Prospective Risk Assessment of Medicine Shortages in Europe and Israel: Findings and Implications.

INTRODUCTION: While medicine shortages are complex, their mitigation is more of a challenge. Prospective risk assessment as a means to mitigate possible shortages, has yet to be applied equally across healthcare settings. The aims of this study have been to: 1) gain insight into risk-prevention against possible medicine shortages among healthcare experts; 2) review existing strategies for minimizing patient-health risks through applied risk assessment; and 3) learn from experiences related to application in practice. METHODOLOGY: A semi-structured questionnaire focusing on medicine shortages was distributed electronically to members of the European Cooperation in Science and Technology (COST) Action 15105 (28 member countries) and to hospital pharmacists of the European Association of Hospital Pharmacists (EAHP) (including associated healthcare professionals). Their answers were subjected to both qualitative and quantitative analysis (Microsoft Office Excel 2010 and IBM SPSS Statistics®) with descriptive statistics based on the distribution of responses. Their proportional difference was tested by the chi-square test and Fisher's exact test for independence. Differences in the observed ordinal variables were tested by the Mann-Whitney or Kruskal-Wallis test. The qualitative data were tabulated and recombined with the quantitative data to observe, uncover and interpret meanings and patterns. RESULTS: The participants (61.7%) are aware of the use of risk assessment procedures as a coping strategy for medicine shortages, and named the particular risk assessment procedure they are familiar with failure mode and effect analysis (FMEA) (26.4%), root cause analysis (RCA) (23.5%), the healthcare FMEA (HFMEA) (14.7%), and the hazard analysis and critical control point (HACCP) (14.7%). Only 29.4% report risk assessment as integrated into mitigation strategy protocols. Risk assessment is typically conducted within multidisciplinary teams (35.3%). Whereas 14.7% participants were aware of legislation stipulating risk assessment implementation in shortages, 88.2% claimed not to have reported their findings to their respective official institutions. 85.3% consider risk assessment a useful mitigation strategy. CONCLUSION: The study indicates a lack of systematically organized tools used to prospectively analyze clinical as well as operationalized risk stemming from medicine shortages in healthcare. There is also a lack of legal instruments and sufficient data confirming the necessity and usefulness of risk assessment in mitigating medicine shortages in Europe.

Maternal education, health profession and cigarette smoking are decisive factors for self-medication in children by parents.

Self-medication of children by their parents (SMCP) is an important public health issue as the effects and potential risks may be unpredictable. The objective of this first national Montenegrin study was to assess the prevalence of and factors influencing SMCP among schoolchildren. Data were obtained from a national representative sample of 4496 schoolchildren aged 7-13 years (50.4 % boys). Parents/caregivers completed a questionnaire concerning their demographic characteristics, socio-economic and cultural status, as well as the self-medication (SM) of their children. The association between SMCP and parents' socio-economic, demographic or cultural status was assessed by logistic regression analyses. The prevalence rate of SMCP was 24.6 %. Univariate logistic regression showed that maternal socio-demographic characteristics (educational level, employment status, health care profession and smoking habits) were relevant for SMCP. In a multiple logistic regression the independent effect /adjusted odds ratio (AOR) (95 % CI)/of maternal factors on SMCP remained for: education /2.23 (1.18-4.24)/, university-level vs. no education; profession /1.50 (1.07-3.00)/, health profession vs. non-health profession; and smoking habit /1.22 (1.04-1.42)/smokers vs. non-smokers. SMCP may be expected for every fourth child in Montenegro. Specific maternal factors that independently raise the probability of SMCP are higher education, health profession and smoking.

Kidney, skeletal muscle and myocardium as potential target sites of Pygeum africanum toxicity in Wistar rats / Riñón, musculoesquelético y miocardio como posibles lugares diana de los efectos tóxicos de Pygeum africanum en las ratas de raza Wistar

Objective: Extract of Pygeum africanum (PAE) is commonly used herbal medication in the treatment of benign prostatic hyperplasia. In Montenegro and neighboring countries, PAE is primarily advertised as dietary supplement in the treatment of erectile dysfunction. The purpose of this study was to broaden the current cognition concerning its safety profile. Material and methods: Twenty-four adult male Wistar rats were used. The first control group (O) received water and second control group (OO) received olive oil for 30 days. The third and fourth groups (PA5 and PA10) were treated with PAE dissolved in olive oil (50 and 100mg/kg p.o. daily). The behavior of animals was observed continuously, bodyweight gain (BWG) was calculated weekly and the weight of selected organs was measured at the end of experiment. Total protein and glutathione content of the liver were analyzed. Standard biochemical analyses were also performed. Results: BWG was higher in PA5 compared to both controls at all measuring intervals. Liver weight/body weight ratio was significantly higher in PA10 in comparison with O. Prostate weight/body weight ratio was lower in both PA5 and PA10 compared to OO, achieving statistical significance in PA5. The value of creatinine was higher in PA5 and PA10 compared to both control groups, but achieving statistical significance in PA10 only. LDH was also increased in PA5 and PA10 compared to both controls. Conclusions: Both dosage regimens of PAE, particularly PA10, caused some toxicological effects in Wistar rats after one month of application. Kidney, skeletal muscle and/or myocardium are suspected as target sites of PA toxicity most likely. In order to provide more reliable conclusion it is necessary to conduct an additional research on the basis of these findings

Objetivo: El extracto de Pygeum africanum (PAE) es un producto de origen vegetal que frecuentemente se utiliza en el tratamiento de la hiperplasia benigna de próstata. En Montenegro y en los países limítrofes, el PAE se anuncia principalmente como suplemento dietético en el tratamiento de la disfunción eréctil. El propósito de este estudio fue ampliar el conocimiento actual respecto a su perfil de seguridad. Material y métodos: Se utilizaron 24 ratas macho adultas de raza Wistar. El primer grupo de control (O) recibió agua y el segundo grupo de control (OO) recibió aceite de oliva durante 30 días. El tercer y cuarto grupos (PA5 y PA10) se trataron con PAE disuelto en aceite de oliva (50 y 100mg/kg vo diariamente). Se observó continuamente el comportamiento de los animales, semanalmente se calculó el incremento del peso corporal (IPC), y el peso de los órganos seleccionados se midió al final del experimento. Se analizaron el contenido total de proteína y glutatión del hígado. También se realizaron análisis bioquímicos habituales. Resultados: El IPC fue mayor en PA5 que en los 2 grupos control en todos los intervalos de medición. La relación entre peso del hígado y peso corporal fue considerablemente mayor en PA10 que en O. La relación entre peso de la próstata y peso corporal de la próstata fue menor tanto en PA5 como en PA10 en comparación con OO, por lo que se obtuvo significación estadística en PA5. El valor de la creatinina fue más elevado en PA5 y PA10 en comparación con ambos grupos de control, pero alcanzó significación estadística solo en PA10. La LDH también se incrementó en PA5 y PA10 en comparación con los 2 grupos control. Conclusiones: Las 2 pautas de dosificación de PAE, sobre todo en PA10, provocaron algunos efectos toxicológicos en ratas de raza Wistar después de un mes de aplicación. Se sospecha que muy probablemente el riñón, el musculoesquelético o el miocardio sean lugares diana de los efectos tóxicos de PAE. Para ofrecer una conclusión más fiable, es necesario llevar a cabo más investigación sobre la base de estos hallazgos

Kidney, skeletal muscle and myocardium as potential target sites of Pygeum africanum toxicity in Wistar rats.

OBJECTIVE: Extract of Pygeum africanum (PAE) is commonly used herbal medication in the treatment of benign prostatic hyperplasia. In Montenegro and neighboring countries, PAE is primarily advertised as dietary supplement in the treatment of erectile dysfunction. The purpose of this study was to broaden the current cognition concerning its safety profile. MATERIAL AND METHODS: Twenty-four adult male Wistar rats were used. The first control group (O) received water and second control group (OO) received olive oil for 30 days. The third and fourth groups (PA5 and PA10) were treated with PAE dissolved in olive oil (50 and 100mg/kg p.o. daily). The behavior of animals was observed continuously, bodyweight gain (BWG) was calculated weekly and the weight of selected organs was measured at the end of experiment. Total protein and glutathione content of the liver were analyzed. Standard biochemical analyses were also performed. RESULTS: BWG was higher in PA5 compared to both controls at all measuring intervals. Liver weight/body weight ratio was significantly higher in PA10 in comparison with O. Prostate weight/body weight ratio was lower in both PA5 and PA10 compared to OO, achieving statistical significance in PA5. The value of creatinine was higher in PA5 and PA10 compared to both control groups, but achieving statistical significance in PA10 only. LDH was also increased in PA5 and PA10 compared to both controls. CONCLUSIONS: Both dosage regimens of PAE, particularly PA10, caused some toxicological effects in Wistar rats after one month of application. Kidney, skeletal muscle and/or myocardium are suspected as target sites of PA toxicity most likely. In order to provide more reliable conclusion it is necessary to conduct an additional research on the basis of these findings.

The association between pro-arrhythmic agents and aortic stenosis in young adults: is it sufficient to clarify the sudden unexpected deaths?

Most young patients with mild-to-moderate aortic stenosis show no symptoms, and sudden death appears only occasionally. We hypothesised that malignant ventricular arrhythmias could be responsible for the high incidence of sudden death in such patients. If multiple factors such as asymptomatic aortic stenosis in association with arrhythmia-provoking agents are involved, could it be sufficient to account for sudden unexpected death? In this study, eight cases of sudden death in young adults, with ages ranging from 22 to 36 years, who had never reported any symptoms that could be related to aortic stenosis, were investigated. Full autopsies were performed, and congenital aortic stenosis in all eight cases was confirmed. DNA testing for channelopathies was negative. Comprehensive toxicological analyses found an electrolyte imbalance, or non-toxic concentrations of amitriptyline, terfenadine, caffeine, and ethanol. Collectively, these results suggest that congenital asymptomatic aortic stenosis without cardiac hypertrophy in young adults is not sufficient to cause sudden death merely on its own; rather, an additional provoking factor is necessary. According to our findings, the provoking factor may be a state of physical or emotional stress, a state of electrolyte imbalance, or even taking a therapeutic dose of a particular drug.

Systemic Measures and Legislative and Organizational Frameworks Aimed at Preventing or Mitigating Drug Shortages in 28 European and Western Asian Countries.

Drug shortages have been identified as a public health problem in an increasing number of countries. This can negatively impact on the quality and efficiency of patient care, as well as contribute to increases in the cost of treatment and the workload of health care providers. Shortages also raise ethical and political issues. The scientific evidence on drug shortages is still scarce, but many lessons can be drawn from cross-country analyses. The objective of this study was to characterize, compare, and evaluate the current systemic measures and legislative and organizational frameworks aimed at preventing or mitigating drug shortages within health care systems across a range of European and Western Asian countries. The study design was retrospective, cross-sectional, descriptive, and observational. Information was gathered through a survey distributed among senior personnel from ministries of health, state medicines agencies, local health authorities, other health or pharmaceutical pricing and reimbursement authorities, health insurance companies and academic institutions, with knowledge of the pharmaceutical markets in the 28 countries studied. Our study found that formal definitions of drug shortages currently exist in only a few countries. The characteristics of drug shortages, including their assortment, duration, frequency, and dynamics, were found to be variable and sometimes difficult to assess. Numerous information hubs were identified. Providing public access to information on drug shortages to the maximum possible extent is a prerequisite for performing more advanced studies on the problem and identifying solutions. Imposing public service obligations, providing the formal possibility to prescribe unlicensed medicines, and temporary bans on parallel exports are widespread measures. A positive finding of our study was the identification of numerous bottom-up initiatives and organizational frameworks aimed at preventing or mitigating drug shortages. The experiences and lessons drawn from these initiatives should be carefully evaluated, monitored, and presented to a wider international audience for careful appraisal. To be able to find solutions to the problem of drug shortages, there is an urgent need to develop a set of agreed definitions for drug shortages, as well as methodologies for their evaluation and monitoring. This is being progressed.

[Antibiotic prescribing policy of the Republic Health Insurance Fund of Montenegro in the period 2000 - 2004: effects of drug utilization reform strategy].

INTRODUCTION: Monitoring of antibiotic prescribing promotes rational use of these drugs, reduces costs and slows down the progress of resistance. The objective of present study was to analyze the effects of drug utilization reform strategy realized by the Republic Health Insurance Fund of Montenegro, during the period 2000-2004. MATERIAL AND METHODS: This before-after comparative pharmacoepidemiological study comprised a sample of 100% prescription only antibiotics available in public pharmacies during the period 2000 - 2004. The drug use was calculated using ATC/DDD methodology and Wilcoxon's test for matched pairs was used in order to calculate the statistical significance of difference. RESULTS: Antibiotic prescribing was approximately lower by 12% in 2004 in regard to 2000 (12.80 vs. 14.57 DDDs, p > 0.05). The participation of this pharmacotherapeutic group in the total drug dispensing has remained almost equal (approximately 8%). The highest increase in prescribing was established for macrolides (1.05 vs. 1.64 DDDs, 59%); penicillins were also prescribed more frequently (6.41 vs. 6.56 DDDs, 2%), but other subgroups were prescribed less frequently: cephalosporins--(23%) (3.11 vs. 2.43 DDDs) and quinolones--(63%) (1.10 vs. 0.47 DDDs). CONCLUSION: The drug utilization reform strategy showed mostly positive effects on antibiotic prescribing during the period 2000 - 2004. Further educational activities are necessary in order to establish more rational approach to prescribing and utilization of antibiotics.

[The outpatient use of beta lactam antibiotics in Montenegro before the introduction of new reform strategy on drug market].

INTRODUCTION: The study represents the first investigation of outpatient use of beta lactam antibiotics in Montenegro carried out in accordance with internationally approved methodology (DDD/ATC). OBJECTIVE: The objective of our study was to establish both the scope and overall use of beta lactam antibiotics, and to assess their compatibility with current pharmacotherapeutic guidelines and their use in developed countries. METHODS: The retrospective pharmaco-epidemiological study comprised a 100%-sample of beta lactams that were used in the period prior to introduction of new reform strategy on drug market. RESULTS: Beta lactam antibiotics (J01C, J01D) were the most frequently applied anti-infectives for systemic use (ATC group J) in 2000 (11.3 DDD/1000 inh./day, 61%). Penicillins (J01C) were the most utilized (8.0 DDD/1000 inh./day, 71%). Cephalosporin derivatives (cephalexin and cefaclor) accounted for the remaining 29% (3.3 DDD/1000 inh./day). Aminopenicillins were prevailing among penicillins (85%). Beta lactamase sensitive penicillins were in the second place and approximately accounted for 14%. CONCLUSION: The results of our study showed that the use of beta lactam antibacterials could be estimated as partially satisfactory. There is a need to make additional efforts with a view of further rationalization.

[Did a reform strategy in drug management improve doctors' prescribing habits in Montenegro: the example for the cardiovascular drugs].

BACKGROUND/AIM: A comprehensive reform strategy in drug management has been applying for a few years in Montenegro in order to promote a rational use of drugs. The reform strategy covered: an information system named "The Control of Distribution and Use of Drugs", a new List of Essential Drugs (that are reimbursed by the Republic Fund for Health), legislative and regulatory measures in order to establish a better control of drug prescribing and more efficient processing of the prescriptions. The aim of this study was to evaluate the effects of the reform strategy on the doctors' prescribing habits and the subsequent use of cardiovascular drugs within the outpatient setting of Montenegro. METHODS: A retrospective-prospective pharmacoepidemiologic study included a sample of 100% of cardiovascular drugs that were taken with prescription from state pharmacies during 2000 and 2004. The results were presented by the number of defined daily doses (DDD) per 1000 inhabitants per day. All the drugs were classified according to the uniform anatomical-therapeutic-chemical (ATC) classification of the drugs. The Wilcoxon test for matched pairs was used in order to calculate the significance of difference in cardiovascular drugs utilization before and after the introduction of new measures. RESULTS: Although prescribing and the resulting outpatient use of cardiovascular drugs (ATC group C) that were reimbursed by the Republic Fund for Health was increased approximately by 13% in 2004 in comparison with 2000 (67.98 vs. 60.17 DDD/1000 inh./day), we did not find a statistically significant difference (p > 0.05). Prescribing of ACE inhibitors (C09A) increased approximately by 45% during the investigated period (15.30 vs. 22.17 DDD/1000 inh./day). The selection of drugs was also altered: cilazapril, ramipril and quinapril were left out, captopril and enalapril were more prescribed, and a newly-induded fosinopril was prescribed mostly (31.5%). Calcium-channel blockers (C08) were prescribed 33.7% more (7.12 vs. 9.52 DDD/1000 inh./day), mostly because of seven times higher prescribing of amlodipine in 2004. Pentaerythritol tetranitrate was left out, but isosorbide dinitrate and isosorbide mononitrate were prescribed more frequently. High-priced atorvastatin was replaced with the older simvastatin, that was prescribed three times more. CONCLUSION: The reform strategy in drug management mostly improved the doctors' prescribing habits and the subsequent use of cardiovascular drugs within the outpatient setting. For the most part, the noticed changes were in accordance with the actual recommendations, but some cases need additional measures. Regulatory policy, however, could not compensate for the continual education of doctors that prescribe drugs.