Nontherapeutic equivalence of a generic product of imipenem-cilastatin is caused more by chemical instability of the active pharmaceutical ingredient (imipenem) than by its substandard amount of cilastatin.

BACKGROUND: We demonstrated therapeutic nonequivalence of "bioequivalent" generics for meropenem, but there is no data with generics of other carbapenems. METHODS: One generic product of imipenem-cilastatin was compared with the innovator in terms of in vitro susceptibility testing, pharmaceutical equivalence, pharmacokinetic (PK) and pharmacodynamic (PD) equivalence in the neutropenic mouse thigh, lung and brain infection models. Both pharmaceutical forms were then subjected to analytical chemistry assays (LC/MS). RESULTS AND CONCLUSION: The generic product had 30% lower concentration of cilastatin compared with the innovator of imipenem-cilastatin. Regarding the active pharmaceutical ingredient (imipenem), we found no differences in MIC, MBC, concentration or potency or AUC, confirming equivalence in terms of in vitro activity. However, the generic failed therapeutic equivalence in all three animal models. Its Emax against S. aureus in the thigh model was consistently lower, killing from 0.1 to 7.3 million less microorganisms per gram in 24 hours than the innovator (P = 0.003). Against K. pneumoniae in the lung model, the generic exhibited a conspicuous Eagle effect fitting a Gaussian equation instead of the expected sigmoid curve of the Hill model. In the brain infection model with P. aeruginosa, the generic failed when bacterial growth was >4 log10 CFU/g in 24 hours, but not if it was less than 2.5 log10 CFU/g. These large differences in the PD profile cannot be explained by the lower concentration of cilastatin, and rather suggested a failure attributable to the imipenem constituent of the generic product. Analytical chemistry assays confirmed that, besides having 30% less cilastatin, the generic imipenem was more acidic, less stable, and exhibited four different degradation masses that were absent in the innovator.

Main Reasons for Registration Application Refusal of Generic and Similar Pharmaceutical Drug Products by the Brazilian Health Regulatory Agency (ANVISA).

Objective. The marketing authorization of generic and similar pharmaceutical drug products involves the analysis of proposing company's administrative aspects as well as drug product technical description and scientific evaluations. This study evaluated the main reasons for registration refusal of generic and similar pharmaceutical drug products in Brazil. The aim is to help future applicants to better organize the proposal. Methods. A retrospective search of drug products registration processes was performed on the Brazilian Government Official Gazette from January 1, 2015, and December 31, 2015. Results. Drug product quality control, drug product stability study, deadline accomplishment, API quality control made by drug manufacturer, active pharmaceutical ingredient (API), and production report were the main reasons for marketing authorization application refusal of generic and similar pharmaceutical drug products in 2015. Conclusion. Disclosure of the reasons behind failed applications is a step forward on regulatory transparency. Sharing of experiences is essential to international regulatory authorities and organizations to improve legislation requirements for the marketing authorization of generic and similar pharmaceutical drug products.

In vivo pharmacodynamics of piperacillin/tazobactam: implications for antimicrobial efficacy and resistance suppression with innovator and generic products.

Recent studies have shown that the pharmacodynamic (PD) index driving the efficacy of ß-lactam/ß-lactamase inhibitor combinations such as ceftazidime/avibactam and ceftolozane/tazobactam is the percentage of time the free inhibitor concentration is above a threshold (fT>threshold). However, data with piperacillin/tazobactam (TZP) are scarce. Here we aimed to assess the relationship between fT>threshold and TZP antibacterial efficacy by a population pharmacokinetic study in mice and dose-effect experiments in a neutropenic murine thigh infection model with two isogenic strains of Escherichia coli differentially expressing TEM-1 ß-lactamase. We also explored the dynamics of resistance selection with the innovator and a non-equivalent generic, extrapolated the results to the clinic by Monte Carlo simulation of standard TZP doses, and estimated the economic impact of generic-selected resistance. The fT>threshold index described well the efficacy of TZP versus E. coli, with threshold values from 0.5 mg/L to 2 mg/L and mean exposures of 42% for stasis and 56% for 1 log10 kill. The non-equivalent generic required a longer exposure (fT>threshold 33%) to suppress resistance compared with the innovator (fT>threshold 22%), leading to a higher frequency of resistance selection in the clinical simulation (16% of patients with the generic vs. 1% with the innovator). Finally, we estimated that use of TZP generics in a scenario of 25% therapeutic non-equivalence would result in extra expenses approaching US$1 billion per year in the USA owing to selection of resistant micro-organisms, greatly offsetting the savings gained from generic substitution and further emphasising the need for demonstrated and not assumed therapeutic equivalence.

Post-marketing surveillance of generic amoxicillin using a microbiological assay and pharmacokinetic approach in rats.

Generic medicines were developed to increase population access to health treatment, to reduce costs and to allow drugs with the same outcomes to be purchased at lower prices. They are therapeutically equivalent to their brand-name counterparts and are interchangeable with them. However, the acceptance of generic medicines by physicians and general consumers is often affected by distrust related to quality and efficacy. In this study three different brands of generic amoxicillin were tested. The results showed that two of them were indistinguishable from the innovator in terms of microbiological potency; however, generic B was unable to reach the Brazilian Pharmacopoeia specifications for potency limits. In contrast, generic B was bioequivalent to the innovator amoxicillin in pharmacokinetic assessment and, surprisingly, generic A, which was approved in the microbiological potency assay, lacked pharmacokinetic equivalence compared with the innovator. Both tests, when used singly, may not be effective at detecting quality deviations in antimicrobial medicines, which indicates that pharmacokinetic tests in rats in association with microbiological potency assays are a valuable tool for post-marketing surveillance of generic antibiotics.

Clinical implications for substandard, nonproprietary medicines in multiple sclerosis: focus on fingolimod.

Both proprietary and nonproprietary medicines are expected to undergo rigorous preapproval testing and both should meet stringent health authority regulatory requirements related to quality to obtain approval. Nonproprietary (also known as copy, or generic) medicines, which base their authorization and use on the proprietary documentation and label, are often viewed as a means to help lower the cost and, thus, increase patient access. If these medicines fail to meet quality standards, such as good manufacturing practice and bioequivalence (in humans), they are then defined as substandard copies and can pose serious risks to patients in terms of safety and efficacy. Potentially noncontrolled or different manufacturing process and excipients in nonproprietary medicines may result in poor batch-to-batch reproducibility (accurate and consistent quantity of each ingredient in each capsule/tablet) and lower quality. Substandard, nonproprietary copies of medicines that are immunomodulatory or immunosuppressive are of concern to patients due to their possible untoward safety and lack of efficacy events. This article reviews the potential risks associated with nonproprietary medicines that do not meet the regulatory requirements of the United States Food and Drug Administration, the European Medicines Agency, or the World Health Organization. The clinical implications for patients are described. This article focuses on nonproprietary medicines for multiple sclerosis, particularly fingolimod, that are not identical to proprietary versions and could thus fail to meet efficacy expectations or have different impact on the safety of patients with multiple sclerosis.

Relevance of variation in use of terminology to define generic pharmaceutical products / Relevancia de la variación en el uso de la terminología para definir los medicamentos genéricos

The World Health Organization (WHO) promotes the use of generic drug policies to foster competition in the pharmaceutical sector, reduce drug prices, and increase access to therapeutic drugs. However, little is known about how countries implement these policies. This article describes different terminology adopted by national regulatory authorities to define generic versus proprietary drug products in developing countries, including those in Latin America, and challenges that arise in their application of WHO guidelines, such as labeling issues. The author concludes that variation in generics terminology in these countries is a result of institutional context (i.e., the public sector setting as well as the body of laws and regulations that exists in the country) and policy legacies, such as intellectual property regimes, and highlights the need for further analysis of pharmaceutical regulations to improve understanding of the barriers and political implications of generic drug policies.

La Organización Mundial de la Salud (OMS) promueve el uso de políticas de medicamentos genéricos para estimular la competencia en el sector farmacéutico, reducir los precios y aumentar el acceso a los medicamentos. Sin embargo, hay poca información sobre la aplicación de dichas políticas por parte de los países. Este artículo describe la terminología empleada por los organismos regulatorios nacionales para definir los medicamentos genéricos frente a las especialidades farmacéuticas de marca en los países en desarrollo, incluidos los de América Latina, así como las dificultades que se encuentran en la aplicación de las directrices de la OMS, como por ejemplo en el etiquetado. El autor llega a la conclusión de que la variación en la terminología de los medicamentos genéricos en estos países es resultado del contexto institucional (es decir, el sector público y el ordenamiento jurídico-administrativo del país) y de los legados de las políticas, como los regímenes de propiedad intelectual, y destaca la necesidad de analizar más a fondo los reglamentos farmacéuticos a fin de conocer mejor los obstáculos y las implicaciones de las políticas en materia de medicamentos genéricos.

Drug-laboratory interaction between beta-lactam antibiotics and the galactomannan antigen test used to detect mould infections.

Several studies have demonstrated that piperacillin/tazobactam produces a false-positive result for the galactomannan antigen test. However, the most recent literature has demonstrated that this interaction is no longer a concern. There is little information regarding the drug-laboratory interaction with the generics of piperacillin/tazobactam or other broad-spectrum beta-lactams, such as ceftaroline, doripenem, imipenem/cilastatin, and meropenem. The purpose of this study was to determine if a drug-laboratory interaction exists with these antibiotics. Tests showed that one lot of imipenem/cilastatin by Hospira Healthcare India Private Limited produced a false-positive result for the galactomannan antigen test. All other medications tested, including piperacillin/tazobactam from seven manufacturers and imipenem/cilastatin by Hospira Inc., did not produce positive results. Since the reason for this drug-laboratory interaction with imipenem/cilastatin is unknown, more studies are needed to further investigate this interaction. Providers also should be educated of these findings: no drug-laboratory interaction with piperacillin/tazobactam and a possible drug-laboratory interaction with imipenem/cilastatin (Hospira Healthcare India Private Limited).

Clinical efficacy, safety and anti-inflammatory activity of two sevelamer tablet forms in patients on low-flux hemodialysis.

Sevelamer hydrochloride is an ionic exchange resin with high affinity for phosphate. This phosphate-binding agent has few serious adverse reactions with the advantage of reducing total and low density lipoprotein (LDL) cholesterol levels. However, it is controversial as to whether sevelamer hydrochloride can modulate the inflammatory response via endotoxin reduction. Therefore, a single-center, open-label, prospective and randomized study was performed to compare the clinical efficacy, safety and anti-inflammatory activity of two sevelamer hydrochloride tablet forms a branded tablet form, Renagel (Genzyme manufacturer) and its generic equivalent (EMS manufacturer). Twenty-eight chronic kidney disease volunteer patients at stage 5 (CDK 5D), on chronic low-flux hemodialysis carried out in 4-hour sessions, three times a week, were studied. The serum phosphorus, ionic calcium, total cholesterol and fractions, bicarbonate, blood pH, interleukin (IL)-6, IL-10, IL-1 beta and tumor necrosis factor-alpha (TNF-alpha) levels were collected prior to dialysis at mid-week. The incidence of gastrointestinal adverse effects were determined at the end of the phosphate-binder washout period as well as at the end of the fourth and eighth weeks of use of both tablet forms. The same magnitude of reduction in serum phosphorus was observed with both sevelamer tablet forms. Only the Renagel group showed lower total cholesterol and lower LDL cholesterol levels at the fourth and eighth week versus baseline. No significant differences in serum cytokine levels were identified in either drug group. However, the incidence of intestinal obstipation was higher among patients who used the generic equivalent form. In conclusion, Renagel and its EMS generic equivalent tablet forms have a similar clinical efficacy in reducing phosphorus in CKD 5D patients on low-flux hemodialysis and a similar safety profile.

Therapeutic equivalence requires pharmaceutical, pharmacokinetic, and pharmacodynamic identities: true bioequivalence of a generic product of intravenous metronidazole.

Animal models of infection have been used to demonstrate the therapeutic failure of "bioequivalent" generic products, but their applicability for this purpose requires the accurate identification of those products that are truly bioequivalent. Here, we present data comparing one intravenous generic product of metronidazole with the innovator product in a neutropenic mouse thigh anaerobic infection model. Simultaneous experiments allowed comparisons (generic versus innovator) of potency and the concentration of the active pharmaceutical ingredient (API), analytical chemistry (liquid chromatography/mass spectrometry [LC/MS]), in vitro susceptibility testing, single-dose serum pharmacokinetics (PK) in infected mice, and in vivo pharmacodynamics (PD) against Bacteroides fragilis ATCC 25825 in synergy with Escherichia coli SIG-1 in the neutropenic mouse thigh anaerobic infection model. The Hill dose-response model followed by curve-fitting analysis was used to calculate and compare primary and secondary PD parameters. The generic and the innovator products were identical in terms of the concentration and potency of the API, chromatographic and spectrographic profiles, MIC and minimal bactericidal concentrations (MBC) (2.0 mg/liter), and mouse PK. We found no differences between products in bacteriostatic doses (BD) (15 to 22 mg/kg of body weight per day) or the doses needed to kill 1 log (1LKD) (21 to 29 mg/kg per day) or 2 logs (2LKD) (28 to 54 mg/kg per day) of B. fragilis under dosing schedules of every 12 h (q12h), q8h, or q6h. The area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC ratio) was the best PD index to predict the antibacterial efficacy of metronidazole (adjusted coefficient of determination [AdjR(2)] = 84.6%), and its magnitude to reach bacteriostasis in vivo (56.6 ± 5.17 h) or to kill the first (90.8 ± 9.78 h) and second (155.5 ± 22.2 h) logs was the same for both products. Animal models of infection allow a thorough demonstration of the therapeutic equivalence of generic antimicrobials.

Patentes, suministro de medicamentos y protección de la Salud Pública / Patents, supply of medicines and protection of public health

INTRODUCCIÓN: A fin de cumplir con las obligaciones asumidas en la Organización Mundial del Comercio, Argentina comenzó a conceder patentes sobre medicamentos en octubre de 2000. Cerca de 1.000 patentes farmacéuticas fueron concedidas entre 2000 y 2007. OBJETIVOS: caracterizar el patentamiento farmacéutico y, en particular, establecer el tipo de materias protegidas, las aplicaciones terapéuticas y el origen de los titulares de patentes otorgadas; examinar el posible impacto del nuevo régimen de patentamiento sobre las adquisiciones públicas de medicamentos; clarificar en qué situaciones y con qué procedimientos pueden otorgarse licencias obligatorias, especialmente en casos de emergencia sanitaria; y examinar qué implicaciones tiene el marco legal nacional e internacional de la propiedad intelectual sobre las políticas de salud pública. MÉTODOS: Se diseñó y analizó una base de datos con las patentes concedidas en el período indicado. Se revisaron los procedimientos de adquisición de medicamentos del Ministerio de Salud de la Nación y el marco legal aplicable, así como las negociaciones internacionales en curso. RESULTADOS: casi la totalidad de las patentes otorgadas pertenecen a empresas extranjeras; la mayoría se refiere a enfermedades del sistema nervioso e incluyen reivindicaciones del tipo “Markush”. La mayoría de las patentes son de derivados o variantes de productos existentes(sales, formulaciones, polimorfos, etc.). CONCLUSIONES: El estudio concluye con recomendaciones, sobre los procedimientos de adquisición, concesión de licencias obligatorias y la transparencia del sistema de patentes en lo concerniente a medicamentos.

INTRODUCTION: In order to comply with its obligationsin the World Trade Organization, Argentina started to grant patents on pharmaceutical products in October 2000. In the period 2000-2007 near one thous and pharmaceutical patents were granted. OBJECTIVES: To characterize pharmaceutical patenting and, in particular, to establish the type of protected subject matter, the therapeutic uses and the origin of patent owners; to examine the possible impact of the new patentin gregime on public procurement of medicines; to clarify in which situations and with which procedures compulsory licenses can be granted, particularly in cases of health emergencies;to examine the implications of the national and international legal framework of intellectual property on public health policies.METHODS: A data base with the patents granted in the above-mentioned period was designed and analyzed, the procurement procedures of the National Ministry of Health were studied, as well as the applicable legal framework and ongoing international negotiations. RESULTS: The study revealed that almost all granted patents belong to foreign companies. The majority refers to diseases of the nervous system and includes‘Markush-type’. In addition, the great majority of patents relate to derivatives or variants of existing products (salts, formulations, polymorphs, etc. ). CONCLUSIONS: The study concludes with recommendations, about procurement procedures, the grant of compulsory licenses and the transparency of the patent system as regards medicines.

Generic vancomycin products fail in vivo despite being pharmaceutical equivalents of the innovator.

Generic versions of intravenous antibiotics are not required to demonstrate therapeutic equivalence with the innovator because therapeutic equivalence is assumed from pharmaceutical equivalence. To test such assumptions, we studied three generic versions of vancomycin in simultaneous experiments with the innovator and determined the concentration and potency of the active pharmaceutical ingredient by microbiological assay, single-dose pharmacokinetics in infected mice, antibacterial effect by broth microdilution and time-kill curves (TKC), and pharmacodynamics against two wild-type strains of Staphylococcus aureus by using the neutropenic mouse thigh infection model. The main outcome measure was the comparison of magnitudes and patterns of in vivo efficacy between generic products and the innovator. Except for one product exhibiting slightly greater concentration, vancomycin generics were undistinguishable from the innovator based on concentration and potency, protein binding, in vitro antibacterial effect determined by minimal inhibitory or bactericidal concentrations and TKC, and serum pharmacokinetics. Despite such similarities, all generic products failed in vivo to kill S. aureus, while the innovator displayed the expected bactericidal efficacy: maximum antibacterial effect (Emax) (95% confidence interval [CI]) was 2.04 (1.89 to 2.19), 2.59 (2.21 to 2.98), and 3.48 (2.92 to 4.04) versus 5.65 (5.52 to 5.78) log10 CFU/g for three generics and the innovator product, respectively (P<0.0001, any comparison). Nonlinear regression analysis suggests that generic versions of vancomycin contain inhibitory and stimulatory principles within their formulations that cause agonistic-antagonistic actions responsible for in vivo failure. In conclusion, pharmaceutical equivalence does not imply therapeutic equivalence for vancomycin.

In vitro and in vivo comparison of the anti-staphylococcal efficacy of generic products and the innovator of oxacillin.

BACKGROUND: Oxacillin continues to be an important agent in the treatment of staphylococcal infections; many generic products are available and the only requirement for their approval is demonstration of pharmaceutical equivalence. We tested the assumption that pharmaceutical equivalence predicts therapeutic equivalence by comparing 11 generics with the innovator product in terms of concentration of the active pharmaceutical ingredient (API), minimal inhibitory (MIC) and bactericidal concentrations (MBC), and antibacterial efficacy in the neutropenic mouse thigh infection model. METHODS: The API in each product was measured by a validated microbiological assay and compared by slope (potency) and intercept (concentration) analysis of linear regressions. MIC and MBC were determined by broth microdilution according to Clinical and Laboratory Standard Institute (CLSI) guidelines. For in vivo efficacy, neutropenic ICR mice were inoculated with a clinical strain of Staphylococcus aureus. The animals had 4.14 +/- 0.18 log10 CFU/thigh when treatment started. Groups of 10 mice per product received a total dose ranging from 2.93 to 750 mg/kg per day administered q1h. Sigmoidal dose-response curves were generated by nonlinear regression fitted to Hill equation to compute maximum effect (Emax), slope (N), and the effective dose reaching 50% of the Emax (ED50). Based on these results, bacteriostatic dose (BD) and dose needed to kill the first log of bacteria (1LKD) were also determined. RESULTS: 4 generic products failed pharmaceutical equivalence due to significant differences in potency; however, all products were undistinguishable from the innovator in terms of MIC and MBC. Independently of their status with respect to pharmaceutical equivalence or in vitro activity, all generics failed therapeutic equivalence in vivo, displaying significantly lower Emax and requiring greater BD and 1LKD, or fitting to a non-sigmoidal model. CONCLUSIONS: Pharmaceutical or in vitro equivalence did not entail therapeutic equivalence for oxacillin generic products, indicating that criteria for approval deserve review to include evaluation of in vivo efficacy.

Determination of therapeutic equivalence of generic products of gentamicin in the neutropenic mouse thigh infection model.

BACKGROUND: Drug regulatory agencies (DRA) support prescription of generic products of intravenous antibiotics assuming therapeutic equivalence from pharmaceutical equivalence. Recent reports of deaths associated with generic heparin and metoprolol have raised concerns about the efficacy and safety of DRA-approved drugs. METHODOLOGY/PRINCIPAL FINDINGS: To challenge the assumption that pharmaceutical equivalence predicts therapeutic equivalence, we determined in vitro and in vivo the efficacy of the innovator product and 20 pharmaceutically equivalent generics of gentamicin. The data showed that, while only 1 generic product failed in vitro (MIC = 45.3 vs. 0.7 mg/L, P<0.05), 10 products (including gentamicin reference powder) failed in vivo against E. coli due to significantly inferior efficacy (E(max) = 4.81 to 5.32 vs. 5.99 log(10) CFU/g, P

Bioactivities of a series of phosphodiesterase type 5 (PDE-5) inhibitors as modelled by MIA-QSAR.

A series of cyclic guanine derivatives, phosphodiesterase type 5 (PDE-5) inhibitors, have been modelled using an image-based approach for quantitative structure-activity relationships (MIA-QSAR). The calibration model showed to be robust with a R(2) of 0.864 using five PLS components. The predictive ability of the model was tested through leave-one-out cross-validation, giving a Q(2)(CV) of 0.605 (Q(2)(CV) improves to 0.721 after removing two outliers). An external validation set was also used to give an account for the modelling capability, and the results agreed with the ones obtained from a 3D methodology previously applied to this series of compounds. The method showed to be a potential tool for predicting new drug-like compounds, as exemplified by calculating the activities of two new proposed congeners derived from the training set.

Estudo comparativo da atividade antimicrobiana da ceftriaxona, ciprofloxacina e ampicilina nas formas comerciais de medicamento genérico e de marca frente a linhagens de Escherichia coli isoladas de infecção urinária / Comparative study of the antimicrobial activity of ceftriaxone, ciprofloxacin and ampicillin in the proprietary drug forms of generic drug and brand front of the escherichia coli strains isolated from urinary tract infection

Escherichia coli é o principal agente na etiologia de infecção no trato urinário, onde sua resistência a diversas drogas tem sido motivo de preocupação das autoridades. O presente trabalho teve como objetivos determinar a sensibilidade antimicrobiana in vitro de linhagens de Escherichia coli e comparar a eficácia dos antimicrobianos na forma de medicamento genérico e de marca®. Foram obtidos 79 linhagens provenientes de urina de pacientes com infecção no trato urinário e internados no Hospital das Clinicas de Botucatu, UNESP, No período de fevereiro a abril de 2004. Foram analisadas in vitro, a suscetibilidade, a ceftriaxona, ciprofloxacina e ampicilina através da difusão da droga a partir de discos impregnados (Antibiograma) e da Determinação da Concentração Inibitória Mínima (CIM). A análise da curva da morte de algumas linhagens observou a dinâmica da ação das drogas e a capacidade de produção de Beta-lactamase. os resultados alcançados demonstram excelente atividade antimicrobiana da ceftriaxona, com 97,5 por cento de linhagens sensíveis pelo método do antibiograma e 93,7 por cento e 92,4 por cento pela CIM para a droga genérica e de marca®, respectivamente. À ciprofloxacina observou-se 79,8 por cento de linhagens sensíveis pelo antibiograma e 68,6 por cento e 69,6 por cento pela CIM para a droga genérica e de marca® respectivamente. Entretanto, à ampicilina caracterizou elevado percentual de linhagens resistentes, com 51,9 por cento pelo antibiograma e 62 por cento e 72,1 por cento através da CIM, para a droga genérica e de marca®, respectivamente. Através da análise dos resultados da CIM e da curva da morte, verificou-se que a droga genérica e a de marca apresentam a mesma efetividade. Em relação à produção de beta-lactamase, 98,7 por cento das linhagens produziram a enzima. A efetividade dos antimicrobianos genéricos ainda demanda novos e mais amplos estudos para a caracterização de possíveis discrepâncias de resultados, mormente a partir de produtos...

Mebendazol: identificaçào das formas polimórficas em diferentes matérias-primas e medicamentos (referência e genéricos) disponíveis no mercado nacional / Mebendazole: identification of polymorphs of the drug in several different bulk substance and dosage forms (reference brand and generic) avaiable in Brazil

A presença de polimorfos diferentes em uma formulação pode comprometer a dissolução de um fármaco a partir de sua forma farmacêutica, uma vez que os polimorfos freqüentemente apresentam diferentes solubilidades.No entanto, as monografias farmacopéicas não apresentam, normalmente, ensaios para a identificação das possíveis formas polimórficas de um mesmo fármaco.O mebendazol possui três formas polimórficas diferentes, conhecidas como formas A, B e C, que apresentam diferentes propriedades físico-químicas e biofarmacêuticas.Estas formas apresentam, inclusive, diferentes comportamentos in vivo, sendo o polimorfo C o recomendado para formas farmacêuticas sólidas de uso oral.No presente trabalho utiliza-se a espectroscopia de infravermelho e o perfil de dissolução in vitro para caracterizar matérias-primas e comprimidos (referência e genéricos) existentes no mercado brasileiro.O perfil de dissolução para três medicamentos que apresentavam as formas polimórficas A, B e C, foi obtido utilizando-se método da Farmacopéia Americana modificado, uma vez que o meio de dissolução farmacopéico não possibilita a distinção entre as formas polimórficas do mebendazol, devido à adição de lauril sulfato de sódio ao meio.Os resultados obtidos demonstram que as três formas polimórficas do mebendazol estão presentes nos medicamentos e duas delas em matérias-primas, sugerindo que um maior controle deveria ser utilizado para a seleção de matérias-primas que apresentam polimorfismo, assegurando, através de testes simples e rápidos, a qualidade de medicamentos genéricos.

Comparación entre el bromuro de pancuronio genérico y el Pavulon½1 / Comparison between generic pancuronium bromide and Pavulon½1

Históricamente se ha planteado el conflicto sobre la eficacia y la seguridad terapéutica entre marcas genéricas y la marca original, lo cual llevó a desarrollar el siguiente estudio. Objetivos: 1) realizar ensayos fisicoquímicos de ampollas que contenían 4 mg/2ml de bromuro de pancuronio, en una marca genérica (G) y en una original (P = Pavulon½), 2) determinar la eficacia y la seguridad terapéutica de ambas drogas, y 3) comparar los resultados entre ambas marcas, tomando como patrón de referencia la marca original. Materiales y métodos: Ensayos fisicoquímicos realizados conforme la Farmacopea Británica 2001 (FB). Eficacia y seguridad terapéutica evaluada mediante un estudio prospectivo, randomizado y doble ciego en cincuenta pacientes ASA I-II a quienes se administró 2 mcg/kg de citrato de fentanilo, 5 mg/kg de tiopental sódico cinco minutos después y 0.1 mg/kg de bromuro de pancuronio. La anestesia se mantuvo con sevoflurano 2 por ciento. Se evaluó el tiempo T1 para alcanzar los valores porcentuales 95,75,25,0 y 25 de recuperación o duración clínica. Comparación: Test de Mann - Whitney, p < 0.05. Resultados: Los ensayos fisicoquímicos para el grupo genérico y el Pavulon½ cumplieron con las especificaciones de la FB. En el grupo genérico, los tiempos necesarios para que T1 disminuya hasta 95 y 75 por ciento resultaron respectivamente 33.15 y 48.36 segundos; para que disminuya al 25 por ciento y 0 por ciento, 1.50 Y 2.97 minutos, y la duración clínica fue de 108.99 minutos. En el grupo Pavulon½, el tiempo requerido para T1 = 95 Y 75 por ciento fue de 24.89 y 41.54 segundos respectivamente, mientras que para llegar al 25 y 0 por ciento fueron necesarios 1.34 y 2.71 minutos; la duración clínica en este grupo fue de 111.99 minutos. Conclusiones: Los tiempos evaluados no arrojaron diferencia estadística significativa entre ambas marcas. (AU)