Nociceptin and Pilot Experiments to Detect Pharmacological Effects of its Short-Chain Analogues

Nociceptin, or orphanin FQ, is an endogenous ligand for the nociceptin receptor (NOP, ORL-1). It is a potent antianalgesic agent. The receptor is widely distributed in brain structures. Peptidomimetics are short-chain molecules designed to mimic peptides and with typical pharmacokinetic properties. The aim of the study is to investigate the basic pharmacological and toxicological effects of two newly-synthesized neuropeptides (P1 and P2) in mice. Their activity on the CNS and their inf luence on the hexobarbital- induced narcosis as well were studied. The analgesic activity of these two compounds was examined by using acetic acid test. Dose-dependent effect of the analgesic activity of compound P2 was independently studied by means of the same method. It was established that P2 possessed antinociceptive properties which makes it suitable for further research in this direction

Dangerous food-drug interactions

Aim: To increase patients` awareness of the health risks of certain drug-food interactions and to present their competence in the problem.Materials and methods: Systematic approach of available scientific literature on the problem and specially designed questionnaire.Results: Interactions between food and drugs may affect treatment results and be the reason of undesirable side effects. The clinical significance of this type of cooperation is varied. Some foods may sensitively influence the rate and extent of absorption of the active substance. That in turn could cause serious side effects, toxicity or treatment failure. In other cases, the food-drug interaction could have a favorable aftereffect by increasing the drug efficacy or reducing the side effects. Our dynamic present offers increasingly wide range of medicines. This requires the study of precisely these two types of interactions with food before the release of a drug on the marketConclusions: The results of the survey should reflect on patients` general health culture and their awareness of proper drug intak

Newly synthesized neuropeptides with central nervous activity in mice

Aim: Object of present study are two newly synthesized neuropeptides with short chains: analogues of Tyr-MIF – 1 with code P1 and of Nociceptine with code P2. Materials and Methods: On male albino mice we studied the changes in the cognitive functions of animals after 3, 7 and 14-days pretreatment with both compounds (5 mg/kg intraperitoneally- i.p.) via: step through test (for learning and memory), Rot-a-rod test (for muscular coordination) and Hole board test (for exploratory activity). Their potential analgesic effect was evaluated by Acetic acid test and their activity on the cen-tral nervous system (CNS) was evaluated via interaction with hexobarbital (HB- 100 mg/kg i.p). Statistics were performed with Student – Fisher test.Results: On the 3rd day after treatment daily both compounds had no effect on cognitive functions of animals, but on the 7th day the analogue of Tyr- MIF –1 (peptide P1) significantly improved the memory (by 60%) and decreased also the exploratory activity of treated animals. The analogue of Nociceptine-P2 demonstrated significant dose-dependent analgesic effect. On the 14th day both compounds improved neuro-muscular coordination of animals. In single doses two compounds shorten significantly duration of hexobarbital narcosis (Р1 by 40% and Р2 by 50%) via unknown mechanism, probably related to functional antagonism between the neuropeptides and hexobarbital on CNS level. Conclusion: Newly synthesized neuropeptides are promising biological active substances with effect on CNS. The analogue of Tyr-MIF–1 improves cognitive function of animals and the analogue of Nociceptine has significant dose-dependent analgesic effect

A review of drug stereochemistry

Introduction: Many of the pharmacologically active substances, used in various pharmaceutical products, are chiral organic compounds and can exist in one of several optically active isomer forms. Usually one of the enantiomers is pharmacologically active, while the inactive enantiomer can show unwanted side effects, and in some cases, even antagonistic or toxic effects can be observed. Therefore, a need for resolution of the enantiomers and for enantiomeric purity control arises.Aim: To overview the bases of drug stereochemistry with regard to pharmacokinetic and pharmacodynamic parameters of chiral pharmaceuticals, used as single enantiomers or racemates, as well as the analytical methods for isolation and separation of the different enantiomer isoforms.Materials and Methods: systematic review of web databases (PubMed, ScienceDirect and Google Scholar) on the problem. Results: The different enantiomers and diastereomers of chiral pharmaceutical substances can vary in the terms of their absorption and bioavailability, protein binding and distribution throughout the organism, metabolism pathways and excretion, as well as the extent of the pharmacological activity, therapeutic effect and toxicity. Since obtaining pure drug enantiomers through enantioselective synthesis is not always practical, separation of the racemic mixtures can be achieved with chromatographic and electroseparation techniques, which prove to be more cost-effective.Conclusions: A better understanding of the pharmacological differences between drug enantiomer forms is required. Furthermore, administration of single enantiomer products rather than racemates or vice versa can lead to treatment options that are more successful. The required resolution of drug enantiomers can be achieved to a desirable extent using modern analytical methods

Antioxidant mechanism in the preventive effect of myrtenal on Alzheimer`s disease progression on experimental mouse model

Introduction: Alzheimer’s disease (AD) is the most common form of dementia causing problems with mem-ory, thinking and behavior. So far there is no unified theory for AD pathogenesis and effective treatment. Scientific reports indicate many natural substances possessing neuroprotective properties. New studies demonstrated that natural monoterpen myrtenal combines antioxidant and anti-acetylcholinesterase activ-ity. Our unpublished data reveal significant improving effect of myrtenal on cognitive function of rodents. Aim: Goal of this study is to examine the effect of myrtenal on AD progression using animal model. Materials and Methods: Experimental model of dementia from AD type was produced on male Albino mice via scopolamine treatment (1 mg/kg i.p., 11 days) and was verified with cognitive test (Step through) and biochemical markers: lipid peroxidation and glutathione content in brain. Dement animals were treat-ed simultaneously with myrtenal (20 mg/kg i.p., 11 days). Its preventive effect was evaluated when compared with the effect of lipoic acid (30mg/kg i.p., 11 days) and galantamine (1 mg/kg i.p., 11 days) as referents. Data were analyzed using t-test of Student-Fisher.Results: Myrtenal produced a significant restoration of cognitive function (with 33%) in dement mice in comparison to scopolamine controls. In healthy rodents, myrtenal had antioxidant activity and decreased significantly brain lipid peroxidation, but in dement animals showed pro-oxidant activity. Administered to-gether myrtenal and lipoic acid demonstrated even better prevention on memory and also decreased estab-lished pro-oxidant activity of myrtenal in dement mice. Conclusion: Analyzed changed parameters (cognitive and biochemical) suggest antioxidant mechanism in myrtenal preventive effect on AD progression

Antimicrobial properties and use of star anise

Introduction: Star anise (Illicium verum, Schisandraceae) is a Chinese native evergreen tree with wide uses in medicine, perfumery, culinary and other fields. The star-shaped fruit, along with the seeds, has shown to have various pharmacological properties such as carminative, stimulant, diuretic, antirheumatic, antioxi-dant, analgesic, antibacterial, antifungal and antiviral.Aim: In the wake of a worldwide antibiotic resistance epidemic it is important to explore various sources of antibiotic alternatives. The aim of this report is to examine the diverse properties of star anise, describe its current use and suggest further research into its potent qualities.Materials and Methods: Gathering and systematizing of information using various research papers from around the world.Results: The properties are attributed to the numerous compounds including essential oil, polyphenols, anthocianins, tannins and phenolic acids. Around 90% of the world‘s star anise crop is used for extraction of shikimic acid, a primary precursor in the pharmaceutical synthesis of anti-influenza drug oseltamivir (Tamiflu®). Numerous in vitro studies have shown that extracts from the fruit of star anise show antimicrobial activity against infamous pathogens such as Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Candida albicans and Aspergillus flavus. A study reports that crude extract of star anise is also active against some of the most common fish pathogens and could be used instead of antibiotics to treat fish.Conclusions: These facts could serve useful by diminishing the antibiotic overuse and thus help against the development of antibiotic resistant “superbugs”.

Advanced drug treatment of chronic lymphocytic leukemia (CLL)

Introduction: In the context of the increasing number of neoplastic diseases, which have become a leading reason for death during last years, and the related to that drug resistance, it is important new pharmaceu-tical approaches to be found. CLL is the most commonly diagnosed adult leukemia and approximately one-third of all cases of leukemia. Chemotherapy has been the standard-of-care for CLL, but a considerable prog-ress in treatment has been made with the introduction of anti-CD20 monoclonal antibodies, B-cell receptor (BCR) kinase inhibitors and PI3Kδ kinase inhibitors.Aim: To rewiew the drugs‘ development and the breakthrough therapy for CLL, represented by ofatumum-ab (Arzerra®), obinutuzumab (Gazyva®), ibrutinib (Imbruvica®) and idelalisib (Zydelig®).Materials and Methods: Systematic review of web databases on the problem.Results: Four new drugs (two monoclonal antibodies-ofatumumab, obinutuzumab and two kinase inhibi-tors-ibrutinib, idelalisib) for CLL have been approved by the FDA during the last few years. Тhese targeted drugs can offer the possibility of chemotherapy-free treatment, especially in cases of poor response to che-motherapy, geriatric patients with comorbidities and contraindications. They have shown significant activ-ity in patients with refractory or relapsed CLL. Clinical trials reveal improved progression-free survival in comparison with previous generations anti-CD20 antibodies, kinase inhibitors or chemotherapy.Conclusions: CLL treatment strategy has changed dramatically with the regulatory approval of ofatumum-ab, obinutuzumab, ibrutinib and idelalisib in the past 2 years. The introduction and evolvement of targeted therapy for CLL has the potential to reduce the need of chemotherapy in future

Sofosbuvir/Ledipasvir - new pharmaceutical approach against hepatitis C

Introduction: Hepatitis C is an inflammation of the liver, which is caused by a hepatitis C virus (HCV). Over 170 million people worldwide are infected with HCV. The present treatment of hepatitis C includes pegylated interferon alpha and ribavirin for 24 to 48 weeks.Aim: Review of the new medicines against hepatitis C.Materials and Methods: Systematic review of web databases: www.hepatitisc.uw.edu, www.harvoni.com.Results: On October 10, 2014, the fixed-dose combination ledipasvir-sofosbuvir (Harvoni®) was approved by the FDA for the treatment of chronic hepatitis C genotype 1 infection in adults. Ledipasvir is a potent inhibitor of HCV NS5A, a viral phosphoprotein that plays an important role in viral replication, assembly, and secretion. Sofosbuvir is a nucleotide analog inhibitor of hepatitis C virus NS5B polymerase – the key enzyme mediating HCV RNA replication. The treatment with this combination is suitable for naive and treatment-experienced patients. Its duration depends on prior treatment experience and the presence or absence of cirrhosis. Genotype 1 treatment-naïve patients with or without cirrhosis: 12 weeks. Genotype 1 treatment-experienced patients without cirrhosis: 12 weeks. Genotype 1 treatment-experienced patients with cirrhosis: 24 weeks.Conclusions: The fixed dose combination of ledipasvir-sofosbuvir provides a very attractive and effective one pill once a day option for treatment of genotype 1 chronic hepatitis C infection. This regimen is the first FDA-approved interferon- and ribavirin-free regimen to treat hepatitis C

Bigel formulations of St. John’s wort extract in wound healing: toxicological aspects

AbstractThis study aimed to investigate the toxicological profile of hyperforin (HP) in silico and to assess it in vivo after topical application of an HP-rich St. John’s wort (SJW) extract. The former analysis predicted low toxicity because of HP’s inability to bind DNA or proteins, but structural alerts for skin irritation/corrosion, carcinogenicity, and mutagenicity were found. Animal studies involved the treatment of excision wounds in Wistar rats with poloxamer 407/borage oil formulations (bigels; Bs) containing HP-rich SJW extract previously developed by us. The effects of semisolids comprising ‘free’ extract (B/SJW) or extract loaded in nanostructured lipid carriers (B/NLC-SJW) were compared to positive (commercial herbal product) and negative (untreated) controls after 2-, 7-, 14-, and 21-day applications. Malondialdehyde (MDA) and ABTS assays evaluated the degree of oxidative stress—treatment with bigels did not affect MDA favorably but led to an increased radical-cation scavenging capacity (compared to controls). Gamma-glutamyl transferase (GGT), aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT), and lactate dehydrogenase (LDH) enzyme levels were measured as indicators for liver/tissue damage. Treatment with both B/SJW and B/NLC-SJW for 21 days resulted in lower GGT and ASAT levels than those in controls. Two-day application of the biphasic semisolids contributed to normalized ALAT levels (lower than in both negative and positive controls), and the same trends were observed in LDH levels after a 7-day treatment. The promising results obtained after the B/NLC-SJW application suggest that this drug delivery system may not only preserve HP in SJW extract effectively but also ‘expose’ its cyto-/hepatoprotective potential

Bigel formulations of St. John’s wort extract in wound healing: toxicological aspects

This study aimed to investigate the toxicological profile of hyperforin (HP) in silico and to assess it in vivo after topical application of an HP-rich St. John’s wort (SJW) extract. The former analysis predicted low toxicity because of HP’s inability to bind DNA or proteins, but structural alerts for skin irritation/corrosion, carcinogenicity, and mutagenicity were found. Animal studies involved the treatment of excision wounds in Wistar rats with poloxamer 407/borage oil formulations (bigels; Bs) containing HP-rich SJW extract previously developed by us. The effects of semisolids comprising ‘free’ extract (B/SJW) or extract loaded in nanostructured lipid carriers (B/NLC-SJW) were compared to positive (commercial herbal product) and negative (untreated) controls after 2-, 7-, 14-, and 21-day applications. Malondialdehyde (MDA) and ABTS assays evaluated the degree of oxidative stress—treatment with bigels did not affect MDA favorably but led to an increased radical-cation scavenging capacity (compared to controls). Gamma-glutamyl transferase (GGT), aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT), and lactate dehydrogenase (LDH) enzyme levels were measured as indicators for liver/tissue damage. Treatment with both B/SJW and B/NLC-SJW for 21 days resulted in lower GGT and ASAT levels than those in controls. Two-day application of the biphasic semisolids contributed to normalized ALAT levels (lower than in both negative and positive controls), and the same trends were observed in LDH levels after a 7-day treatment. The promising results obtained after the B/NLC-SJW application suggest that this drug delivery system may not only preserve HP in SJW extract effectively but also ‘expose’ its cyto-/hepatoprotective potential.</p