Developing natural product drugs: Supply problems and how they have been overcome.

The development of natural product-derived drugs has some unique problems associated with the process, which can be best described as the "problem of supply". In this short review, four examples are given demonstrating how the "supply problem" was overcome using as examples the development of Picato® from a plant, Kyprolis® modified from a microbial metabolite, Halaven® a totally synthetic compound based on a marine sponge metabolite and Yondelis® isolated from a marine tunicate and now known to be from an as yet uncultured microbe in the tunicate. The methods used are described in each case and show how all scientific disciplines are necessary to succeed. All of these are antitumor agents and the time involved ranged from a low of 13years to greater than 29years from the initial identification of an active compound.

High frequency of the 23S rRNA A2058G mutation of Treponema pallidum in Shanghai is associated with a current strategy for the treatment of syphilis.

The preferred drugs for the treatment of syphilis, benzathine and procaine penicillin, have not been available in Shanghai for many years, and currently, the incidence of syphilis is increasing. Alternative antibiotics for patients with syphilis during the benzathine and procaine penicillin shortage include macrolides. The failure of macrolide treatment in syphilis patients has been reported in Shanghai, but the reason for this treatment failure remains unclear. We used polymerase chain reaction technology to detect a 23S rRNA A2058G mutation in Treponema pallidum in 109 specimens from syphilis patients. The use of azithromycin/erythromycin in the syphilis patients and the physicians' prescription habits were also assessed based on two questionnaires regarding the use of macrolides. A total of 104 specimens (95.4%) were positive for the A2058G mutation in both copies of the 23S rRNA gene, indicating macrolide resistance. A questionnaire provided to 122 dermatologists showed that during the penicillin shortage, they prescribed erythromycin and azithromycin for 8.24±13.95% and 3.21±6.37% of their patients, respectively, and in the case of penicillin allergy, erythromycin and azithromycin were prescribed 15.24±22.89% and 7.23±16.60% of the time, respectively. A second questionnaire provided to the syphilis patients showed that 150 (33.7%), 106 (23.8%) and 34 (7.6%) individuals had used azithromycin, erythromycin or both, respectively, although the majority did not use the drugs for syphilis treatment. Our findings suggest that macrolide resistance in Treponema pallidum is widespread in Shanghai. More than half of the syphilis patients had a history of macrolide use for other treatment purposes, which may have led to the high prevalence of macrolide resistance. Physicians in China are advised to not use azithromycin for early syphilis.

Impacto de un modelo integrado para el uso racional de antimicrobianos (proyecto Miura) en una área de salud / Impact of integrated model for rational use of antibiotics in a health area (project MIURA)

Fundamento: MIURA (Modelo Integrado para el Uso Racional de Antimicrobianos) es un proyecto que se inicio en enero de 2004 y finalizó en diciembre de 2006. Mediante intervenciones trimestrales y formativas dirigidas a médicos, farmacéuticos y pacientes, pretendió mejorar el uso de antibióticos en un área de salud. El objetivo ha sido analizar la evolución en el consumo de antibióticos y evaluar la repercusión de la implantación de este proyecto en un área de salud. Método: Se realizó un estudio comparativo sobre la evolución de la dispensación de antibióticos con receta durante los periodos 2000-03 (pre-MIURA), 2004-06 (MIURA) y 2007-08 (post-MIURA) en el Departamento de Salud 11 de la Comunidad Valenciana. La información se obtuvo a través de la aplicación informática GAIA (Generalitat Valenciana) que recoge información sobre los medicamentos facturados por las oficinas de farmacia a través de las recetas oficiales. Como unidad técnica de medida se empleó la DHD (Dosis diaria definida/1.000 Habitantes/Día). Resultados: Durante el periodo de implantación del proyecto (2004 a 2006), se detectó un descenso global de 4,02 DHD en el consumo de antibióticos, lo que representa una reducción global y significativa del 15% (p<0.05). Durante el periodo del MIURA se observó una disminución estadísticamente significativa en los valores de DHD para los grupos terapéuticos de macrólidos (especialmente claritromicina) y de cefalosporinas; también se detectó una disminución, aunque no significativa, para el grupo de las quinolonas, mientras que los grupos correspondientes a las penicilinas y a otros antibióticos no presentaron cambios. En el periodo post-MIURA se detectó un nuevo incremento en la dispensación de los antibióticos. Conclusiones: El programa MIURA ha influido positivamente en la disminución de la prescripción de antibióticos en nuestra área de salud, como demuestra el descenso en DHD durante el periodo de intervenciones(AU)

Background: MIURA (Integrated Model for the Rational Use of Antimicrobials) is a project that began in January 2004 and ended in December 2006. Through quarterly and training interventions intented for physicians, pharmacists and patients, pretends to improve antibiotic use in a health area. The goal was to analyze the evolution of antibiotic consumption and assess the impact of implementing this project in a health area. Method: A comparative study on the evolution of antibiotic dispensed during the periods 2000-03 (pre-MIURA), 2004-06 (MIURA) and 2007-08 (post-MIURA) in the Department of Health 11 of Valencia was conduced. Antibiotics information was obtained through the GAIA application (Generalitat Valenciana) that collects information about the drugs billed by the pharmacy through the official prescriptions. Technical unit of measurement was used DHD (daily dose defined/1.000 inhabitants / day). Results: During the implementation of the project (2004-2006), antibiotic consumption was reduced in 4.02 DHD. It represents a statistically significant overall reduction from 15% (p= <0.05). Since interventions started, a statistically significant decrease in DHD values was observed for macrolides (especially clarithromycin) and cephalosporines. It also exist an average decrease, not significant, for the group of quinolones, whereas penicillins and other antibiotics haven’t showed variability in the consumption data. In the post-MIURA period was detected a further increase in the dispensing of antibiotics. Conclusions: MIURA program has positively influenced on decreasing antibiotic prescription in our health area, as shows the decrease in DHD during the interventions(AU)

An assessment of antimicrobial consumption in food producing animals in Kenya.

Antimicrobial agents are useful for control of bacterial infections in food animals and man. Their prudent use in these animals is important to control any possible development and transfer of resistance between animals and man. The objective of this study was to generate quantitative information to evaluate antimicrobial usage patterns by animal species, route of administration, antimicrobial class and type of use from 1995 to 1999 in Kenya. Theses data are essential for risk analysis and planning and can be helpful in interpreting resistance surveillance data, and evaluating the effectiveness of prudent use efforts and antimicrobial resistance mitigation strategies. Data on quantities of active substance classes were collected from the official records of the Pharmacy and Poisons Board of the Ministry of Health and analysed in MS Excel 2000 program. The mean antimicrobial consumption for the 5-year period was 14 594 +/- 1457 kg per year. This was distributed in the various antimicrobial classes as follows: 7975 kg (54.65%) of tetracyclines, 3103.96 kg (21.27%) of sulfonamides and 954.5 kg (6.56%) of aminoglycosides, 905 kg (6.20%) of beta-lactams, 94 kg (0.64%) of quinolones, 35 kg (0.24%) of macrolides and 24 kg (0.16%) of others (tiamulin). Mean consumption per year among the various food animals was: 10 989 +/- 357 kg in large animals (cattle, sheep, pigs and goats), 2906 +/- 127 kg in poultry alone and 699 +/- 427 kg in both large animals and poultry. These quantities represented 56.56% (8255 kg) consumption per year for parenteral use, 41.79% (6098 kg) for oral use and 1.65% (241 kg) for topical use (intramammary and eye ointments) in cattle. With respect to intended use in food producing animals, the mean consumption per year was: 13 178 kg (90.30%) for therapeutic use (ST), 4 kg (0.03%) for prophylactic treatment (PT) and 1411 +/- 246 kg (9.67%) was used both for therapeutic and prophylactic purposes (GPT). The study confirmed that antimicrobials are not used for growth promotion in Kenya. There was no specific trend in the quantities of active antimicrobial classes. This study has revealed that the tetracyclines, sulfonamides and trimethoprim, nitrofurans aminoglycosides, beta-lactams and the quinolones are the most commonly used drugs in food-producing animals in Kenya. Tetracyclines contributed approximately 55% of the total consumption, and there was an increasing trend in the consumption of quinolones from 1998.