Stability of Olmesartan Medoxomil Extemporaneous Suspensions.

Background: Olmesartan medoxomil (OLM) is only available in the United States as tablets. The United States Pharmacopoeia (USP) has placed OLM on its priority list of preparations that require stability data to support practitioner compounding. Objective: The purpose of the study was to develop a stability-indicating assay and then determine the beyond-use date (BUD) for an extemporaneous OLM suspension. Methods: A reverse-phase high-performance liquid chromatography (HPLC) assay was developed and validated according to guidelines for USP official compounded monographs. OLM 2 mg/mL suspensions were compounded with Ora-Sweet and Ora-Plus and stored at room temperature or in a refrigerator. Suspensions were assayed periodically over 90 days for OLM concentration and observed for physical stability. The pH was measured at the beginning and end of the study. Results: The OLM concentration remained above 97% of the starting concentration for 90 days when stored in the refrigerator and above 94% of the starting concentration for 90 days when stored at room temperature. The suspension pH did not change and indicators of physical stability were unchanged for 90 days. Conclusion: OLM 2 mg/mL suspensions were chemically and physically stable at room temperature and in the refrigerator for 90 days. The BUD may be set at 90 days under either storage condition.

Stability and Beyond-Use Date of a Compounded Thioguanine Suspension.

Background: Thioguanine (TG) is available only in the form of 40 mg tablets in the United States, and the patient population in which TG is used comprises mostly children. Recognizing its importance as a therapeutic agent and limited stability data for its compounded preparation, the United States Pharmacopoeia has listed TG in its priority list of compounded preparations monographs. Objective: The goal of the present study was to generate stability data and establish a beyond-use date for compounded TG suspension. Methods: Suspensions were compounded using TG tablets and ORA-Plus and ORA-Sweet as vehicles. A robust high-performance liquid chromatography method was developed and validated. TG and guanine (G) in suspensions were quantified immediately after compounding and at regular intervals for 90 days. Physical stability of suspensions was evaluated by observation of organoleptic properties. Results: Results from the study indicate that average TG levels in suspensions remained above 90% of the starting concentration and G formation was less than 2.5% for 90 days. There was no statistically significant difference in the amount of TG degraded over 90 days between suspensions stored at room temperature and in refrigerated conditions. There was also no statistically significant difference in G concentration of suspensions between day 0 and day 90. Conclusion: TG suspensions are stable for 90 days when stored at room temperature or refrigerated conditions and the beyond-use date can be set to 90 days.

Indole and Indoline Scaffolds in Antimicrobials: Overview, Synthesis and Recent Advances in Antimicrobial Research.

At present, a pandemic of antibiotic-resistant infectious diseases is an evergrowing threat. The need for new antibiotics and ways to combat antibiotic resistance is glaring. This review will focus on two different privileged scaffolds, the indole and the indoline, as useful nuclei for novel antibacterial compounds. The indole, a moiety found in numerous approved drugs for many disease states, has recently been studied for its usefulness as a scaffold for compounds that have activity against antibiotic-resistant bacteria, especially against methicillin-resistant Staphylococcus aureus (MRSA). The indoline is a scaffold with significantly less historical studies and FDA-approved drugs and it has attracted new interest in drug design and development. In recent years, indoline-containing compounds have been shown to have antibacterial activity as well as activity as a resistance- modifying agent (RMA), which act to improve the effectiveness of current antibiotic therapies that have known resistance.

[Educating general practitioners in Latin America: a challenge for universal healthFormação de clínicos gerais na América Latina: um desafio para a saúde universal]. / Formación de médicos generales en América Latina: un reto para la salud universal.

OBJECTIVE: To gather opinions from medical schools regarding the existence of public policies on the health workforce (human resources for health) and whether sufficient public financing and regulatory mechanisms are in place for undergraduate medical education; and to identify areas of opportunity to improve the availability of general practitioners in the Region of the Americas. METHODS: Cross-sectional, descriptive study conducted with 105 medical schools (51 public and 54 private) in 17 countries. A questionnaire with a Likert scale was used to explore three dimensions (political, economic, and regulatory contexts) composed of 4, 2, and 4 variables each, respectively, and validated with the Delphi method. Frequencies of responses to the questions were estimated. A frequency analysis was performed, as well as a bivariate analysis to identify differences between public and private schools, applying the Chi-square test to compare percentages. RESULTS: The political context was considered favorable by 64% of the schools; the economic context, by 37%; and the regulatory context, by 23%. The only significant differences between public and private schools were in the financial resources they administer. CONCLUSIONS: It is necessary to strengthen public policies, public investment, and the regulation of medical education in order to improve the education and availability of general practitioners in the countries of the Region.

OBJETIVO: Conhecer a opinião das faculdades de medicina sobre o volume de políticas públicas e financiamento público e mecanismos reguladores para graduação médica e identificar áreas que possibilitem aumentar o número de clínicos gerais na Região das Américas. MÉTODOS: Estudo transversal descritivo realizado com 105 faculdades de medicina (51 públicas e 54 particulares) em 17 países. Um questionário com uma escala tipo Likert foi usado para explorar três dimensões (contexto político, contexto econômico e regulamentação), contendo 4, 2 e 4 variáveis cada, e foi validado com o método Delphi. As frequências de respostas às perguntas do questionário foram calculadas e analisadas. A fim de identificar diferenças entre as faculdades públicas e particulares, uma análise bivariada com teste qui-quadrado foi realizada para comparar porcentagens. RESULTADOS: O contexto político foi considerado favorável por 64% das faculdades; o contexto econômico por 37%; e a regulamentação por 23%. Apenas foi observada diferença significativa entre as faculdades públicas e particulares na variável recursos financeiros geridos. CONCLUSÕES: É necessário fortalecer as políticas públicas, o investimento público e a regulamentação da educação médica para melhorar a formação e aumentar o número de clínicos gerais nos países da Região.

Formación de médicos generales en América Latina: un reto para la salud universal

[RESUMEN]. Objetivo. Conocer la opinión de las escuelas de medicina sobre la existencia de políticas públicas y la suficiencia de financiamiento público y mecanismos regulatorios para la formación médica de pregrado e identificar áreas que permitan mejorar la disponibilidad de médicos generales en la Región de las Américas. Métodos. Estudio transversal, descriptivo realizado con 105 escuelas de medicina, 51 públicas y 54 privadas, de 17 países. Se utilizó un cuestionario con una escala tipo Likert para explorar tres dimensiones (contextos político, económico y regulatorio) integradas por 4, 2 y 4 variables cada una, respectivamente, y validado con el método Delphi. Se estimaron frecuencias de respuestas a las preguntas del cuestionario. Se realizó un análisis de frecuencias, y para identificar diferencias entre escuelas públicas y privadas se efectuó un análisis bivariante aplicando la prueba de Chi cuadrado para comparar porcentajes. Resultados. El contexto político fue favorable para 64% de las escuelas, el contexto económico, para 37% y la regulación, para 23%. Sólo hubo diferencias significativas entre escuelas públicas y privadas en la variable recursos financieros que ellas administran. Conclusiones. Es necesario fortalecer las políticas públicas, la inversión pública y la regulación de la educación médica, para mejorar la formación y disponibilidad de médicos generales en los países de la Región.

[ABSTRACT]. Objective. To gather opinions from medical schools regarding the existence of public policies on the health workforce (human resources for health) and whether sufficient public financing and regulatory mechanisms are in place for undergraduate medical education; and to identify areas of opportunity to improve the availability of general practitioners in the Region of the Americas. Methods. Cross-sectional, descriptive study conducted with 105 medical schools (51 public and 54 private) in 17 countries. A questionnaire with a Likert scale was used to explore three dimensions (political, economic, and regulatory contexts) composed of 4, 2, and 4 variables each, respectively, and validated with the Delphi method. Frequencies of responses to the questions were estimated. A frequency analysis was performed, as well as a bivariate analysis to identify differences between public and private schools, applying the Chi-square test to compare percentages. Results. The political context was considered favorable by 64% of the schools; the economic context, by 37%; and the regulatory context, by 23%. The only significant differences between public and private schools were in the financial resources they administer. Conclusions. It is necessary to strengthen public policies, public investment, and the regulation of medical education in order to improve the education and availability of general practitioners in the countries of the Region.

[RESUMO]. Objetivo. Conhecer a opinião das faculdades de medicina sobre o volume de políticas públicas e financiamento público e mecanismos reguladores para graduação médica e identificar áreas que possibilitem aumentar o número de clínicos gerais na Região das Américas. Métodos. Estudo transversal descritivo realizado com 105 faculdades de medicina (51 públicas e 54 particulares) em 17 países. Um questionário com uma escala tipo Likert foi usado para explorar três dimensões (contexto político, contexto econômico e regulamentação), contendo 4, 2 e 4 variáveis cada, e foi validado com o método Delphi. As frequências de respostas às perguntas do questionário foram calculadas e analisadas. A fim de identificar diferenças entre as faculdades públicas e particulares, uma análise bivariada com teste qui-quadrado foi realizada para comparar porcentagens. Resultados. O contexto político foi considerado favorável por 64% das faculdades; o contexto econômico por 37%; e a regulamentação por 23%. Apenas foi observada diferença significativa entre as faculdades públicas e particulares na variável recursos financeiros geridos. Conclusões. É necessário fortalecer as políticas públicas, o investimento público e a regulamentação da educação médica para melhorar a formação e aumentar o número de clínicos gerais nos países da Região.

Lead selection of antiparasitic compounds from a focused library of benzenesulfonyl derivatives of heterocycles.

A library of 89 synthetic benzenesulfonyl derivatives of heterocycles with drug-like properties was assayed for in vitro antiparasitic activity and the results were added to our previously reported derivatives for a comprehensive SAR evaluation. Four compounds showed an IC50 between 0.25 and 3µM against Leishmania donovani and low cytotoxicity. Compound G{16} (1-(2,3,5,6-tetramethylphenylsulfonyl)-2-methylindoline), was particularly interesting with an IC50 similar to the reference drug miltefosine. Seven compounds showed an IC50 below 6µM against Trypanosoma cruzi, and three of them (E{3}, E{9} and G{3}) were identified as lead scaffolds for further optimization based on their activity-toxicity profile. Two promising structures (B{15} and G{15}) showed moderate inhibitory activity against Plasmodium falciparum. In general, the presence of a benzenesulfonyl moiety improves the antiparasitic activity of the heterocycles included in this study (with the exception of Trypanosoma brucei rhodesiense), validating the criteria used in the selection of the privileged structures and diversification used to generate this library. SAR analysis showed that the presence of lipophilic and electron withdrawing groups were favorable for the antiparasitic activity.

Qualitative Methods in the Development of a Bilingual and Bicultural Quality of Life Outcomes Measure for Pediatric Patients With Craniofacial Conditions.

INTRODUCTION: Craniofacial surgeons treat patients with diverse craniofacial conditions (CFCs). Yet, little is known about the health-related quality of life (HRQoL) impact of diverse CFCs. Currently, there are no suitable instruments that measure the HRQoL of patients with diverse CFCs from the perspective of children and parents. The objective of this study was to develop the items and support the content validity of a comprehensive patient and parent-reported outcomes measure. METHODS: An iterative process consisting of a systematic literature review, expert opinion and in-depth interviews with patients and parents of patients with diverse CFCs was used. The literature review and expert opinion were used to generate in-depth interview questions. We interviewed 127 subjects: 80 parents of patients ages 0 to 18 years or older and 47 patients ages 7 to 18 years or older. English and Spanish speakers were represented in our sample. The majority of subjects originated from the United States and Mexico (83%). Craniofacial conditions included were cleft lip/palate, craniosynostosis, craniofacial microsomia, microtia, and dermatological conditions. Semistructured interviews were conducted until content saturation was achieved. Line-by-line analysis of interview transcripts identified HRQoL themes. Themes were interpreted and organized into larger domains that represent the conceptual framework of CFC-associated HRQoL. Themes were operationalized into items that represent the HRQoL issues of patients for both parent and patient versions. RESULTS: Six final bilingual and bicultural scales based on the domains derived from the literature review, expert opinion, and in-depth interviews were developed: (1) "Social Impact," (2) "Psychological Function," (3) "Physical Function," (4) "Family Impact," (5) "Appearance," And (6) "Finding Meaning." Some cultural differences were identified: in contrast to children from Mexico and other developing nations, families from the United States did not report public harassment or extremely negative public reactions to patients' CFC. Religion and spirituality were common themes in interviews of Spanish-speaking subjects but less common in interviews of English-speaking subjects. CONCLUSIONS: Qualitative methods involving pediatric patients with diverse CFCs and their parents in the item development process support the content validity for this bilingual and bicultural HRQoL instrument. The items developed in this study will now undergo psychometric testing in national multisite studies for validation.

Survey of Pharmacy Schools' Approaches and Attitudes toward Curricular Integration.

Objective. To identify ways in which curricular integration is addressed in US pharmacy schools, the structure of therapeutics and foundational science courses, and perceptions of the effects current curricular integration methods have on student learning. Methods. An electronic survey was sent to academic leaders representing 131 pharmacy schools in the United States. Frequency data was tabulated and demographic analysis was performed. Results. Respondent data represents 94 schools of pharmacy. Arranging similar content from various disciplines in a course, a skills laboratory and pharmacy practice experiences were the most common methods for achieving curricular integration. More than one half of the schools indicated that foundational sciences were integrated with therapeutics. The most common reported challenge to curricular integration was logistics. Conclusion. Pharmacy education in the United States has evolved in addressing curricular integration in the curricula, which is consistent with changes in accreditation standards. Most pharmacy schools reported a variety of methods for achieving the intent of curricular integration.

New antibacterial germacrene from Verbesina negrensis.

Several health benefits have been attributed to members of the Verbesina genus, including promotion of urinary and gastrointestinal health. Verbesina species are also reported to exhibit antibacterial, antiparasitic, and antioxidant activities. Although members of the Verbesina genus produce various pharmacologically relevant chemicals as secondary metabolites, including eudesmanes, flavonoids, guanidine alkaloids, acetylenic compounds, and germacrenes, the active compounds required for these benefits remain unknown. To investigate potential antimicrobial activities of Verbesina negrensis, crude extracts from plant aerial structures were evaluated. Following chemical fractionation, the chloroformic extract from Verbesina negrensis was subjected to bioassay-guided isolation using disk diffusion assays to determine antimicrobial activity. The active compound was characterized as 6ß-cinnamoyloxy-1ß-hydroxy-10α-metoxy-3-oxo-germacra-4,5Z-ene (1). Fractions containing 1 inhibited both Enterococcus faecalis (ATCC 29 212) and Staphylococcus aureus (ATCC 29213). The MIC for 1 was determined by microbroth dilution assay to be 64 µg/mL for both E. faecalis and S. aureus.

SAR analysis of new dual targeting fluoroquinolones. Implications of the benzenesulfonyl group.

When a benzenesulfonyl moiety (BS) was bound to the N-piperazinyl ring of antibacterial fluoroquinolones (AMFQs) norfloxacin (NOR) or ciprofloxacin (CIP), the resulting benzenesulfonyl-fluoroquinolone (BSFQs) analogs showed an improved in vitro activity against Gram-positive strains. A bioisosterical replacement of the sulfonyl group for a carbonyl group led to the benzenecarboxamide-fluoroquinolones (BCFQs) that showed a similar trend in the antibacterial activity and spectrum. The BSFQs and BCFQs are considered members of the "dual targeting" fluoroquinolones, targeting both DNA gyrase and topoisomerase IV. To disclose the real contribution of the BS/BC moiety in anti-staphylococcal activity, a 3D-QSAR analysis that included calculation of theoretical molecular descriptors and pharmacophore generation was performed. Previous and present QSAR results have confirmed the positive influence on activity of small electron donating p-substituent on the BS or BC moiety. The generated phamacophore model showed that both phenyl and SO2/CO groups are involved in the interaction with receptor. We postulate that the enhanced potency of BSFQs against Staphylococcus aureus compared to CIP and NOR could be caused by the presence of the BS moiety that resulted in enhanced binding to DNA gyrase of Sa. Additionally, their greater ability to enter bacterial cells by diffusion and a reduced susceptibility to FQ-specific efflux pumps could also make a contribution.

A unique binding epitope for salvinorin A, a non-nitrogenous kappa opioid receptor agonist.

Salvinorin A is a potent kappa opioid receptor (KOP) agonist with unique structural and pharmacological properties. This non-nitrogenous ligand lacks nearly all the structural features commonly associated with opioid ligand binding and selectivity. This study explores the structural basis to salvinorin A binding and selectivity using a combination of chimeric and single-point mutant opioid receptors. The experiments were designed based on previous models of salvinorin A that locate the ligand within a pocket formed by transmembrane (TM) II, VI, and VII. More traditional sites of opioid recognition were also explored, including the highly conserved aspartate in TM III (D138) and the KOP selectivity site E297, to determine the role, if any, that these residues play in binding and selectivity. The results indicate that salvinorin A recognizes a cluster of residues in TM II and VII, including Q115, Y119, Y312, Y313, and Y320. Based on the position of these residues within the receptor, and prior study on salvinorin A, a model is proposed that aligns the ligand vertically, between TM II and VII. In this orientation, the ligand spans residues that are spaced one to two turns down the face of the helices within the receptor cavity. The ligand is also in close proximity to EL-2 which, based on chimeric data, is proposed to play an indirect role in salvinorin A binding and selectivity.

Antinociceptive profile of salvinorin A, a structurally unique kappa opioid receptor agonist.

Salvinorin A, is a structurally unique, non-nitrogenous, kappa opioid receptor (KOP) agonist. Given the role of KOPs in analgesic processes, we set out to determine whether salvinorin A has antinociceptive activity in thermal and chemo-nociceptive assays. The tail-flick assay was employed to investigate 1) salvinorin A's (0.5, 1.0, 2.0, and 4.0 mg/kg) dose-response and time-course (10, 20, and 30 min) effects in a thermal nociceptive assay, and 2) the ability for the KOP antagonist norBNI (10.0 mg/kg) to prevent salvinorin A antinociception. The hotplate assay was utilized as a second thermal nociceptive measure to test salvinorin A's dose-response effects. The acetic acid abdominal constriction assay was used to study salvinorin A's dose-response and time-course (over 30 min) effects in a chemo-nociceptive assay. Together, these studies revealed that salvinorin A produces a dose-dependent antinociception that peaked at 10 min post-injection but rapidly returned to baseline. Additionally, pretreatment with the KOP antagonist norbinaltorphimine (norBNI) reversed salvinorin A-induced antinociception. These findings demonstrate that salvinorin A produces a KOP mediated antinociceptive effect with a short duration of action.

Solution-phase parallel synthesis of spirohydantoins.

Spirohydantoins are considered privileged structures, making them attractive for the preparation of compound libraries with the potential for diverse biological activity. However, very few modifications of this scaffold have been reported to date. The spirohydantoin template was elaborated into a library of 168 compounds through a two-step solution-phase parallel synthesis starting from various N-substituted piperidinones. The Strecker reaction was employed to generate alpha-amino nitriles from aniline and TMSCN (or KCN). Subsequent reaction of the anilido nitrogen with a diverse set of isocyanates, followed by refluxing under acidic conditions, afforded the title library in high yield and purity.

Synthesis and complement inhibitory activity of B/C/D-ring analogues of the fungal metabolite 6,7-diformyl-3',4',4a',5',6',7',8',8a'-octahydro-4,6',7'-trihydroxy- 2',5',5',8a'-tetramethylspiro[1'(2'H)-naphthalene-2(3H)-benzofuran].

This paper reports the synthesis and the bioassay of 4-methoxy- and 4-hydroxyspiro[benzofuran-2(3H)-cyclohexane] partial analogues (5) of the complement inhibitory sesquiterpene fungal metabolite 6,7-diformyl-3',4',4a',5',6',7',8',8a'-octahydro-4,6',7'-trihydroxy-2',5',5',8a'-tetramethylspiro[1'(2'H)-naphthalene-2(3H)-benzofuran] (1a, K-76) and its silver oxide oxidized product (1b, K-76COOH). The described target compounds represent spirobenzofuran B/C/D-ring analogues lacking the A-ring component of the prototype structure. The target compounds were evaluated by the inhibition of total hemolytic complement activity in human serum. It was observed that the structurally simplified analogue 4-methoxyspiro[benzofuran-2(3H)-cyclohexane]-6-carboxylic acid (5a) exhibited an IC(50) = 0.53 mM similar to the IC(50) = 0.57 mM that was observed for the natural product derivative 1b. Exhibiting an IC(50) = 0.16 mM, the three-ringed partial structure 6-carboxy-7-formyl-4-methoxyspiro[benzofuran-2(3H)-cyclohexane] (5k)was found to be the most potent target compound. Like the natural product, 5k appears to inhibit primarily at the C5 activation step and inhibits both the classical and alternative human complement pathways. Several other analogues inhibited complement activation in vitro at concentrations similar to those required for inhibition by the natural product 1b.