REGULATORY CONSIDERATIONS OF BIOSIMILARS AND CLINICAL DILEMA OF THEIR USE

Biomedical products are complex molecules, produced by living cells. More accurately, they are molecules that are naturally produced in the human body, like hormones or growth factors, monoclonal antibodies, blood products, immunological medicinal products, sera and vaccines, allergens, and advanced technology products such as gene and cell therapy products. Copies of these drugs, known as biosimilars, are comparable but not identical and are not generic version of innovator biological products. Specific regulatory requirements and abbreviated registration process apply in the case of biosimilars, in order to demonstrate efficacy and safety profile and to prove that product is similar to the original biomedical product. Like all medicines, biological medicines work by interacting with the body to produce a therapeutic outcome, but the mechanisms by which they do this may vary from product to product and through indications. Therefore the role of the physicians in treatment of patients with these complex medicinal products is particularly important. Regulatory issues, manufacturing, safety, physicians have part in develop use of biosimilars as much as generic drugs. Even though, the most important factor for market of biosimilar are commercial factor, still, real clinical dilemma of use are present, so it is necessary to have clear regulatory framework and postmarketing data on the use of biosimilar

Impact of the SARS-CoV-2 pandemic on routine immunization of the population in the Republic of North Macedonia

Immunization is one of the most powerful and cost-effective public health interventions, preventing about 2 to 3 million deaths each year. The SARS-COV-2 pandemic has spread all over the world and as a direct result of the virus, millions of lives were lost. The indirect effects of the pandemic are equally important. Routine childhood immunization systems were heavily influenced globally and in May 2020 the WHO announced that at least 80 million children under the age of one were put at risk of missing the important and scheduled life-saving vaccines. Data in this paper are from the submitted annual reports on conducted and completed mandatory immunization against infectious diseases in the Republic of North Macedonia, delivered by the Centres for Public Health and their regional units and/or health institutions that implement immunization in the country, as well as the processing and analysis of data obtained from the Institute of Public Health in Skopje, North Macedonia. Decrease in coverage with all types of vaccinations and revaccinations was present in 2020 and 2021, mainly due to current COVID-19 pandemic. There is no doubt that the pandemic had also a huge impact on other health services which are not related to the control and prevention of COVID-19, including mandatory routine immunization. Although the vaccination process was continuous and uninterrupted, the pandemic restriction measures and limitations had a strong impact on reducing the coverage percentage. The impact of restrictive measures in 2020 that included frequent restrictions on population movement and delays in vaccination due to fears of COVID-19 infection played a major role in reducing the coverage, while in 2021 there was an additional factor such as engagement of vaccination teams in COVID-19 vaccination, which resulted in a further reduction of mandatory routine vaccination coverage. Campaigns for public health awareness and educational interventions for healthcare workers and parents are more than necessary to ensure adequate catch-up of delayed or missed immunizations to prevent potential outbreaks of vaccine-preventable diseases

The influence of Covid-19 pandemic on the vaccination of the population with the influenza vaccine in the Republic of North Macedonia

The implemented actions to minimize the spread of the COVID-19 pandemic had a powerful effect on the transmission of other respiratory viruses, particularly influenza viruses. Influenza is a disease of viral aetiology that causes epidemics and occasionally pandemics during the wintertime almost every year. Generally, it is a mild and self-limiting disease, but it can represent high morbidity and even mortality when affecting the elderly population or people with latent chronic diseases. The existing circumstances of a persistent and ongoing epidemic caused by the SARS-CoV-2 virus, increase the probability of having active coincidence with the anticipated annual epidemic of influenza. Thus, the key is a logistic strategy for clinical and viral diagnosis of the SARS-CoV-2 virus that will determine the importance of understanding the role of influenza vaccines in virus-induced COVID-19 disease. This paper aims to compare the potential impact of the COVID-19 pandemic on the vaccination coverage of the population with the influenza vaccine. The official data for seasonal influenza vaccination were used, obtained from the weekly reports on the influenza situation in the Republic of North Macedonia from the Institute of Public Health as well as the data from the national system “MojTermin” for total vaccinated individuals with influenza vaccine for the season 2020/2021 and 2021/2022 including the 5th week. The analyzed data for the season 2021/2022 show an increase of applied doses by 8.3% compared to the season 2020/2021 and an increase of 11.5% compared to the season 2019/2020. Regarding the target groups in the season 2021/2022, including the 5th week, the coverage of influenza vaccination in children aged 6 months to 5 years has a significant decrease of 87.9% compared to the season 2020/2021. There is an increase in coverage in health professionals by 24.3% compared to last season, in the chronically ill the decrease of the applied doses is by 11.4% compared to last season, and in the elderly, over 65 it is noticeable an increase in coverage by 100% compared to the 2020/2021 season. Furthermore, there is a significant decrease of 95.7% in the vaccines administered to pregnant women compared to last season. The reduced coverage of influenza vaccination is partly due to the ambiguities arising from the influenza immunization campaign, which emphasized the importance of receiving a vaccine to minimize the spread of the influenza virus as an additional threat to the presence of COVID-19. Although the influenza vaccine does not protect against COVID-19, influenza vaccination has been part of the public health strategy to flatten the disease curve caused by respiratory viruses that attack the respiratory system, to protect and preserve the health of healthcare professionals providing care to patients with COVID-19. Influenza vaccination is still the most efficient preventive measure against influenza infections at our disposal and it is recommended by the most expert bodies including CDC, WHO, ECDC, and the National Committee for Immunization of the Republic of North Macedonia

A Simple Isocratic RP-HPLC Method for Determination of Nitisinone in Pharmaceuticals

Nitisinone is a reversible inhibitor of 4-hydroxyphenylpyruvate dioxygenase and an active substance in the orphan drug used for the treatment of hereditary tyrosinemia type I, a rare genetic disease caused by mutations in the gene for the enzyme fumarylacetoacetase. The aim of our study was to develop a simple and accurate RP–HPLC method with UV detection for routine determination of nitisinone in commercially available pharmaceutical forms. The chromatographic separation was achieved on a reversed-phase column Purospher STAR® RP–8 end–capped (150 x 4.6 mm i.d., particle size 5 μm), with a mobile phase consisted of a mixture of acetonitrile and water acidified with o-phosphoric acid with pH adjusted to 3.0, 65:35 (V/V), filtered through 0.45μm nylon filter. The flow rate was kept at 1 mL/min. A diode array detector measured the UV absorbance at 272 nm. The injection volume was 10 μl. The method was validated by a determination of system suitability, specificity, linearity, range, accuracy, precision, detection limit and quantitation limit. Then, the method was applied for determination of nitisinon in commercially available capsules. The proposed RP-HPLC method allows a simple, accurate, precise and rapid determination of nitisinone in pharmaceuticals. The advantages of the method include simple sample treatment, good precision (RSD less than 2%) and high recovery (greater than 99%). The method could be recommended for routine analysis in quality control laboratories, in stability studies as well as for the evaluation of potentially counterfeit capsules containing nitisinone

The role of molecular mimicry in the etiology of Guillain Barré Syndrome

Molecular mimicry between host tissue structures and microbial components has been proposed as the pathogenic mechanism for triggeringof autoimmune diseases by preceding infection. Recent studies stated that molecular mimicry as the causative mechanism remains unproven for most of the human diseases. Still, in the case of the peripheral neuropathy Guillain-Barré syndrome (GBS) this hypothesis is supported by abundant experimental evidence. GBS is the most frequent cause of acute neuromuscular paralysis and in some cases occurs after infection with Campylobacter jejuni (C. jejuni). Epidemiological studies, showed that more than one third of GBS patients had antecedent C. jejuni infection and that only specific C. jejuni serotypes are associated with development of GBS. The molecular mimicry between the human gangliosides and the core oligosaccharides of bacterial lipopolysaccharides (LPSs) presumably results in production of antiganglioside cross-reactive antibodies which are likely to be a contributory factor in the induction and pathogenesis of GBS. Antiganglioside antibodies were found in the sera from patients with GBS and by sensitization of rabbits with gangliosides and C. jejuni LPSs animal disease models of GBS were established. GBS as prototype of post-infection immune-mediated disease probably will provide the first verification that an autoimmune disease can be triggered by molecular mimicry

Regulatory considerations of biosimilars and clinical dilemma of their use

Biomedical products are complex molecules, produced by living cells, molecules that are naturally produced in the human body, like hormones or growth factors, monoclonal antibodies, blood products, immunological medicinal products, sera and vaccines, allergens, and advanced technology products such as gene and cell therapy products. Copies of these drugs, known as biosimilars are comparable but not identical and are not generic version of innovator biological products. Specific regulatory requirements and abbreviated registration process apply in the case of biosimilars, in order to demonstrate efficacy and safety profile and prove that product is similar to the original biomedical product. Like all medicines, biological medicines work by interacting with the body to produce a therapeutic outcome, but the mechanisms by which they do this may vary from product to product and across indications. Therefore the role of the physicians in treatment of patients with these complex medicinal products is particularly important. Regulatory issues, manufacturing, safety, physicians have part in developing use of biosimilars as much as generic drugs. Even though, the most important factor for the market of biosimilars is the commercial factor, still, real clinical dilemma of their use is present, so it is necessary to have clear regulatory framework and postmarketing data on the use of biosimilars

Optimization of RP-HPLC method with UV detection for determination of ursodeoxycholic acid in pharmaceutical formulations

Due to the low absorptivity of bile acids, the aim of this study was to develop and validate a simple and sensitive HPLC/UV method for quantification of ursodeoxycholic acid (UDCA) in pharmaceutical formulations. Effective separation was achieved on C18 end–capped column, with gradient elution of a mobile phase composed of 0.001 M phosphate buffer (pH 2.8 ± 0.5) – acetonitrile mix, at flow rate 1.5 mL min-1, UV detection at 200 nm and injection volumes were 50 μL. The proposed HPLC method was fully validated according to the ICH guidelines and it was found to be simple, accurate, precise, and robust

Design, synthesis and determination of physical and chemical characteristics of glycoconjugates as model for oligosaccharide vaccines against vibrio cholerae

Cholera is toxin-mediated enteroinfection, with epidemic character and there are approximately 120000 death cases per year worldwide. Protection against cholera has not been accomplished due to deficiencies in the licensed vaccines. Serum vibriocidal activity mediated by LPS antibodies is the only immune segment correlated with the resistance of cholera. On the basis of literature data (Robbins JB, 1990; Ogawa Y, 1996) we synthesized glucoconjugates, composed of detoxified LPS from Vibrio cholerae and protein carriers. Conjugate vaccines were prepared by binding acetic acid and hydrazine-treated lipopolysaccharide (LPS) from Vibrio cholerae O1, serotype Inaba, to cholera toxin B-subunit (CT-B) and bovine serum albumin (cBSA). Adipic acid dihydrazide was used for derivatization of oligosaccharides and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) as conjugating agent. SDS-PAGE, glycoprotein detection and TLC dot-blot were used for physical and chemical analysis of the prepared four types of conjugates. Safe level of endotoxins, measured by LAL assay was detected in all conjugates. The synthesized conjugates can be used for monitoring immunization schemes on experimental animals. It is to be expected that conjugated vaccines are safe and efficient and that will have high immunogenic and T-dependant characteristics with long immune protection against cholera

Assessment of Patient Satisfaction with Pharmaceutical Community Services in R. Macedonia

Measuring and analyzing patients’ satisfaction with pharmacist’s consultation is a relatively new development which is enforced by the new demands of society. High number of variables, such as their state of health, socio-demographic variables (age, sex, and cultural level), characteristics of their healthcare provider (affective care, quantity of information, technical expertise, etc), or waiting time are related to patients’ satisfaction. At present, in R.Macedonia, there are 834 community pharmacies, which accounts for pharmacy vs. population ratio of 1:2500. The pharmacies are situated in 8 different regions (the Vardar region, Pelagonia, North-East, South-West, Polog, East and South East). The present cross-sectional descriptive study based on interview data was carried out in order to ascertain patients’ satisfaction from their experience with the cumulative quality of pharmaceutical services. A total of 651 patients of both sexes (59,3% male and 39,1% female) were included in the study. The results from our analysis showed the influence of different factors in the process of choosing pharmacy: distance, medicines price, well-stocked with medicines, professional advice by the employees in the pharmacy, hygiene in pharmacies, the privacy they offer, waiting time, possibility for private conversation with professionals

Patents and licensing in pharmaceutical industry

Intellectual property rights (IPR) have been defined as ideas, inventions, and creative expressions based on which there is a public willingness to bestow the status of property. IPR provide certain exclusive rights to the inventors or creators of that property, in order to enable them to reap commercial benefits from their creative efforts or reputation. There are several types of intellectual property protection like patent, copyright, trademark, etc. Patent is recognition for an invention, which satisfies the criteria of global novelty, non-obviousness, and industrial application. IPR is prerequisite for better identification, planning, commercialization, rendering, and thereby protection of invention or creativity. Each industry should evolve its own IPR policies, management style, strategies, and so on depending on its area of specialty. Pharmaceutical industry currently has an evolving IPR strategy requiring a better focus and approach in the coming era. The protection of inventions with patents in the pharmaceutical industry have a specific role in the development of society and represent one of the drivers of economic development. The license agreements are considered as one of the most common types of transfer of industrial property rights. The right holders often transfer their rights to patents by concluding licensing agreement. While the patent license may give the license a right to use the technology many license agreements have provisions for the transfer of know-how in addition to the patent