A study on enhanced intestinal permeability of clarithromycin nanoparticles

The main objective of the present study was to determine the permeability of clarithromycin (CLA)-PLGA nanoparticles using single-pass intestinal perfusion technique in rats. Clarithromycin nanoparticles were prepared by nano-precipitation according to the modified quasi emulsion solvent diffusion technique and evaluated for their physicochemical characteristics. Permeability coefficients (Peff) in anaesthetized rats were determined at 3 different concentrations. Drug solution or suspensions in PBS was perfused through a cannulated jejunal segment and samples were taken from outlet tubing at different time points up to 90 min. Microbiological assay of CLA and phenol red in the samples were analyzed using an agar well diffusion procedure and HPLC method respectively. The average particle size of prepared nanoparticles was 305 ± 134 nm. The mean Peff of CLA solution in concentrations of 150, 250 and 400 µg/mL was found to be 1.20 (±0.32) ×10-3, 9.62 (±0.46) ×10-4, and 1.36 (±0.95) ×10-3 cm/sec, respectively. The corresponding values for the same concentration of nanoparticles were found to be 2.74 (±0.73) ×10-3, 2.45 (±0.88) ×10-3, and 3.68 (±0.46) ×10-3 cm/s, respectively. The two-tailed Student’s t-test showed that the intestinal permeability of CLA nanoparticle suspensions in prepared concentrations were significantly increased in comparison with its solution.

O objetivo principal do presente estudo foi determinar a permeabilidade de nanopartículas de claritromicina (CLA)-PLGA, utilizando a técnica de perfusão intestinal de passo único em ratos. As nanopartículas de claritromicina foram preparadas por nanoprecipitação, de acordo com a técnica modificada de difusão de solvente quase-emulsão, e suas características físico-químicas avaliadas. Os coeficientes de permeabilidade (Peff) em ratos anestesiados foram determinados em três concentrações diferentes. A solução, ou suspensões, do fármaco em PBS foi perfundida através do segmento de jejuno canulado e as amostras foram tomadas do tubo externo em diferentes tempos até 90 minutos. Os ensaios microbiológico de CLA e de vermelho de fenol das amostras foram realizados, utilizando-se o procedimento de difusão em poço de ágar e de CLAE, respectivamente. O tamanho médio das partículas das nanopartículas preparadas foi de 305 ± 134 nm. O Peff médio da solução de CLA em concentrações de 150, 250 and 400 µg/mL foi de 1.20(±0.32)×10-3, 9.62(±0.46)]×10-4 e de 1.36(±0.95)×10-3 cm/s, respectivamente. O valor correspondente para a mesma concentração de nanopartículas foi de 2.74 (±0.73)×10-3, 2.45(±0.88)×10-3 e de 3.68 (±0.46)×10-3 cm/s, respectivamente. O teste t de Student com duas variáveis mostrou que a permeabilidade intestinal das suspensões de nanopartículas de CLA nas concentrações preparadas foram significativamente aumentadas em comparação com sua solução.

A PK/PD approach on the effects of clarithromycin against oral and nasal microbiota of healthy volunteers.

OBJECTIVE: To assess the pharmacokinetics of clarithromycin (CLR) and its effects on oral and nasal microbiota in healthy volunteers in an open, randomized, two-period crossover design. METHODS: A single 500 mg oral dose of CLR (Group 1: Merck; Group 2: Klaricid) was administered observing a 1-week interval between doses. Blood samples were collected from pre-dose to 24 h. Plasmatic concentrations of CLR were quantified by the LC-MS-MS method. Saliva and nasal mucosa swabs were obtained previously and after 1.33, 2, 6 and 12 h of drug administration. Pharmacokinetics and PK/PD (t > MIC, %t > MIC and AUC0-24/MIC ratio) parameters were estimated. The microorganism counts were obtained on different culture media. RESULTS: No statistically significant differences were observed between the two formulations (p > 0.05) regarding the pharmacokinetic parameters. Total microorganisms, staphylococci and streptococci counts did not show statistical differences (p > 0.05) between the two groups during each sampling time. Considering the microorganisms of each group, no statistically significant differences were found after drug administration, but all differed from pre-dose counts (p < 0.05). The observed t > MIC ranged from 14.45 h (+/- 1.69) to 1.19 h (+/- 2.17) considering MICs of 0.25 microg/ml and 2.0 microg/ml, respectively. There was no correlation between any t > MIC, %t > MIC or AUC0-24 and bacterial reduction (between 0- and 12-h periods). However, the profile of reduction of microorganisms in both saliva and nasal samples were compatible with high values of t > MIC verified for both clarithromycin formulations. CONCLUSION: Both formulations of clarithromycin had similar pharmacokinetics and efficacy.

Effect of Helicobacter pylori infection and acid blockade by lansoprazole on clarithromycin bioavailability.

The effect of proton pump inhibitors and Helicobacter pylori infection on the bioavailability of antibiotics is poorly understood. We determined the effects of 5-day oral administration of 60 mg lansoprazole on the bioavailability of clarithromycin in individuals with and without H. pylori infection. Thirteen H. pylori-infected and 10 non-infected healthy volunteers were enrolled in a study with an open-randomized two-period crossover design and a 21-day washout period between phases. Plasma concentrations of clarithromycin in subjects with and without lansoprazole pre-treatment were measured by liquid chromatography coupled to a tandem mass spectrometer. Clarithromycin Cmax and AUC0-10 h were significantly reduced after lansoprazole administration. In addition, lansoprazole treatment of the H. pylori-positive group resulted in a statistically significant greater reduction in Cmax (40 vs 15%) and AUC0-10 h (30 vs 10%) compared to lansoprazole-treated H. pylori-negative subjects. Thus, treatment with lansoprazole for 5 days reduced bioavailability of clarithromycin, irrespective of H. pylori status. This reduction, however, was even more pronounced in H. pylori-infected individuals.

Effect of Helicobacter pylori infection and acid blockade by lansoprazole on clarithromycin bioavailability

The effect of proton pump inhibitors and Helicobacter pylori infection on the bioavailability of antibiotics is poorly understood. We determined the effects of 5-day oral administration of 60 mg lansoprazole on the bioavailability of clarithromycin in individuals with and without H. pylori infection. Thirteen H. pylori-infected and 10 non-infected healthy volunteers were enrolled in a study with an open-randomized two-period crossover design and a 21-day washout period between phases. Plasma concentrations of clarithromycin in subjects with and without lansoprazole pre-treatment were measured by liquid chromatography coupled to a tandem mass spectrometer. Clarithromycin Cmax and AUC0-10 h were significantly reduced after lansoprazole administration. In addition, lansoprazole treatment of the H. pylori-positive group resulted in a statistically significant greater reduction in Cmax (40 vs 15 percent) and AUC0-10 h (30 vs 10 percent) compared to lansoprazole-treated H. pylori-negative subjects. Thus, treatment with lansoprazole for 5 days reduced bioavailability of clarithromycin, irrespective of H. pylori status. This reduction, however, was even more pronounced in H. pylori-infected individuals.

Comparative bioavailability of clarithromycin formulations in healthy brazilian volunteers.

OBJECTIVE: To compare the bioavailability of clarithromycin 500 mg tablets (Merck S.A Industrias Quimicas, Sao Paulo, SP, Brazil, used as test formulation) and Klaricid (Abbott Laboratórios do Brasil Ltda, Sao Paulo, SP, Brazil, used as reference formulation) in 24 healthy volunteers. MATERIAL AND METHODS: The study was conducted using an open, randomized, two-period crossover design with one-week interval between doses. Blood samples were collected at pre-dose, 0.33, 0.66, 1, 1.33, 1.66, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 20 and 24 hours after the administration. AUC was calculated by the trapezoidal rule extrapolation method. Cmax and tmax were compiled from the plasmatic concentration-time data. Analysis of variance was carried out using logarithmically transformed AUC(0-inf), AUC(0-24 h), Cmax and untransformed tmax. RESULTS: Intraindividual coefficient of variation (CV%) values were 14.25% and 12.62%, respectively for Cmax and AUC(0-24 h). The geometric mean values (+/- SD) for AUC(0-24 h) (microg x h/ml), AUC(0-inf) (microg x h/ml), and Cmax (microg/ml) for test medication were 18.56 (+/- 6.87), 18.8 (+/- 5.70) and 2.45 (+/- 0.88); the obtained values for reference medication were 18.29 (+/- 5.39), 19.10 (+/- 7.21) and 2.5 (+/- 0.69). 90% Cl for clarithromycin geometric mean of AUC(0-24 h), AUC(0-inf) and Cmax ratios (test/reference) were: 93.6-105.9%, 93.8-106.2% and 89- 103.2%. CCONCLUSION The test medication was considered bioequivalent to the reference medication based on the rate and extent of absorption.

Transfer of clarithromycin to gastric juice is enhanced by omeprazole in Helicobacter pylori-infected individuals.

BACKGROUND: The effects of proton-pump inhibitors and Helicobacter pylori infection on the distribution of drugs employed for the eradication of H. pylori are poorly understood. The aim of this study was to investigate the effects of a 7-day oral administration of 20 mg omeprazole on the distribution of clarithromycin in the gastric juice of individuals with H. pylori infection. METHODS: Eighteen H. pylori-infected dyspeptic male volunteers without endoscopic lesions were enrolled in a study with an open, randomized, two-period crossover design and a 21-day washout period between phases. Plasma and gastric juice concentrations of clarithromycin in subjects with and without omeprazole pretreatment were measured by means of liquid chromatography coupled to tandem mass spectrometry. RESULTS: The maximum concentration of clarithromycin (Cmax) and the area under the time-concentration curve from 0 to 2 h (AUC0-2h) were significantly higher in gastric juice than in plasma. Omeprazole treatment further augmented clarithromycin Cmax and AUC0-2h in gastric juice approximately 2-fold (P < 0.05). CONCLUSIONS: Short-term treatment with omeprazole in H. pylori-positive volunteers increases the amount of clarithromycin transferred to the gastric juice, confirming a synergism between these drugs. Our results suggest the presence of an active transport mechanism for clarithromycin from plasma to the gastric lumen, which is influenced by omeprazole.

Clarithromycin bioequivalence study of two oral formulations in healthy human volunteers.

OBJECTIVE: To assess the bioequivalence of two tablet formulations of clarithromycin (Clamicin 500 mg from Medley Indlistria Farmaceutica, Brazil, as the test formulation, and Biaxin 500 mg from Abbott Industries, USA, as the reference formulation). METHODS: A single 500 mg oral dose of each formulation was administrated in 24 healthy volunteers of both sexes (12 males and 12 females). The study was conducted open, randomized, two-period crossover design with a 7-day interval between doses. The plasma concentrations of clarithromycin were quantified by reversed phase liquid chromatography coupled to tandem mass spectrometry (LC-MS-MS) with positive ion electrospray ionization using multiple reaction monitoring (MRM) method. 14-hydroxyclarithromycin concentration was estimated semiquantitatively as equivalent of clarithromycin/ml. The precision of the method was evaluated using calibration curves and plasma quality control samples. The pharmacokinetic parameters calculated for both compounds included: AUC(0 - 48h), AUC(0 - infinity), Cmax, Cmax/AUC(0 - 48h), Tmax, T1/2 and Ke. RESULTS: Standard curves of clarithromycin in plasma were linear in the range of 0.05 microg x ml(-1) to 10 microg x ml(-1) (r > 0.999). The limit of quantification was 5 ng/ml. Within- and between-run plasma quality control CV were 5.8% and 15.7%, respectively. Inaccuracy within- and between-runs were 14% and 17%, respectively. 90% CI for clarithromycin geometric mean AUC(0 - 48h), AUC(0 - infinity) and Cmax ratios (test/reference) were: 8.7% - 103.1%, 89.4% - 103.7% and 85.4% - 99.6%, respectively, and for hydroxyclarithomycin were 80.3% - 108.6%, 80.1% - 110.1% and 85.4% - 112.6%, respectively. CONCLUSION: The method described for the quantification of charithomycin and its main metabolite is accurate and sensitive. Clamicin was considered bio-equivalent to Biaxin based on the rate and extent of absorption. Since these were no significant differences in the bioequivalence determined using the pharmacokinetic parameters of either clarithromycin or 14-hydroxyclarithromycin, we suggest that future bioequivalence trials of this drug may be performed by quantifying clarithromycin only.

Macrólidos en vías respiratorias altas / Macrolides in upper respiratory tract

Los macrólidos no son el tratamiento de primera línea para amigdalitis estreptocóccica, pero sí una alternativa en caso de alergia a penicilina. Para el tratamiento antimicrobiano de OMA,amoxicilina continúa siendo el fármaco de primera elección. Si el tratamiento fracasa por producción de B lactamasa, los nuevos macrólidos son una alternativa válida. Comparados con las otras alternativas, no presentan ninguna ventaja ni desventajas importantes. La única excepción que pesa a favor puede ser la muy larga vida media de azitromicina, que ofrece la ventaja de un corto curso de tratamiento de tres o cinco días. Respecto al neumococo resistente, falta la información local para saber si los nuevos macrólidos son una alternativa útil, o no. La ventaja muy especial de los macrólidos, su actividad contra Chlamydia sp, Mycoplasma sp,M catarrhalis, legionella sp o Mycobacterium avium, no tiene mayor trascendencia en las infecciones respiratorias altas

Macrólidos en vías respiratorias bajas / Macrolides in lower respiratory tract

Los nuevos macrólidos se han constituido en terapias alternativas seguras para el tratamiento de neumonías leves o moderadas adquiridas en la comunidad y en individuos sin patología asociada. Son los antibióticos de elección frente a neumonías atípicas excepto para la producida por C. psittaci. Las mayores ventajas que aportan los macrólidos son la excelente tolerancia oral, su elevada concentración tisular e intracelular y una vida media prolongada que permite la fácil dosificación y la introducción de terapias acortadas asegurando una mejor adherencia al tratamiento. Las desventajas destacables son sus bajos niveles séricos y el elevado costo actual. Por último, se requiere de un uso racional de estos antibióticos y estudios de sensibilidad para estar alertas a la emergencia de resistencia como ya se ha descrito en otras latitudes, v.g. S. pneumoniae y S. pyogenes resistentes a todos los macrólidos

Actividad comparativa in vitro de la combinación amoxicilina-sulbactam y otros 4 antimicrobianos frente a bacterias aisladas de pacientes con infecciones respiratorias adquiridas en la comunidad / In vitro activity of amoxicillin-sulbactam and other 4 antimicrobial agents against community acquired respiratory pathogens

En los últimos años, a nivel mundial se han producido cambios en la etiología de la infección respiratoria y los microorganismos causases muestran resistencia progresiva a los antimicrobianos de uso habitual. Esto ha llevado a la búsqueda de nuevas alternativas terapéuticas. El propósito de este estudio fue comparar la susceptibilidad antimicrobiana in vítro, de 150 cepas bacterianas aisladas durante el primer semestre 1997, de adultos y niños con infeccion respiratoria superior o inferior, frente a la nueva asociación amoxicilina/ sulbactam (amox/sul) y otros 4 antimicrobianos de uso frecuente en Chile en estas patologías. Se determinó la CIM mediante técnica de dilución en agar de amoxicilina (amox), amox/ sul, cefuroxima (cefu), azitromicina (azit) y claritromicina (ciarl) frente a 55 cepas de S. pneumoniae, 44 cepas de H. ínfluenzae, 19 cepas de S. pyogenes y 32 S. aureus. Resultados. De las 55 cepas de S. pneumoniae, 9.1 por ciento fueron resistentes 1 amox, 7,3 por ciento a amox/Sul y cefu y ninguna presentó resistencia a azit o ciarl. Las 19 cepas de S. pyogenes estudiadas fueron sensibles a los 5 antimicrobianos, aunque cepas presentaron CIM límite a azit y ciarl (igual al valor de corte). De las 44 cepas de H. influenzae, 12,3 por ciento presentaron resistencia a amox y 9,1 por ciento a clarí. No se observó resistencia a amox/sul, cefu ni azit. En las cepas de S. aureus se observó resistencia importante a todos los antimicrobianos estudiados: 96 por ciento para amox, 56,3 por ciento para cefu, 59,4 por ciento para ciarl y azit y 46,9 por ciento para amox/sul. Conclusión: De acuerdo a nuestros resultados in vitro, la combinación amoxicilina/sulbactam, frente a bacterias causantes de infecciones respiratorias, tiene una cobertura comparable a otros antimicrobianos en uso e incluidos en este estudio (entre 100 y 54 por ciento) con la excepción de S. aureus que debería ser tratado con antimicrobianos con actividad antiestafilocóccica específica

Orally administered clarithromycin for the treatment of systemic Mycobacterium avium complex infection in children with acquired immunodeficiency syndrome.

OBJECTIVE: To determine the safety, tolerance, pharmacokinetics, and antimycobacterial activity of orally administered clarithromycin in children with acquired immunodeficiency syndrome and disseminated Mycobacterium avium complex (MAC) infection. DESIGN: Phase I study with a 10-day pharmacokinetic phase followed by a 12-week continuation therapy phase. PATIENTS: Twenty-five patients with a median age of 8.3 years were enrolled. Ten were receiving zidovudine and 13 were receiving didanosine at the time of enrollment. INTERVENTION: Clarithromycin suspension was administered to each patient at one of three dose levels: 3.75, 7.5, and 15 mg/kg per dose every 12 hours. Clarithromycin and antiretroviral pharmacokinetics were measured during single-drug and concurrent-drug administration. Clinical and laboratory monitoring was performed biweekly. MEASUREMENTS AND MAIN RESULTS: Clarithromycin was well tolerated at all dose levels. Plasma clarithromycin concentrations increased proportionately with increasing doses, and significant pharmacokinetic interactions were not observed during concurrent administration with zidovudine or didanosine. Decreases in mycobacterial load in blood were observed only at the highest clarithromycin dose level. Decreased susceptibility to clarithromycin developed rapidly (within 12 to 16 weeks) in the majority of MAC strains isolated from study patients.