Autophagy Is a Potential Target for Enhancing the Anti-Angiogenic Effect of Mebendazole in Endothelial Cells

Mebendazole (MBZ), a microtubule depolymerizing drug commonly used for the treatment of helminthic infections, has recently been noted as a repositioning candidate for angiogenesis inhibition and cancer therapy. However, the definite anti-angiogenic mechanism of MBZ remains unclear. In this study, we explored the inhibitory mechanism of MBZ in endothelial cells (ECs) and developed a novel strategy to improve its anti-angiogenic therapy. Treatment of ECs with MBZ led to inhibition of EC proliferation in a dose-dependent manner in several culture conditions in the presence of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) or FBS, without selectivity of growth factors, although MBZ is known to inhibit VEGF receptor 2 kinase. Furthermore, MBZ inhibited EC migration and tube formation induced by either VEGF or bFGF. However, unexpectedly, treatment of MBZ did not affect FAK and ERK1/2 phosphorylation induced by these factors. Treatment with MBZ induced shrinking of ECs and caused G2-M arrest and apoptosis with an increased Sub-G1 fraction. In addition, increased levels of nuclear fragmentation, p53 expression, and active form of caspase 3 were observed. The marked induction of autophagy by MBZ was also noted. Interestingly, inhibition of autophagy through knocking down of Beclin1 or ATG5/7, or treatment with autophagy inhibitors such as 3-methyladenine and chloroquine resulted in marked enhancement of anti-proliferative and pro-apoptotic effects of MBZ in ECs. Consequently, we suggest that MBZ induces autophagy in ECs and that protective autophagy can be a novel target for enhancing the anti-angiogenic efficacy of MBZ in cancer treatment.

Albendazole and Praziquantel: Review and Safety Monitoring in Korea

Albendazole (ADZ) and praziquantel (PZQT) have been used as anthelmintics for over 30 years. Worldwide, hundreds of millions tablets are administered to people and livestock every year. ADZ is poorly orally absorbed ( 75%) and uptake is enhanced by carbohydrate-rich meals. Both ADZ and PZQT are safe, but not recommended for children < 2 years or for women in the first trimester of pregnancy. Serious adverse events occur following high dose and prolonged administration of these drugs for treatment of echinococcosis or neurocysticercosis, especially in patients with poor liver function. The adverse events may be induced by the drugs, or by the dead worms themselves. The Korea Institute of Drug Safety & Risk Management monitors drug-related adverse events in Korea, and its database included 256 probable or possible ADZ-associated events and 108 PZQT-associated events between 2006 and 2015. Such low incidence rates in Korea are due to the low single dose treatments of ADZ, and the short-term use of PZQT. The number of serious adverse events due to drug interaction induced by ADZ and PZQT were six and two, respectively. We conclude that ADZ and PZQT are generally safe drugs, but they must be used with caution in people with poor liver function or those being comedicated for gastroesophageal reflux disease.

Albendazole and Praziquantel: Review and Safety Monitoring in Korea

Albendazole (ADZ) and praziquantel (PZQT) have been used as anthelmintics for over 30 years. Worldwide, hundreds of millions tablets are administered to people and livestock every year. ADZ is poorly orally absorbed ( 75%) and uptake is enhanced by carbohydrate-rich meals. Both ADZ and PZQT are safe, but not recommended for children < 2 years or for women in the first trimester of pregnancy. Serious adverse events occur following high dose and prolonged administration of these drugs for treatment of echinococcosis or neurocysticercosis, especially in patients with poor liver function. The adverse events may be induced by the drugs, or by the dead worms themselves. The Korea Institute of Drug Safety & Risk Management monitors drug-related adverse events in Korea, and its database included 256 probable or possible ADZ-associated events and 108 PZQT-associated events between 2006 and 2015. Such low incidence rates in Korea are due to the low single dose treatments of ADZ, and the short-term use of PZQT. The number of serious adverse events due to drug interaction induced by ADZ and PZQT were six and two, respectively. We conclude that ADZ and PZQT are generally safe drugs, but they must be used with caution in people with poor liver function or those being comedicated for gastroesophageal reflux disease.

Desenvolvimento de método para avaliação do perfil de dissolução de suspensões de mebendazol / Method development for dissolution profile evaluation of mebendazol suspensions

Este trabalho teve por finalidade desenvolver um método para a caracterização do perfil de dissolução de suspensões de mebendazol (MBZ), discriminatório para as formas polimórficas do fármaco. Pertencendo a classe II do Sistema de Classificação Biofarmacêutica (SCB), além da baixa solubilidade, o MBZ é bastante crítico por apresentar-se comercialmente disponível em duas formas polimórficas (A e C) e misturas destas. Além disso, pouca informação é encontrada acerca de métodos de dissolução de suspensões. O material apresentado está dividido em três capítulos, sendo o primeiro deles uma revisão da literatura sobre a dissolução de suspensões de fármacos que apresentam polimorfismo. Neste capítulo é feita uma abordagem sobre questões relacionadas ao desenvolvimento de métodos, como inserção das amostras na cuba de dissolução, agitação, uso de tensoativos no meio e a quantificação do fármaco. No segundo capítulo é apresentado o desenvolvimento do método de dissolução, com ênfase no estudo da solubilidade das formas polimórficas A e C de MBZ e sua interação com tensoativos. Foram realizados ensaios de solubilidade pelo método do equilíbrio, cálculo de concentração micelar crítica para os tensoativos lauril sulfato de sódio e polissorbato 80, sendo ao final realizado delineamento experimental (DOE) para o desenvolvimento do método. Pela avaliação do DOE, o local de inserção da amostra não influencia a dissolução de MBZ, por outro lado, a presença de tensoativo, assim como a forma polimórfica empregada, exercem efeito nos resultados apresentados. A partir destas informações, o método indicado para avaliação das suspensões de MBZ com potencial discriminatório de suas formas polimórficas foi definido pela utilização do aparato 2 (pá) a 75 rpm, com 2 litros de HCl 0,1 M sem tensoativo, como meio de dissolução. No último capítulo, o método desenvolvido foi utilizado na avaliação de especialidades farmacêuticas adquiridas no Brasil e em alguns países da América Latina, sendo os respectivos perfis de dissolução, comparados por meio de uma análise multivariada de componentes principais, com formulações contendo o MBZ em diferentes proporções de polimorfos. A partir dos resultados, foi possível observar que grande parte das formulações comercializadas não apresentaram perfil de dissolução satisfatório, isso pode estar relacionado com a presença considerável de polimorfo A nas matérias-primas utilizadas, comprometendo assim a sua solubilidade

The aim of this work was to develop a method for characterization of the dissolution profile of mebendazole (MBZ) suspensions, being discriminatory for the polymorphic forms of the drug. MBZ belongs to class II of the Biopharmaceutics Classification System (BCS), besides its low solubility, it is very critic, being commercially available in two polymorphic forms (A and C) and their mixtures. Moreover, there is low information about dissolution methods for suspensions. The text presented herein is divided into three chapters, the first chapter is a literature review about dissolution of suspensions containing drugs that present polymorphism. In this chapter is made a discussion about the variables of the method, as sample insertion in the dissolution vessel, rotation speed, use of surfactants in the dissolution medium and drug quantification. The development of the dissolution method, focused on the solubility study of MBZ polymorphic forms A and C and their interaction with surfactants is presented in the chapter 2. Some tests were performed: solubility using shake flask method, calculation of micellar critical concentration for the surfactants sodium lauryl sulphate and polysorbate 80, and an experimental design (DOE) was done for developing the method. By DOE evaluation, the sample insertion site does not influence on MBZ dissolution, but the presence of surfactant and the polymorphic form used, show effect on the results. Based on these information, the method indicated for evaluation of MBZ suspensions, with discriminatory power for its polymorphic forms was defined by using apparatus 2 (paddle) at 75 rpm and 2 L of 0.1M HCl without surfactant as dissolution medium. In chapter 3, the method developed was used to evaluate pharmaceutical suspensions from Brazil and from some countries of Latin America. The respective dissolution profiles were compared by means of multivariate analysis of principal components with formulations containing MBZ in different polymorphs ratios. From the results, it was possible to observe that a great part of the commercially available formulations do not presented a satisfactory dissolution profile, and this fact can be related to a considerable amount of the crystalline form A in the raw material, which compromises its solubility

Blood Profil of Dogs Experimentally Infected with Single Trypanosoma brucei, Ancylostoma caninum and Conjunct Trypanosoma brucei and Ancylostoma caninum and Treatment with Diminazene Aceturate and Mebendazole.

The present study was designed to ascertain the level of haematological alterations in single Trypanosoma brucei (T. brucei), Ancylostoma caninum (A. caninum) and conjunct infections of both parasites in dogs and effect of treatment with diminazene aceturate and mebendazole on haematology. Sixteen dogs grouped into 4 of 4 members each were used in the study. Group 1 (GPI) was uninfected (control), GPII was infected with A. caninum, GPIII was infected with T. brucei and GPIV was infected with conjunct infections of T. brucei / A. caninum. Post acclimatization, GPII and GPIV were infected with A. caninum, 2 weeks after GPIII and GPIV were infected with T. brucei. By week 6 post infection, GPII and GPIV were treated with 100 mg of mebendazole given twice daily for 3 days and a repeat given 2 weeks later. GPIII and GPIV were also treated with diminazene aceturate at 7 mg/kg once. Treatment was repeated at week 8 and 9 of the experiment. There was a significant (p < 0.05) decreases in pack cell volume (PCV), haemoglobin concentration (Hb), red blood cell count (RBC) in all the experimental groups (GPII, GPIII and GPIV). The decreases were more in the conjunct group (GPIV) compared to the others. A significant (p < 0.05) decrease in white blood cell (WBC) count was recorded in all the experimental groups (GPII, GPIII and GPIV). It was reflected in significant (p <0.05) decreases in lymphocytes, neutrophil, monocyte, basophil counts in T. brucei infected group. Conversely there were significant (p <0.05) increases in neutrophil, eosinophil, monocyte and basophil count but a decrease in lymphocyte count in A. caninum group. The haematological alterations were more in T. brucie group compared to the A. caninum group. Similarly the effect was more in the conjunct T. brucei /A. caninum group compared to the single T. brucei. Treatment with 7 mg/kg diminazene aceturate and 100 mg mebendazole given once daily for 3 days caused some improvement in haematology. These findings would enhance clinicians’ knowledge of the effect of single and mixed infections of T. brucei and A. caninum in dogs.

Symptoms and Response to Treatment with Diminazene Aceturate and Mebendazole in Dogs Infected with Single Trypanosoma congolense, Ancylostoma caninum and Combination of Trypanosoma congolense and Ancylostoma caninum.

The economic losses associated with diseases caused by Trypanosoma congolense and the devastating effect of Ancylostoma caninum (A. caninum) in dogs’ necessitated the present study. Sixteen dogs grouped into 4 of 4 members each were used in the study. GROUP I was uninfected dogs (control), GROUP II was infected with Trypanosoma congolense (T. congolense) infection, GROUP III was mixed infections of Trypanosoma congolense and Ancylostoma caninum (T. congolense /A. caninum) and GPIV was infected with Ancylostoma caninum. At first Ancylostoma caninum infection was done on GPIII and GPIV. Two weeks later T. congolense infections was done on GPII and superimposed on GPIII. Three weeks post trypanosome infection; GPII and GPIII were treated with diminazene aceturate. Mebendazole was used on GPIII and GPIV and treatment repeated 2 weeks later. The prepatent period of T. congolense infection was 14.00±1.40 days in single infection and 9.00±1.10 days in conjunct infection of T. congolense and A. caninum. Persistent parasitaemia resulted in repeated treatment with diminazene aceturate at 7 mg/kg and mebendazole at 100mg twice daily for 3 days. The predominant signs revealed include; lethargy, vomition, enlargement of popliteal lymphnodes, pyrexia, oedema of fore and hind limbs and ocular discharges, anaemia, and slight emaciation. The symptoms were more severe in GPIII compared to GPII and GPIV. The egg per gram of faeces (EPG) in (GPIV) was significantly higher than the conjunct infection (GPIII). Treatment only slightly improved clinical manifestations. In conclusion, conjunct infections of T. congolense / A. caninum would result to more severe disease condition than in single infection of either disease in dogs. The severity of symptoms of the diseases were more in conjunct T. congolense / A. caninum as evidenced by high mortality compared with the single infections. Therefore symptoms of the diseases could serve as a surrogate diagnostic tool in diagnosis and vigorous treatment of infected dogs.

Clinical Effects of Mixed Infection of Trypanosomes and Ancylostoma caninum in Dogs and Treatment with Diminazene and Mebendazole (Nigeria).

The socio-economic importance of trypanosomosis and ancylostomosis in both humans and animal necessitated the investigation of the clinical signs of single and conjunct infection of both parasites in dogs. Sixteen dogs grouped into 4 of 4 members each were used in the study. GROUP I was uninfected dogs (control), GROUP II was infected with Ancylostoma caninum GROUP III was infected with Trypanosoma brucei (T. brucei), GROUP IV was mixed infections of Trypanosoma brucei and Ancylostoma caninum (T. brucei/A. caninum). Post acclimatization, Ancylostoma caninum infection was done on GPII and GPIV. Two weeks later Trypanosoma brucei infections was done on GPIII and superimposed on GPIV. Three weeks post trypanosome infection; GPIII and GPIV were treated with 7 mg/kg diminazene aceturate (Veribin®, CEVA Sante Animale- La Ballasteiére 33501 Libourne Cedex, France) x intramuscularly x once. Mebendazole (Vermin®, Janssen-Cilag Ltd 50 - 100 Holmers Farm Way, High Wycombe, Bucks, HP12 4EG UK) at 100 mg x per os twice daily for 3 days was used only on GPII and GPIV and a repeat treatment given 2 weeks later. Prepatent period of T. brucei infection was 5.00±1.30 days in single infection and 3.00±1.40 days in conjunct infection of T. brucei and A. caninum. Persistent parasitaemia resulted in repeated treatment with diminazene aceturate at 7 mg/kg and mebendazole at 100 mg twice daily for 3 days. The predominant signs revealed include; fluctuation in weight, lethargy, vomition, enlargement of popliteal lymphnodes, pyrexia, oedema of lower jaw and ocular discharges, enlarged abdomen, anaemia, cornea opacity and slight emaciation. The clinical signs were most severe in GPIV compared to GPIII. The egg per gram of faeces (EPG) in GPII was significantly higher than the mixed infection (GPIV). Treatment only slightly improved clinical manifestations. In conclusion, most signs shown were consistent with trypanosomosis in dogs except abdominal enlargement which is a complication of A. caninum. Clinical signs therefore could serve as a diagnostic tool in the treatment of both conditions in dogs.

Efficacy of nitazoxanide against toxocara canis: larval recovery and humoral immune response in experimentally infected mice / Eficácia da nitazoxanida contra Toxocara canis: recuperação larvária e resposta imune humoral em camundongos experimentalmente infectados

SUMMARYThe efficacy of nitazoxanide (NTZ) against toxocariasis was investigated in an experimental murine model and results were compared to those obtained using mebendazole. Sixty male BALB/c mice, aged six to eight weeks-old, were divided into groups of 10 each; fifty were orally infected with 300 larvaed eggs of T. canisand grouped as follows, G I: infected untreated mice; G II: infected mice treated with MBZ (15 mg/kg/day) 10 days postinfection (dpi); G III: infected mice treated with NTZ (20 mg/kg/day) 10 dpi; G IV: infected mice treated with MBZ 60 dpi; G V: infected mice treated with NTZ 60 dpi; GVI: control group comprising uninfected mice. Mice were bled via retro-orbital plexus on four occasions between 30 and 120 dpi. Sera were processed using the ELISA technique to detect IgG anti- Toxocaraantibodies. At 120 dpi, mice were sacrificed for larval recovery in the CNS, liver, lungs, kidneys, eyes and carcass. Results showed similar levels of anti- ToxocaraIgG antibodies among mice infected but not submitted to treatment and groups treated with MBZ or NTZ, 10 and 60 dpi. Larval recovery showed similar values in groups treated with NTZ and MBZ 10 dpi. MBZ showed better efficacy 60 dpi, with a 72.6% reduction in the parasite load compared with NTZ, which showed only 46.5% reduction. We conclude that administration of these anthelmintics did not modify the humoral response in experimental infection by T. canis. No parasitological cure was observed with either drug; however, a greater reduction in parasite load was achieved following treatment with MBZ.

RESUMOFoi investigada a eficácia da nitazoxanida (NTZ) na toxocaríase murina experimental e os resultados comparados com os obtidos usando mebendazol (MBZ). Sessenta camundongos BALB/c machos, com idade entre seis e oito semanas foram divididos em grupos de 10 cada, 50 foram infectados oralmente com 300 ovos larvados de T. canise agrupados a seguir: GI: camundongos infectados não tratados; GII: camundongos infectados tratados com MBZ (15 mg/kg/dia) 10 dias pós-infecção (dpi); GIII: camundongos infectados tratados com NTZ (20 mg/kg/dia) 10 dpi, GIV: camundongos infectados tratados com MBZ 60 dpi; GV: camundongos infectados tratados com NTZ 60 dpi; GVI: controle não infectado. Os camundongos foram sangrados via plexo retro orbitário em quatro ocasiões entre o 30º e 120º dpi. Os soros foram processados pela técnica de ELISA para detecção de anticorpos IgG anti- Toxocara.Aos 120 dpi, os animais foram sacrificados para a recuperação larvária do SNC, fígado, pulmões, rins, olhos e carcaça. Os resultados mostraram níveis similares de anticorpos IgG anti- Toxocaraentre os camundongos infectados mas não submetidos a tratamento e os grupos infectados e tratados com MBZ ou NTZ, aos 10 e 60 dpi. Os valores da recuperação larval foram similares nos grupos tratados com NTZ e MBZ 10 dpi. MBZ mostrou melhor eficácia aos 60 dpi, com redução de 72,6% da carga parasitária comparada com NTZ, que mostrou redução somente de 46,5%. Concluímos que a administração destes anti-helmínticos não modificou a resposta humoral na infecção experimental por T. canis. Não foi observada cura parasitológica com nenhuma das drogas; porém maior redução na carga parasitária foi obtida após o tratamento com MBZ.

Evaluation and study of mebendazole polymorphs present in raw materials and tablets available in the Brazilian pharmaceutical market.

The dissolution of a drug can be compromised by the presence of different polymorphs, which may have different solubilities. Importantly, the pharmacopoeiamonographs,usually not have tests for the characterization of these polymorphic forms of a drug. Was performed a study of polymorphic forms of mebendazole present in raw materials and also pills available in the Brazilian pharmaceutical market through the techniques of infrared (FTIR), differential scanning calorimetry (DSC), dissolution , solubility and X-ray diffraction pattern (XRPD). Through the analysis of FTIR and DSC curves showed that there are three main polymorphic forms of mebendazole present in raw materials and tablets that compound. The data obtained in the dissolution and solubility tests showed that Form A is less soluble than Form B which is less soluble than the C form, when using a dissolution medium without added surfactant. It has been found that in some tablets mebendazole there is a mixture of polymorphic forms, and that the raw materials present two major polymorphic forms. Then it is suggested the need of quality control regarding the type of polymorph used in the production of mebendazole tablets to ensure greater therapeutic efficacy.

Disseminated toxocariasis in an immunocompetent host

Toxocariasis is a zoonotic infection caused by Toxocara canis, or less commonly, Toxocara cati, which is one of the most common zoonotic infections worldwide. It commonly affects the pediatric and immunocompromised population; however, it has rarely been reported in the immunocompetent adults. Two of the well-recognized syndromes in children are visceral larva migrans and ocular larva migrans. Infection in adults usually ranges from asymptomatic to nonspecific symptoms which makes the diagnosis challenging. A case of 36 year-old male was presented with disseminated toxocariasis with pulmonary and hepatic involvement and striking peripheral eosinophilia.

Disseminated toxocariasis in an immunocompetent host

Toxocariasis is a zoonotic infection caused by Toxocara canis, or less commonly, Toxocara cati, which is one of the most common zoonotic infections worldwide. It commonly affects the pediatric and immunocompromised population; however, it has rarely been reported in the immunocompetent adults. Two of the well-recognized syndromes in children are visceral larva migrans and ocular larva migrans. Infection in adults usually ranges from asymptomatic to non-specific symptoms which makes the diagnosis challenging. A case of 36 year-old male was presented with disseminated toxocariasis with pulmonary and hepatic involvement and striking peripheral eosinophilia.

Evaluación de la eficacia de drogas antihelmínticas para el control de Trichuris trichiura y otras helmintiasis en el estado Aragua, Venezuela / Evaluation of the efficacy of antihelmintic drugs for the control of Trichuris trichiura and other helminthic diseases in the state of Aragua, Venezuela

Un ensayo clínico de cuatro brazos fue llevado a cabo en 14 comunidades del estado Aragua para evaluar cuatro esquemas de tratamientos antihelmínticos para geohelmintos: Mebendazol y albendazol como monoterapias y cada una de estas drogas en combinación con ivermectina como terapias combinadas. Los tratamientos fueron administrados posteriormente a un examen coproparsitoscópico inicial, con reevaluaciones a los 7 y 21 días. Quedó en evidencia que las tasas de curación observadas a los 7 días posteriores al tratamiento, a favor de los esquemas combinados, particularmente la combinación albendazol + ivermectina (χ2 = 10,85; P < 0,0009), pero no se reflejaron a los 21 días después de la administración de los tratamientos y ningún esquema demostró una eficacia superior. Trichuris trichiura aún responde satisfactoriamente a los tratamientos convencionales. A pesar de la similitud en la eficacia de las monoterapias y terapias combinadas, el porcentaje de pacientes curados con T. trichiura solo o con infecciones mixtas fue elevada (> 93%). Las uncinarias fueron curadas en 100% (cero huevos en heces), seguido de A. lumbricoides (98,2%) y las infecciones mixtas de T. trichiura + A. lumbricoides + uncinarias (100%). La reducción porcentual de huevos por gramo de heces fue de 100% para las uncinarias, 89,3% para A. lumbricoides y 81,7% para T. trichiura. Las tasas de fracasos fueron bajas para los cuatro esquemas terapéuticos: mebendazol (5,14%), albendazol (6,20%), albendazol + ivermectina (2,02%) y mebendazol + ivermectina (2,22%). El grupo de edad de 0 a 9 años registró el mayor número de fracasos terapéuticos (n = 13). Quizás convendría emplear esquemas combinados en casos de fracasos terapéuticos. Pero, surge la duda si se está evidenciando la posibilidad de resistencia a estos medicamentos, dado que la mayoría de los fracasos terapéuticos se observaron en pacientes con bajas cargas parasitarias que bien podrían revertirse en el tiempo.

A four-arm clinical trial was carried out in 14 communities in the State of Aragua to evaluate four antihelminthics treatments, as monotherapy and combined treatments for soil-transmitted helminthiasis: Mebendazole, albendazole and each of these drugs in combination with ivermectin. Treatments were given after an initial stool specimens were obtained for examination, with two sequential stool reevaluations on days 7 and 21. Cure rates (zero eggs in stools) at day 7 after treatments were favourable for combined treatments, specially albendazole + ivermectin (χ2 = 10.85; P < 0.0009), which was not reflected by day 21 since no treatment showed any superior efficacy. Trichuris trichiura still responds satisfactorily to conventional treatments offered by the national Programme for the Fight against Anclyostomiasis and other Intestinal Parasites. Notwithstanding the similarities of monotherapy and combined treatments efficacy, the percentage of patients cured with T. trichiura solely or with mixed infections was high (> 93%). Hookworm infections were cured a 100% (zero eggs found in feces), followed by A. lumbricoides (98.2%) and mixed infections by T. trichiura + A. lumbricoides + hookworms (100%). However, the mean egg reduction percent was also a 100% for hookworms, 89.3% for A. lumbricoides and 81.7% for T. trichiura. The rates of treatment failure were limited, albendazole 6.20%, mebendazole 5.14%, for the combination of albendazole + ivermectin 2.02% and for mebendazole + ivermectine 2.22%. The majority of treatment failures were seen in the 0-9 age group. It is perhaps convenient to use combined schemes in cases of treatment failure. But, there is doubt as to whether there is the possibility of resistance to these drugs given that the majority of treatment failures observed in patients with low intensity infections which might be subdued in time.

Development and validation of a microbial counting method for mebendazole oral suspension / Desenvolvimento e validação de um método de contagem microbiana para o mebendazol suspensão oral

Mebendazole is an important medicine used to treat helminth infections. These infections affect more than two billion people worldwide. The LAFEPE® (Recife-PE, Brazil) produces the drug mebendazole oral suspension that contains the preservatives methylparaben and propylparaben in its formulation. Drugs that have antimicrobial properties due to preservatives must undergo neutralization of these compounds to allow microbial count testing according to recommendations by the official compendia. In order to obtain a validated method for microbial counting and to ensure its safety and reliability within the pharmaceutical industry, validation of preservative neutralization and of the method for microbial counting was performed according to the USP 30 and PDA Technical Report No. 33. The method used ATCC Gram positive and Gram negative microorganisms, yeasts, most and culture media Tryptic Soy Agar and Sabouraud dextrose agar. The neutralizers were polysorbate 80 and lecithin. Recovery levels of over 70 percent of the microorganisms used in the test indicated the neutralization of antimicrobial activity and proved the absence of toxicity of neutralizers. The microbial counting method validated proved accurate, precise, robust and linear and can be safely used in routine operations.

O mebendazol é um importante medicamento utilizado no tratamento de infecções por helmintos. Essas infecções afetam mais de dois bilhões de pessoas em todo o mundo. O LAFEPE (Recife-PE, Brasil) produz o medicamento mebendazol suspensão oral, que possui em sua formulação os conservantes metilparabeno e propilparabeno. Em medicamentos que possuem propriedades antimicrobianas em decorrência dos conservantes faz-se necessária a neutralização da ação desses compostos para a realização do teste de contagem microbiana segundo preconizado pelos compêndios oficiais. A fim de obter um método de contagem microbiana validado e que garanta sua segurança e reprodutibilidade dentro da indústria farmacêutica foi realizada a validação da neutralização dos antimicrobianos e validação do método de contagem microbiana de acordo com a USP 30 e PDA-Technical Report N° 33. O método desenvolvido utilizou microrganismos ATCC Gram positivos, Gram negativos, leveduras e fungos e meios de cultura Tryptic Soy Agar e Sabouraud-dextrose Agar. Os neutralizantes foram polissorbato 80 e lecitina de soja . Níveis de recuperação superiores a 70 por cento dos microrganismos utilizados no ensaio indicaram neutralização da atividade antimicrobiana e comprovou a ausência de toxicidade dos neutralizantes. O método de contagem microbiana validado revelou-se exato, preciso, robusto e linear podendo ser utilizado com segurança na rotina operacional.

Recent Advances in the Use of Anthelmintics for Treating Nematode Infections

The recent trends of parasitic infections in Korea include remarkable decreases of soil-transmitted nematode infections and elimination of lymphatic filariasis. In comparison, enterobiasis (pinworm infection) continues to be prevalent among children and the cases of zoonotic tissue-invading nematode infection are slightly increasing or they are being increasingly diagnosed. In addition, imported parasitoses continue to be problems from the clinical and public health points of view. In this review, the advances in the management and anthelmintic treatment of these nematode infections are briefly reviewed. Albendazole, mebendazole, thiabendazole, flubendazole, pyrantel pamoate, pyrvinium pamoate, oxantel pamoate, levamisole, ivermectin, and diethylcarbamazine are the examples of anti-nematode anthelmintics that are currently being used. Although several of these drugs are known to be broad-spectrum anthelmintics, selection of each drug should be done specifically for each nematode infection, and with consideration of the specific conditions of each patient and the purposes, for example, when performing individual or mass treatment. It is hoped that the chemotherapy regimens reviewed here will help physicians to treat their patients infected with nematode parasites.

Analysis of Adverse Reactions Induced by Mebendazole / 药物流行病学杂志

Objective:To review literature reports of varieties of ADRs induced by mebendazole to provide a sci- entific foundation for clinical revaluation of mebendazole.Method:The related literatures in the internal and external medi- cine medical database in 1994-2004 were explored,and then both analysis and statistics were conducted with the methods of epidemiolngy and literature analysis.Result:ADRs induced by mebendazole could be involved in multiple organs.Most victims were children and the elderly.Their latent periods were determined by the types of ADRs,which had a variety of forms.Conclusion:Mebendazole was potentially unsafe.So we should strengthen our rational drug use and post-marketing revaluation of safety.

Assessment of mass deworming by Mebendazole after 3, 6 and 18 months in Quynh Luu, Nghe An province

The study was conducted from September 2003 to April 2005 to assess results of the mass deworming campaign in 5 primary schools in Quynh Luu district, central province of Nghe An. A pre-intervention survey showed a cumulative worm prevalence of 98%, of which the highest rate was Trichuris infection: 85.1% followed by Ascaris: 83.6% and hookworm 30.3%. No difference of infection between females and males was found. Mixed infection was high with 54.3% had co-infection with Ascaris and Trichuris (88%), and 24.8% had triple infection, while a low single infection rate (20.8%) of which Trichuris was predominant, was found. A low prevalence of high intensity of infections was found with Ascaris (6.5%), hookworm (1 %), Trichuris (0.5%) while a high prevalence of low intensity was found with all examined samples. The worm prevalence was found reduced after periodical mass deworming (every six months) with mebendazole 500mg, single dose. The cumulative infection reduced from 98% to 84.5% after six months and 72.2% after 18 months. Similarly, the Ascaris infection came down from 83.6% to 52.7% and 32.7%, the Trichuris from 85.1% to 70.6% and 56.1%. However, hookwonn infection remained nearly unchanged (30.3% to 31.3% and 31.1 %). The high and moderate intensity of infection was also reduced after intervention. The egg counts were reduced by 60% after 6 months, 73% after 18 months (after the third treatment) with Ascaris. Accordingly, it was reduced by 40% and 70%, respectively with Trichuris. No changes were found with hookwonn. The intestinal wonn infection control project supported by WHO has been a successful project in tenn of both technical and social aspects. The project was performed with good compliance of school children, their parents and teachers. Expertise and qualification of the provincial staffs were also enhanced with regard to public health in general, and intestinal worm infection control, in particular.

Research Progress on the Efficacy,Metabolism and Bioavailability of Mebendazole in Hydatid Disease / 中国寄生虫学与寄生虫病杂志

Mebendazole is currently used in the treatment of hydatid disease.Its poor absorption from the gastro-intestinal tract and low bioavailability aroused further research on new formulations of mebendazole to increase the bioa-vailability and improve the therapeutic efficacy.This review summarizes the recent research progress.

COMPARATIVE INVIVO OVICIDAL EFFECT OF ALBENDAZOLE AND MEBENDAZOLE ON HOOKWORM EGGS AND IN THE TREATMENT OF INTESTINAL NEMATODE INFECTIONS / 重庆医科大学学报

Albendazole and mebendazole were comparatively evaluated in 22 adult patients for their in vivo effects on hookworm eggs. Both drugs were given 200mg twice daily for three consecutive days. Stool specimens wore collected before treatment and during the following five days. The Stool egg count was carried out by Stolls method and each specimen was also cultured by Hara-da-Mori technique for at least eight days. The mean pre-treatment percentage of incubated hookworm eggs that developed to larvae was 75.3% in albendazole group and 68.8% in mebendazole group respectively. One day following the initiation of treatment the mean percentage was remarkably reduced to 0.25% in albeadaole group and no eggs developed to larval stage beyond day 1. 0ne day and two days following the initiation of treatment the mean percentage was 16.23% and 23.13% respectively in mebendazole group. No eggs developed to larval stage on day 3 and thereafter. Albendazole seems to have better ovicidal effect than mebendazole.Albendazole and mebendazole were also comparatively evaluated in 123 adult patients with single or mixed infections of hookworm, ascarisis, and trichuris. A single dose of 400mg was used for both drugs. 2 and 4 weeks after treatment, their stools were examined by brine flotation technique. The hookworm eggs negative conversion ratss 2 weeks after treatment were 78.8% and 26.4% respectively in albeadazole and mebendazole group; while those 4 weeks after treatment were 74.1% and 25.5% respectivley. For ascariasis, the eggs negative conversion rates were 98.0% and 92.0% respectively. For trichuriasis, the negative conversion rates were only 20.6% and 27.7% respectively

Efficacy of Mebendazole Composite Cream in Treatment of Trichiniasis in Mice by Skin Administration / 第二军医大学学报

Male mice weighting 25-32g were infected with larvae of Trichinella spiralis. Skin administrations of mebendazole composite cream were carried out on the mice in 3 different experiment groups. It was found that there were the reduction rate of worms at 97.3%, 100% and 99. 7% in the adult worm group (50 mg/kg x 1 d), in the invasive larvae group (25 mg/kg x 7 d) and in the encysted larvae group (25 mg/kg x 7 d), respectively. These results indicate that mebendazole composite cream is very effective against both intestinal and muscular phases of T. spiralis.