New approach in the treatment of ophthalmic neovascular disorders: using fusion protein aflibercept

The aim of this review is to appraise the usage of a newly approved anti-vascular endothelial growth factor (anti-VEGF) fusion protein, aflibercept, in ocular neovascular disorders such as diabetic retinopathy and age-related macular degeneration. Aflibercept is a soluble fusion protein, which combines ligand-binding elements taken from the extracellular domains of VEGF receptors 1 and 2 fused to the Fc portion of IgG. This protein contains all human amino acid sequences, which minimizes the risk for immunogenicity in human patients. In this short review we investigate the available literature and data from clinical studies on the efficacy, pharmaceutical and pharmacological properties of aflibercept, and identify its possible advantages over commercially available anti-VEGF drugs.Biomedical Reviews 2014; 25: 59-65

INNs granted with specific storage requirements in Bulgarian pharmacies. Part 2: Antineoplastic and immunomodulating agents

There are drugs that require special storage in Bulgarian pharmacies as well as extra caution during the dispensing process. This is due to serious adverse reactions that may be even fatal. These medicines are included in Appendix № 9 to Art. 17, para. 1 of Ordinance № 28/9.12.2008, issued by the Minister of Health. The performed study of the anticancer drugs listed in the Appendix showed that a major part of these medicines that have a marketing authorization for use in Bulgaria are not included in the Appendix № 9. In addition, there are antitumor drugs that are listed in the appendix but are not authorized in Bulgaria to date. In conclusion, it is necessary to periodically update the drugs in Appendix № 9 as well as to develop clear and precise criteria for the inclusion of medicines in it

In vitro evaluation of combination effects of doxorubicin with methylxanthine fractions isolated from Bancha and Pu-erh teas against breast cancer cells

Background: In the present study we investigated the combination effects of anthracycline antibiotic, doxorubicin, with methylxanthine fractions isolated from Bancha and Pu-erh tea leaves, against MCF-7 and MDA-MB-231 breast cancer cell lines.Methods: Neutral red uptake assay was used for assessment of cytotoxicity effects and fractional effect analysis and combination index for evaluation of the combination effects.Results: Doxorubicin was used in varying concentrations by a double dilution method, whereas the methylxanthine fractions were in fixed concentrations – 100, 200, 400 or 600 μg/ml. Results have shown that methylxanthine fraction isolated from Bancha has synergic effects with doxorubicin, while methylxanthines from Pu-erh displayed antagonistic effects.Conclusions: Тhe obtained results lead us to suspect, that even minor differences in the composition of natural products can lead to significant differences in the biological activity of the product

In vitro antiviral activities of fruit extract from Lycium barbarum and methylxanthines extracted from Pu-erh and Bancha tea leaves

Introduction: Based on traditional medicine, many countries use various plant products (fruits, leaves and other plant parts) as food supplements or in the form of tea. The use of these plant sources has been established through the years of use and the proven benefits of their ingredients to improve human health. Aim: In the present study, we have focused on the effect of Lycium barbarum fruit extract and methylxanthines isolated from Pu-erh (MXP) and Bancha (MXB) tea leaves on Herpes simplex virus type 1 (HSV-1), poliovirus 1 (PV1) and coxsackievirus B1 (CVB1) virus in vitro. Materials and methods: We used in vitro antiviral and virus attachment assays to determine the effects of the three extracts we studied. Results: None of the extracts showed significant inhibition of replication of the three treated viruses but a remarkable inhibitory effect on extracellular virions of HSV-1 was exhibited 30 minutes after exposure, especially by the Lycium barbarum extract. The inhibitory effect of the three extracts on the level of adsorption of the HSV-1 to sensitive cells (MDBK) was also significant, with the most pronounced effect of the MXP. The protective effect of the extracts against herpes infection on healthy cells was also determined, the MXP showing the most notable effect. Conclusions: The three studied extracts can be used effectively in the treatment of herpes infections, as well as in infections with other enveloped viruses

NEW PHARMACOLOGICAL APPROACHES IN THE TREATMENT OF ONCOLOGICAL DISEASES

Malignant diseases are significant and growing health problem in almost all countries of the world. Besides the results achieved in reduction of morbidity and mortality in individual countries, significant progress of science and practice of oncology medicine and the application of new methods of diagnosis and treatment, cancer remains the second leading cause of death after cardiovascular diseases. The past decade has seen breakthroughs in personalized cancer medicine, where new targeted therapies are being developed which inhibit cellular proliferation and survival in tumors with certain specific oncogenic mutations. These new treatment approaches have shown progress in the understanding of the origin and pathogenesis of tumors, and offer hope for a good outcome of neoplastic diseases. In this review the idea is to present up-to-date report on these new molecular mechanisms and to identify their advantages and disadvantages from the pharmacological point of view

Identification, Analysis and Evaluation of Pharmacokinetic and Pharmacodynamics Drug Interaction // Идентификация, анализ и оценка на фармакокинетични и фармакодинамични лекарствени взаимодействия

The identification, analysis, and evaluation of drug interactions are crucial in the preclinical phase of the development and implementation of new drugs. All new drug molecules, substrates, inhibitors, or inducers of drug-metabolizing enzymes or transporters involved in their disposition should be tested to evaluate their risk of drug interactions. These tests are most commonly performed in vitro, and their risk of drug interactions is assessed using state-of-the-art simulation platforms (in silico). On the other hand, the identification, analysis and evaluation of drug interactions is important in clinical practice as many infectious, cardiovascular, oncological and other diseases are treated by the simultaneous use of a large number of drugs - polypharmacy. The aim of the dissertation is to study, analyse and evaluate drug interactions at the pharmacokinetic and pharmacodynamic level through the application of modern and popular software platforms. To demonstrate the effectiveness of these software platforms, plant fractions of L. barbarum (goji berry) and Pu-erh and Bancha teas were selected, as well as endomorphin-2 oligopeptide analogues. Their risk of possible pharmacokinetic drug interactions has been established, and in plant fractions synergistic antitumor effects and organ protection when combined with doxorubicin. The most common pharmacokinetic and pharmacodynamic drug interactions have been identified in selected patients with heart failure.Идентификацията, анализът и оценката на лекарствени взаимодействия е от изключително важно значение в предклиничния етап при разработката и внедряването на нови лекарства. Всички нови лекарствени молекули, субстрати, инхибитори или индуктори на лекарство-метаболизиращи ензими или на транспортери, участващи в тяхната диспозиция, трябва да бъдат тествани за оценка на техния риск от лекарствени взаимодействия. Тези тествания се извършват най-често in vitro и с помощта на модерни симулаторни платформи (in silico) се оценява техния риск от лекарствени взаимодействия. От друга страна, идентификацията, анализът и оценката на лекарствени взаимодействия има важно значение и в клиничната практика, тъй като множество инфекциозни, сърдечно-съдови, онкологични и други заболявания се лекуват чрез едновременната употреба на голям брой лекарства – полифармация. Целта на дисертационния труд е да се проучат, анализират и оценят лекарствени взаимодействия на фармакокинетично и фармакодинамично ниво чрез прилагане на съвременни и популярни софтуерни платформи. За демонстрация ефективността на тези софтуерни платформи са селектирани растителни фракции от L.barbarum (годжи бери) и Пу-ер и Банча чайове, а така също и олигопептидни аналози на ендоморфин-2. Установен е техния риск от възможни фармакокинетични лекарствени взаимодействия, а при растителните фракции синергичнитепротивотуморниефекти и органно протекциятапри едновременно комбиниране с doxorubicin. Установени са най-честите фармакокинетични и фармакодинамични лекарствени взаимодействия при селектирани пациенти със сърдечна недостатъчност

INNs granted with specific storage requirements in Bulgarian pharmacies. Part 1: Medicines acting on cardiovascular and nervous system

Some medicines require special storage in Bulgarian pharmacies due to serious adverse reactions that may be even life-threatening. They are listed in Appendix № 9 to Art. 17, para. 1 of Ordinance № 28 of 9th December 2008, issued by the Minister of Health. The appendix includes 70 medicines from different pharmacotherapeutic groups and with various pharmacological effects. The performed documentary data analysis showed that a major part of these medicines are not registered for use by the Bulgarian Drug Agency to date. In addition, there are a number of medications that have a marketing authorization for use in Bulgaria but are not listed in this specific Appendix, although they belong to the same pharmacotherapeutic group and exert the same pharmacologic action as some included medicines. In conclusion, due to these inconsistencies, it remains unclear whether the Appendix is up to date or needs to be updated

Cardio- and nephroprotective effects of fractions isolated from Lycium barbarum (goji berry) in models of cardio- and nephrotoxicity in rats

AbstractThe aim of the present study was to identify agents that reduce the anthracyclines-induced cardiovascular and renal damage and have the potential to enhance their therapeutic effects. Three fractions of Lycium barbarum (Goji berry), pectin-free, polysaccharide and a combination of the two (1:1, w/w), were tested on rat models of doxorubicin (DOX)-induced cardio- and nephrotoxicity. They were administered p.o. as doses of 2 mg/kg. DOX was applied at a cumulative dose of 20 mg/kg (i.p.). Different biomarkers for cardiotoxicity (creatine kinase, creatine kinase-MB fraction, aspartate aminotransferase, lactate dehydrogenase), nephrotoxicity (creatinine, blood urea nitrogen, uric acid) and the serum potassium levels were evaluated. Histological analysis of hearts and kidneys was performed. The male Wistar rats treated only with DOX showed a drastic increase in all biomarkers for toxicity. Meanwhile, in all cohorts receiving simultaneously any of the plant fractions, the biomarkers for heart and kidney tissue damage were significantly reduced (p < 0.001 for uric acid; p < 0.01 for other parameters). Intriguingly, the pectin-free fraction and the combined one showed the most pronounced decrease in the indicators for toxicity. Histological findings also confirmed these observations, suggesting that the fractions in question need to be investigated as potential enhancers of anthracyclines’ pharmacodynamic effects

Protective Effect of Methylxanthine Fractions Isolated from Bancha Tea Leaves against Doxorubicin-Induced Cardio- and Nephrotoxicities in Rats

Doxorubicin is an anthracycline antibiotic that is used for the treatment of various types of cancer. However, its clinical usage is limited due to its potential life-threatening adverse effects, such as cardio- and nephrotoxicities. Nonetheless, simultaneous administration of doxorubicin and antioxidants, such as those found in green tea leaves, could reduce cardiac and renal tissue damage caused by oxidative stress. The methylxanthine fraction isolated from Bancha tea leaves were tested in vitro for its antioxidant activity and in vivo for its organoprotective properties against doxorubicin-induced cardio- and nephrotoxicities in a rat model. The in vivo study was conducted on male Wistar rats divided into 6 groups. Methylxanthines were administered at high (5 mg/kg body weight) and low (1 mg/kg body weight) doses, while doxorubicin was administered at a cumulative dose of 20 mg/kg body weight. Serum creatinine, uric acid, and urea concentrations, as well as serum enzyme levels (creatinine kinase (CK), creatinine kinase MB fraction (CK-MB), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH)) and electrolytes (Na+, K+, and Cl-), were analysed. In addition, histological analysis was performed to assess cardiac and renal tissue damage. The concomitant administration of Bancha methylxanthines and doxorubicin showed a dose-dependent reduction in the serum biochemical parameters, indicating a decrease in the cardiac and renal tissue damage caused by the antibiotic. Histological analysis showed that pretreatment with methylxanthines at the dose of 5 mg/kg resulted in an almost normal myocardial structure and a significant decrease in the morphological kidney changes caused by doxorubicin exposure compared with the group that received doxorubicin alone. The putative mechanism is most likely related to a reduction in the oxidative stress caused by doxorubicin

RIPK3 expression as a potential predictive and prognostic marker in metastatic colon cancer

Background: Colorectal cancer is one of the primary causes of cancer-related deaths and 5-fluorouracil (5-FU) therapy remains the cornerstone of treatment in these patients. Resistance to 5-FU represents a major obstacle; therefore, finding new predictive and prognostic markers is crucial for improvement of patient outcomes. Recently a new type of programmed cell death was discovered—necroptosis, which depends on receptor interacting protein 3 (RIPK3). Preclinical data showed that necroptotic cell death is an important effector mechanism of 5-FU-mediated anticancer activity. Purpose: To investigate the predictive and prognostic performance of RIPK3 expression in primary tumors. Methods: Colon cancer patients (n=74) with metastatic stage were included in this retrospective study and all were treated with first-line 5-FU based chemotherapy. Immunohistochemical staining was performed. Results: The progression free survival for the low expression group of RIPK3 was 5.6 months (95% CI, 4.4-6.8) vs 8.4 months (95% CI, 6.4-10.3) of the group with high expression (p=0.02). Moreover, patients with high expression of RIPK3 were associated with lower risk of disease progression HR 0.61 (95% CI, 0.38-0.97; p=0.044). Patients with high expression levels of RIPK3 also had significantly longer mean overall survival (OS) of 29.3 months (95% CI, 20.8-37.8) as compared with those with low expression: 18.5 months (95% CI, 15.06-21.9) (p= 0.036). In addition, univariate analysis showed that high level of RIPK3 expression was associated with a longer OS HR 0.59 (95% CI, 0.35-0.98; p=0.044). Conclusions: This study suggests that expression of RIPK3 in primary tumors of metastatic colon cancer patients should be further investigated for its potential as a promising predictive and prognostic marker