below the expected range for R (8-24 mcg/mL) or H (3-6 mcg/mL) in 16/18 patients. Analyzing the drugs individually, 12/18 patients had low serum concentrations of R, 13/18 for H and 8/18 for both drugs. We suggest that there is a decrease in the functional absorptive area of the intestine in TB patients, which would explain the reduced serum concentrations of antituberculosis drugs. There is a need for new approaches to improve drug bioavailability in TB patients.

Bioavailability of rifampicin following concomitant administration of ethambutol or isoniazid or pyrazinamide or a combination of the three drugs.

BACKGROUND & OBJECTIVES: Poor bioavailability of rifampicin (R) in combination with other anti-tuberculosis drugs such as isoniazid (H), pyrazinamide (Z), and ethambutol (E) is a subject of much concern for the last few decades. This could be due to an interaction between R and other drugs. An investigation was therefore undertaken to examine the bioavailability of R in the presence of H, Z and E or a combination of the three drugs. METHODS: The study included eight healthy volunteers, each being investigated on four occasions at weekly intervals once with R alone and with three of the four combinations on the three remaining occasions. A partially balanced incomplete block design was employed and the allocation of R or the drug combinations was random. Plasma concentrations of R at intervals up to 12 h were determined by microbiological assay using Staphylococcus aureus as the test organism. The proportion (%) dose of R as R plus desacetyl R (DR) in urine excreted over the periods 0-8 and 8-12 h was also determined. Bioavailability was expressed as an index (BI) of area under time concentration curve (AUC) calculated from the plasma concentrations or proportion of dose of R excreted as R plus DR in urine with the combinations to that with R alone. RESULTS: The bioavailability indices based on AUC were 0.96 with RE, 0.76 with RH, 1.08 with RZ and 0.65 with REHZ. The indices based on urine estimations (0-8 h) were similar, the values being 0.94, 0.84, 0.94 and 0.75, respectively. A second investigation revealed that the decrease of bioavailability of R with H was not due to the excipients present in H tablets. INTERPRETATION & CONCLUSION: Isoniazid alone or in combination with E and Z reduces the bioavailability of R. Urinary excretion data offer a simple and non invasive method for the assessment of bioavailability of R.

Consideraciones generales sobre el uso de agentes antimicrobianos en pacientes hepáticos / General remarks: antimicrobial agents use in hepatic patients

El hígado juega un papel fundamental en el metabolismo de las drogas, incluyendo los antimicrobianos. En los pacientes con enfermedad hepática, se deben monitorizar cuidadosamente los efectos adversos y toxicidad de estos medicamentos. En este artículo se analizan los aspectos del metabolismo de los antimicrobianos, particularmente relacionados a los cambios farmacocinéticos en los pacientes hepáticos. Además, se dan algunas recomendaciones prácticas sobre su uso en estos pacientes

Poly (DL-lactide-co-glycolide) microparticles as carriers for antimycobacterial drug rifampicin.

Poly (DL-lactide-co-glycolide) polymers were investigated as carriers for the first line antitubercular drug rifampicin. Different formulations of PLG microparticles viz. porous, non porous and hardened exhibited sustained release of rifampicin up to 7 weeks in vitro. However, hardened PLG microparticles exhibited the most sustained release in vivo in different organs up to 6 weeks. In case of free rifampicin, release was detected in vivo only up to 48 hr. In addition, no hepatotoxicity was observed on a biochemical basis (levels of SGPT, ALP and total bilirubin) in comparison to control animals. Taken together, these results suggest that polymer encapsulated antitubercular drug rifampicin may serve as an ideal therapeutic approach for treatment of tuberculous infections.

Clinical relevance of reduced bioavailability of rifampicin.

Bioavailability (BA) of rifampicin (RMP) is a critical factor in successful treatment of tuberculosis. The BA of RMP can be reduced by pharmaceutical factors, patient factors and drug interactions. Failure of treatment and development of drug resistance are potential consequences of reduction in BA and it is necessary to understand and control the factors influencing BA of RMP.

The pharmacokinetics of oral rifampicin in AIDS patients.

Previous studies in AIDS patients have shown that the peak serum concentration of rifampicin at 2 hours after administration are below normal ranges. These may be due to malabsorption of the drug resulting in therapeutic failure. However, there is no published data to demonstrate the pharmacokinetics of rifampicin in these AIDS patients. Therefore, the aim of this study was to provide such data. Eight AIDS patients with tuberculosis participated in this study. All patients were scheduled to receive oral rifampicin 600 mg once daily in the morning on an empty stomach. Rifampicin pharmacokinetics were studied on day 14. The mean Cmax was 9.81 +/- 4.41 ug/ml. The mean Tmax was 2.25 +/- 0.71 h. The mean AUC0-24 was 60.25 +/- 36.88 ug.h/ml. The results of our study did not confirm the previous studies. The absorption of rifampicin in most of our AIDS patients were not reduced and delayed. Therefore, rifampicin dosage adjustment for Thai patients may not be necessary.

Mecanismos de acción bactericida de ciprofloxacina sobre bacilos gram negativos fermentadores y no fermentadores / Mechanisms of bactericidal action of ciprofloxacin against fermentative and non fermentative gram negative bacilli

Ciprofloxacina es una quinolona con mayor actividad sobre bacilos gram negativos fermentadores que sobre los no fermentadores, lo que puede relacionarse con diferentes mecanismos de acción bactericida descritos en estos compuestos. En este trabajo se investiga la actividad bactericida de ciprofloxacina sobre escherichia coli y klebsiella pneumoniae (bacilos gram negativos fermentadores) y sobre pseudomonas aeruginosa y acinetobacter baumannii (bacilos gram negativos no fermentadores) en ausencia y presencia de rifampicina. Rifampicina inhibió parcialmente la actividad bactericida de ciprofloxacina en los bacilos fermentadore y no tuvo acción sobre la acción bactericida en los bacilos no fermentadores. Esto sugiere que ciprofloxacina ejerce los mecanismos bactericidas A y B en los bacilos fermentadores y solamente el mecanismo B sobre los no fermentadores. Estos resultados podrían explicar las diferencias de acción de ciprofloxacina sobre ambos grupos de bacterias

Determination of oral rifampin pharmacokinetic parameters in Mexicans and comparison with other populations: absence of evidence for interethnic variability

Oral pharmacokinetics of rifampin were studied in eight Mexican young healthy male volunteers after administration of a 600 mg oral dose. After and overnight fast, subjects received medication and blood samples were drawn at selected time over a 24-h period. Rifampin plasma levels were determined by HPLC. Pharmacokinetic parameters (mean ñ SEM) were: Cmax 13.514 ñ 1.775 µg/ml, tmax 1.88 ñ 0.30 h, AUC 73.61 ñ 9.48 µg.h/ml anf half-life 2.98 ñ 0.29 h. Results were compared with those obtained for the other populations under similar conditions in order to explore the possibility of interethnic variability, since it has been reported that rifampin pharmacokinetics in Indonesian subjects differ from those found in Europeans. Pharmacokinetic data found in Mexican were comparable with those observed in Brithis, Indian, Japanese and Italian individuals. As the parmacokinetics of rifampin seem to be similar different populations, it is concluded that ethnic origin does not a appear to play and important role. Therefore, dosing regimens designed for Caucasians can be extrapolated for other populations

Pharmacokinetic interactions of ketoconazole with rifampicin in human volunteers

The interaction of ketoconazole [antifungal agent] and rifampicin [antitubeculosis agent] was studied in the serum of ten healty human volunteers [male], having age between 20 to 30 years and weight from 54 to 72 kg. The blood samples were collected after administrating rifampicin alone and currently with ketoconazole at different time intervals. The serum was separated and stored [-20°C]. Reverse phase HPLC was used as analytical tool to determine the serum concentrations of rifampicin. The influence of ketoconazole on the pharmacokinetic parameters [AUC, Cmax, t1/2, Ke, Ka and tmax] of rifampicin was assessed, when both the drugs were administered simultaneously. It was observed that AUC and Cmax got decreased highly significantly [p<0.001], while t ' reduced and Ke increased significantly [p<0.05]. Statistically significant increase in the values of Ka and tmax was also observed

Inhibition of paracetamol induced reduction in hepatic glutathione level by INH of rifampin coadministration in mice

Repated administration of paracetamol induces hepatotoxicity due to depletion of the liver tissue from its glutathione contents. As paracetamol may be currently used in combination with INH and rifampin it was notworthy to explore the effect of these drugs on hepatic glutathione contents. Paracetamol, INH and rifampin were given either alone or in combination. After certain period of drug treatment, the animals were sacrificed and their livers were homogenized to determine its glutathione contents. It was observed that paracetamol significantly decreased while either INH or rifampin significantly increased the glutathione contents of the liver. When given in combination, both INH and rifampin could prevent the decrease in glutathione level when paracetamol was given with either of them for 2 days and only partially when it was given for 7 days. How much this effect can be benificial ? this needs thorough clinical investigation

Efeito da rifampicina sobre a reserva adrenocortical de cortisol em pacientes com tuberculose / Effect of rifampicin upon the adrenocortical reserve of cortisol in patients with tuberculosis

A tuberculose é causa conhecida de insuficiência adrenocortical primária. A administraçäo de rifampicina, parte do esquema tríplice empregado no tratamento da tuberculose, induz a síntese de enzimas hepáticas que aceleram o metabolismo do cortical, Uma vez que a rifampicina pode preciptar crise adrenal em tuberculose com funçäo adrenocortical comprometida, avaliamos possíveis alteraçöes na reserva de corticol em 33 pacientes com tuberculose, subdivididos em dois grupos: Grupo I - 17 pacientes (13M/4F, 21-45 anos) foram estados antes e, novamente, 30 dias após instituiçäo do esquema tríplice; Grupo 2 - 16 pacientes (13M/3F, 18-64 anos) foram estudados ao fim de seis meses de tratamento e, novamente 30 dias após sua interrupçäo. Como controles utilizamos 32 indivíduos normais, pareados para sexo e idade. Em cada estudo determinamos os níveis séricos de cortisol antes e 50 minutos após estímulo com ACTH (250µg i.v.). Nenhum paciente apresentou clínica de insuficência adrenal ou calcificaçöes nas radiográfias de abdome. Os valores do cortisol basal e pós ACTH (em µg/dl, X ñ DP) no Grupo 1 foram: 20,3 ñ 8,5 e 32,9 ñ 8,5 (antes) e 16,3 ñ 5,1 e 30,3 ñ 6,4 (após 30 dias de tratamento); no Grupo 2 foram: 19,1 ñ 7,3 e 35,4 ñ 12,1 (após seis meses de tratamento) e 18,4 ñ 4,6 e 31,7 ñ 8,2 (30 dias após a internaçäo). Nos controles normais obtivemos: 11,3 ñ 3,4 e 26,3 ñ 4,8, definindo limites críticos inferiores (LCL) de 5,7 e 18,4 para cortisol basal e pós-ACTH, respectivamente. Nenhum paciente apresentou níveis basais ou pós-ACTH de cortisol abaixo do LCI. A instituiçäo (Grupo 1) ou interrupçäo (Grupo 2 do tratamento com rifampicina näo modificou a resposta do cortisol ao estímulo com ACTH. Os dois grupos näo diferenciaram quanto aos níveis e repostas do cortisol. Assim, reduçäo da reserva de cortisol näo foi detectada em nenhum de 33 pacientes com tuberculose estudados prospectivamente, nos quais o tratamento breve ou prolongado com rifampicina näo resultou em alteraçöes significantes da resposta ao estímulo com ACTH

Ranitidine--rifampicin interaction.

Newly diagnosed patients of pulmonary tuberculosis (n = 112) were put on a rifampicin-containing drug regimen. Fifty six patients were also given a placebo tablet twice daily while the other fifty-six were given ranitidine 150 mg twice daily. Gastric pH, gastric emptying time, serum rifampicin levels, urinary total and unchanged rifampicin, serum bilirubin and ALT levels were measured serially. Clinical record of adverse symptoms was maintained. Ranitidine increased the basal as well as post-drug gastric pH without altering the gastric emptying time. Concomitant administration of ranitidine and rifampicin did not alter the absorption, metabolism or excretion of the latter but reduced the frequency of gastrointestinal symptoms.

Stability of rifampicin

The stability of pure rifampicin powder was studied at various storage conditions i.e, at different temperatures and under direct sunlight for 864 hours [36 days]. The amount of drug was determined by visible spectrophotometry. Microbial assay was also carried out at the start and at the end of the study and the purpose of this assay was to check the antibacterial activity of the drug. It was found that pure rifampicin is stable at 5°C but looses potency at elevated temperature of 45°C and on exposure to sunlight. The rifampicin capsules with 10% capsule excipient [microcrystalline cellulose, magnesium stearate, lactose] were formulated and their storage stability at different temperatures was compared with commercially available capsules [Rimactane, Rifampin, Rifampicin]. The capsule excipients were compatible with rifampicin at 5°C and room temperature but at 45°C all the capsules were unstable. The different concentrations of rifampicin [0.001%, 0.002%, 0.01%] in phosphate buffer of pH 7.4 were prepared and these solutions were subjected to 30, 40, 50, 60, 70, 80, 90°C for five minutes. These rifampicin solutions were also kept under direct sunlight for 7 days [8 hours per day exposure]. Less concentrated solutions degrade more as compared to more concentrated solutions at all temperatures. Same was the case in the presence of sunlight. To investigate the effect of pH on rifampicin, 0.02% drug solutions having pH 2, 4, 6, 7, 8, 10 were kept in darkness for 72 hours [3 days] both in the absence and in the presence of antioxidant, ascorbic acid. The neutral solutions more stable as compared to acidic or alkaline solutions. The stability of rifampicin particularly in alkaline solutions improved in the presence of ascorbic acid