Valentina Petkova

Metamizole: A Review Profile of a Well-Known “Forgotten” Drug. Part I: Pharmaceutical and Nonclinical Profile

ABSTRACT Metamizole, a nonnarcotic analgesic, has been used to treat pain and fever for almost 90 years in some countries, while in others it is completely unknown or forgotten. It was synthesized by the German company Hoechst AG in 1920, and its mass production started in 1922. Metamizole remained freely available worldwide until the 1970s, when it was found that the drug poses a risk of causing agranulocytosis. Soon after that, metamizole was banned in the United States, Japan, Australia, and part of the European Union. However it is still widely used in some European countries, Turkey, Israel, India, Brazil, and Third World countries. Metamizole is available over-the-counter and remains one of the most popular analgesics in Bulgaria. The objective of this study is to review the pharmaceutical and pharmaco-toxicological aspects of the drug. In Part II, the clinical profile of the drug will be discussed.

Metamizole: A Review Profile of a Well-Known “Forgotten” Drug. Part II: Clinical Profile

ABSTRACT Part I of this review provided the pharmaceutical and non-clinical profile of metamizole, a non-narcotic analgesic with excellent analgesic and antipyretic effects. Metamizole is banned drug in many countries (United States, Japan, Australia, part of the European Union and nearly 30 other countries) for more than 40 years, where it is completely unknown or forgotten, while it is still freely available over-the-counter drug in many other countries, including Bulgaria. The drugs availability in oral and parenteral preparations has allowed its use in a range of clinical situations as monotherapy or in combination. It is known with different generic names, like metamizole, dipyrone, noramidopyrine, sulpyrine, novaminsulfon, methylmelubrin, etc. and marketed under hundreds of brand names worldwide. The objective of Part II of this review is to provide up-to-date scientific evidence for clinical safety and efficacy of the drug, as well as the place of metamizole in Bulgarian pharmaceutical market.

Cost of hospitalizations due to microvascular and macrovascular complications in type 1 and type 2 diabetic patients in Bulgaria

The objective of this study was to evaluate the cost of hospitalizations due to micro- and macrovascular complications in an observed cohort of 433 patients with diabetes. A six-month combined retrospective and prospective observational study was performed. The patients were separated into two groups depending on the type of diabetes and further into subgroups depending on the reason for hospitalization. The total costs for each subgroup were calculated and compared to the total costs of treatment for the observed period. In the type 2 diabetes group (n = 255), there were 128 people with microvascular complications and 215 ones with macrovascular complications, whereas in the type 1 diabetes group, there were only 70 people out of 178 with microvascular complications and 72 ones with macrovascular complications. The total cost of hospitalizations in the type 2 diabetes group was 34 469.76 EUR with the following reported reasons for hospitalizations: poor control of diabetes (45%), microvascular complications (23%) and macrovascular complications (31%). In the type 1 diabetes group, the total hospitalizations cost was equal to 15 319.33 EUR with the following split: 59% due to poor control of diabetes, 22% due to microvascular complications and 19% due to macrovascular complications. Thus, type 2 diabetes is more costly than type 1 when hospitalizations occur. Type 2 diabetes is associated with higher cost of macrovascular complications than of microvascular ones probably due to high hypertension prevalence. Costs are paid by the health insurance fund and the differences need to be systematically revealed.

Comparison of health-related quality-of-life measurement instruments in diabetic patients.

The objective of the study was to compare three different questionnaires (Short Form (SF)-6D, EuroQuol (EQ)-5D and WHO-5) to establish which one is more sensitive and which one gives an adequate assessment of the quality of life in patients with diabetes. In an observational and transversal study with duration of 4 months, in 5 Bulgarian cities, 146 patients were randomly selected. The following quality-of-life measuring instruments were applied: 146 questionnaires SF-6D, 146 questionnaires EQ-5D and 103 questionnaires of WHO-5. Descriptive statistics, chi-Square and correlation coefficients were used for data analysis. The study assessed the quality of life of patients suffering from diabetes mellitus with a mean age of 57.39 years (standard deviation (SD) 17.087); 95% confidence interval (CI) 54.60–60.19; 76% of the patients had diabetes type 2. The patients received a mean SF-6D score of 0.6290, an EQ-5D score of 0.6272, a visual analogue scale score of 0.7158 and a WHO-5 score of 0.4635. Preferences measured by the SF-6D and by the EQ-5D showed significant correlations with one another, and the Pearson coefficient was r = 0.906 (p < 0.01). The most current version of SF-6D, based on the 2002 model, was found to be valid and reliable when compared to the EQ-5D and is a questionnaire alternative to assess preferences in economic analysis carried out in health care.

Clinical characteristics, treatment patterns, and socio-economic burden of COPD in Bulgaria

Abstract Background: While the impact of COPD in Western-Europe is known, data from Eastern-Europe is scarce. This study aimed to evaluate clinical characteristics, treatment patterns, and the socio-economic burden of COPD in Eastern-Europe, taking Bulgaria as a reference case. Methods: A representative sample of Bulgarian patients with COPD was randomly chosen by pulmonologists, based on the following inclusion criteria: COPD diagnosis with at least 1 year of living with COPD, ≥40 years of age, and use of COPD medication. Patient characteristics, treatment, quality-of-life, healthcare resource use, and costs were systematically assessed. Results: A total of 426 COPD patients were enrolled. Approximately 69% were male, 40% had occupational risk factors, 45% had severe and 11% had very severe COPD. Mean CAT scores were 13.80 (GOLD A), 21.80 (GOLD B), 17.35 (GOLD C), and 26.70 (GOLD D). Annual per-patient costs of healthcare utilization were €579. Yearly pharmacotherapy costs were €693. Indirect costs (reduced and lost work productivity) outnumbered direct costs three times. Conclusions: Bulgaria has relatively high percentages of (very) severe COPD patients, resulting in considerable socio-economic burden. High smoking rates, occupational risk factors, air pollution, and a differential health system may be related to this finding. Eastern-European COPD strategies should focus on prevention, risk-factor awareness, and early detection.

Marketing approaches for OTC analgesics in Bulgaria.

The marketing management includes analysis of market opportunities, selection of target markets, planning, developing and implementing of marketing strategies, monitoring and result control. The object of the present study was to analyse the marketing approaches applied for non-steroidal anti-inflammatory drugs (NSAIDs) in Bulgaria. The performed SWOT(planning method used to evaluate the strengths, weaknesses, opportunities, and threats) analysis for one of the leading Bulgarian manufacturers marked the complex corporative strategy for stimulating the sales of NSAIDs. The study results show that the legislation frame in the country gives an opportunity for regulation of the NSAID market in order that incorrect marketing approaches such as disloyal competition are avoided.

Prevalence and Risk Factors for the Development of GD in Some Eastern European Countries – Tendencies and Pharmacoeconomical Assessment for the Choice of Treatment

Diabetes is a metabolic disorder of fat, carbohydrate, and protein metabolism, characterized by resistance to the action of insulin, insufficient insulin secretion, or both. The two major classifications of diabetes mellitus (DM) are type 1 (insulin deficient) and type 2 (combined insulin resistance and relative deficiency in insulin secretion). They differ in clinical presentation, onset, etiology, and progression of disease. Two to five percent of pregnancies are complicated by diabetes, of which 90% are classified as gestational diabetes mellitus (GD) (Satman et al, 2002). GD is defined as glucose intolerance of variable severity which is first recognized during pregnancy, including individuals with previously undiagnosed diabetes as well as those in whom high glucose levels are provoked by pregnancy. This term should not be used for gravid women with previously diagnosed diabetes. GD has much in common with type 2 diabetes with similar genetic susceptibility, corresponding prevalence within a given population or ethnic group and similar risk factors. Both conditions can be considered as a mixture of insulin resistance (IR) and impaired insulin secretion. Indeed, GD is a predictor of future type 2 diabetes with a cumulative incidence of about 50% at 5 years. GD is also a predictor of the metabolic (resistance) syndrome and should probably be considered a cardiovascular risk factor for later life. Since its first description in the early 1950s, GD has been one of the most controversial syndromes in the field of diabetes. Pregnancy is a state of insulin resistance, characterized by raised circulating insulin concentrations as the maternal pancreas compensates for increased peripheral demands. If adequate compensation does not occur, GD develops. GD is a well-established risk factor for adverse infant health outcomes, including fetal macrosomia, birth trauma, neonatal hypoglycemia, and fetal death (Cetin et al., 1997). GD can predict that the children of women who have GD are at an increased risk for obesity, glucose intolerance, and diabetes during adulthood. There is still confusion about the type of diagnostic tests and diagnostic criteria for GD and a screening protocol (e.g. universal versus selective screening). Gestational diabetes complicates about 1-14% of all pregnancies, depending on the

Pilot project for education of gestational diabetes mellitus (GDM) patients - Can it be beneficial?

The objective of this issue is to assess the effectiveness of an educational program on patients with gestational diabetes mellitus (GDM). The study design is a case-control study that includes 30 pregnant women, mild GDM; between 19 and 41 years of age, without severe complications of diabetes. The women were divided into two groups – passing education Group I (n=15), and Group II (n=15), not passing education. A 1-month education was conducted. The clinical data and metabolic control for the two groups were evaluated. Group ІI shows better improvement in comparison with Group I, and also mild improvement in the blood glucose level. The patients’ quality of life improves with about 1.0 point at average according to the applied questionnaire. This is the first time that the education is being done by pharmacists to patients with GDM at pharmacy conditions. The results prove that the educational approach has the potential to improve patient’s quality of life.

Comparative Price Analysis of Biological Products for Treatment of Rheumatoid Arthritis

Biological products for treatment of rheumatoid arthritis usually are cost effective for healthcare systems in Europe, but they are huge financial burden due to the high number of patients and the significant budget impact. The expected saving from introduction on the market of biosimilars are significant and are linked to better access and affordability. The aim of this study was to conduct comparative price analysis of biological products for rheumatoid arthritis therapy among seventeen EU countries. The point of view is that of the Bulgarian pricing and reimbursement system and the chosen countries are those from external reference basket for prices comparison at manufacturing level. All authorized biological products by EMA with therapeutic indication rheumatoid arthritis were selected. The access for treatment is evaluated as the availability of the product on the market and the prices level. We assessed the availability of all trade names in the price lists of the observed countries. The prices data was obtained from the official web pages of the responsible institutions up to date December 2017. The results show that four out of all six INNs have authorized biosimilars in EMA. Despite its earlier authorization biosimilar adalimumab is not present in any of the price lists of countries. From all eighteen countries only in Lithuania and Estonia there were no published prices of any of the selected medicinal products. Countries with higher number of biosimilar prices are Spain and France. Differences in manufacturers’ prices of reference biological products in selected countries in comparison with the lowest manufacturer price are higher with 22 to 69% while the retail prices between 62 and 95%. Differences are mostly notable for rituximab, and less notable for tocilizumab. Manufacturers’ and retail prices of biosimilar products were established only for three INNs (etanercept, rituximab, and infliximab). Manufacturers’ prices differ between 26 and 75%, while retail prices differ between 40 and 92% for biosimilars. Comparison of the differences between manufacturer prices of reference biological product and biosimilars shows 36% difference for etanercept, 39% for rituximab, and 31% for infliximab, while at retail level the differences are 11, 86, and 143%, respectively. The limitation of the study is that the prices are the official ones without discounts due to confidentiality and the real prices may be lower. The second limitation is that the methodology for pricing differs in the countries and this could also influence the prices on both levels (manufacturer and retail). Introduction of biosimilars on the national markets led to significant decrease in reimbursed prices paid by public funds and thus might benefit the patients’ access to biological therapy. The decrease of prices after biosimilars entrance on the market is not as notable as for commodity generics.

Polycystic ovary syndrome impact on women's quality of life: pilot study

Purpose: The aim of this study is to assess the impact of Polycystic Ovary Syndrome (PCOS) on Bulgarian patients’ QoL through a Polycystic Ovary Syndrome Questionnaire (PCOSQ). Methods: A pilot survey was conducted in a sample of individuals aged 15 to 35 (n=24) from Sofia, Bulgaria. Data were collected via PCOSQ. The PCOSQ scale was translated into Bulgarian and standardized by forward translation, backward translation, and a pre-test. Results: The mean age of the sample was 25.6 ± 6.4 (range 15-35). Results from the study found that women with PCOS had a lower appraisal of their appearance because of their weight. The lowest and the highest results were obtained for their mental and emotional status (q.18-1.92 and q.7-4.42). As a factor group-the lowest results were obtained for the questions concerning their overweight-all the 5 questions were in the range of 3.25-3.58. The highest result (-4.42) was reported for in factor group “emotions”. Conclusion: This pilot study found that the mean level of QoL is 3.7 on a scale of 1 to 7. The main problematic question associated with the disease is women’s overweight. The large variance in the levels of emotions of study subjects shows the need to explore this issue further in a larger cohort of patients. It can be concluded that the management of PCOS is urgently needed and the psychological health of these patients must be monitored regularly.