Neuroprotective Activity of a Non-Covalent Imatinib+TP10 Conjugate in HT-22 Neuronal Cells In Vitro.

This study evaluated the probable relevance of a non-covalent conjugate of imatinib with TP10 in the context of a neuroprotective effect in Parkinson's disease. Through the inhibition of c-Abl, which is a non-receptor tyrosine kinase and an indicator of oxidative stress, imatinib has shown promise in preclinical animal models of this disease. The poor distribution of imatinib within the brain tissue triggered experiments in which a conjugate was obtained by mixing the drug with TP10, which is known for exhibiting high translocation activity across the cell membrane. The conjugate was tested on the HT-22 cell line with respect to its impact on MPP+-induced oxidative stress, apoptosis, necrosis, cytotoxicity, and mortality. Additionally, it was checked whether the conjugate activated the ABCB1 protein. The experiments indicated that imatinib+PEG4+TP10 reduced the post-MPP+ oxidative stress, apoptosis, and mortality, and these effects were more prominent than those obtained after the exposition of the HT-22 cells to imatinib alone. Its cytotoxicity was similar to that of imatinib itself. In contrast to imatinib, the conjugate did not activate the ABCB1 protein. These favorable qualities of imatinib+PEG4+TP10 make it a potential candidate for further in vivo research, which would confirm its neuroprotective action in PD-affected brains.

Reports analysis of psychotropic drugs related adverse reactions in Australia and Poland during the COVID 19 pandemic.

BACKGROUND: The COVID-19 pandemic has caused significant changes to the global health care system AIMS: It is unknown whether the COVID-19 pandemic influenced the occurrence of adverse drug reactions (ADR) of antidepressive agents, benzodiazepines, and antipsychotics plus mood stabilizers (AaMS). The study was designed in order to compare the incidence of ADR during the COVID-19 pandemic with the period preceding the pandemic in Poland and Australia, different in terms of their COVID-19 prevention strategy. METHOD: We analysed ADR from the three surveyed pharmacological groups of drugs observed in Poland and Australia in the period prior to, and during the COVID-19 pandemic RESULTS: In Poland, a noticeable increase in the reported ADR of the assessed drug groups was observed during the COVID-19 pandemic. The highest was for antidepressive agents, but the reporting of ADR for benzodiazepines and AaMS drugs also increased significantly. In the case of ADR in Australian patients, the increase in the number of reported ADR for antidepressive agents was modest compared to that seen in Poland, but still noticeable, and there was a significant increase in ADR for benzodiazepines CONCLUSIONS: This study showed that the COVID-19 pandemic has had an impact on the incidence of ADR reported among both Polish and Australian patients but the modality of this was different.

Interactions between selected over-the-counter drugs and food: clinical relevance and prevention.

The use of medicines is associated with both therapeutic and adverse effects and interactions. In particular, interactions between drugs and food are common, and can either enhance the action of drugs or diminish their effect. Health professionals have a responsibility to screen for and educate patients about food-drug interactions, as well as to assist in decreasing their occurrence. The aim of this study was to identify any interactions present between food and selected over-the-counter (OTC) drugs. Sixty-five publications out of a potential 1112 found in the search were included in the study and among them 28 concerned painkillers, 6 - antihistamines, 4 - nasal decongestants, 10 were for proton pump inhibitors and for iron and 8 for sildenafil. Interactions between food and OTC drugs do exist. These drugs should not be taken regardless of the meal. Providing relevant information to the patient will increase drug safety and efficacy.

Muscle pain and muscle weakness in COVID19 patients: Cross-talk with statins - Preliminary results.

BACKGROUND: Muscle pain and muscle weakness, common symptoms among statin-treated patients, may worsen with COVID-19 infection. AIMS: The aim of the paper was to find out if concomitant COVID-19 infections increase the frequency of specific side effects of statins such as muscle pain and muscle weakness. METHOD: A total of 66 patients diagnosed with COVID-19 without comorbidities participated in the study. The patients were divided into two groups: statin-users who had not experienced adverse effects of statins in the past (statin group (SG)) and patients who had not used any drugs in the past six months (control group (CG)). The severity of muscle pain and creatinine kinase (CK) activity was evaluated in each patient, and muscle weakness was confirmed by a dynamometer test (grip strength on both hands). RESULTS: In SG, muscle pain was more common and it was characterized by a high level of intensity. Muscle weakness occurred more frequently in the SG and it was more frequent compared to CG. The CK parameter was observed to be higher in the SG compared to the CG and was often associated with the severity of muscle pain in the range of moderate to severe. CONCLUSIONS: Our study indicates that COVID-19 is associated with the higher risk of occurrence of typical statin-related side effects, especially with more advanced age, which should be considered in future trials and treatments.

A retrospective analysis of the "Neverending Trip" after administration of a potent full agonist of 5-HT2A receptor - 25I-NBOMe.

BACKGROUND: 5-HT2A receptor (e.g. 25I-NBOMe) agonists not only pose risks of acute intoxication but also long-term effects and significant adverse reactions, e.g. hallucinogen persisting perception disorder (HPPD), derealization, and depersonalization. AIMS: We evaluated the risk associated with single and repeated use of 25I-NBOMe. We aimed to identify factors that may increase the risk of HPPD, increase its severity and determine the time when the first symptoms appear. Herein, we report the first extensive evaluation of 25I-NBOMe-induced HPPD. METHOD: We assessed all reports (58) collected by The Pomeranian Pharmacovigilance Centre (PPC) from 2013 to 2020. RESULTS: The study included a total of 58 reports of adverse reactions caused by 25I-NBOMe. In the case of 15 reports (in patients aged 19-26 years), symptoms persisted many months after the discontinuation of 25I-NBOMe. The most common were: pseudohallucinations, bizarre delusions, derealizations and in some cases development or worsening of depression has been diagnosed. HPPD-like symptoms were most common in patients who took the drug regularly (i.e., several times a month). The risk of HPPD-like symptoms is higher in patients who have severe visual pseudohallucinations, severe bizarre delusions, derealization and/or depersonalization onset immediately after taking the drug. Recurrence of HPPD symptoms may be provoked by many factors, however, there is some cases there is no apparent reason. HPPD after 25I-NBOMe use can last from 2 months up to 2 years. In some patients, pharmacological treatment was necessary due to 25I-NBOMe-induced HPPD and depression. CONCLUSIONS: The study showed long-lasting effects after 25I-NBOMe administration and allowed for the determination of HPPD risk factors.

Cell-penetrating peptides improve pharmacokinetics and pharmacodynamics of anticancer drugs.

This review concentrates on the research concerning conjugates of anticancer drugs with versatile cell-penetrating peptides (CPPs). For a better insight into the relationship between the components of the constructs, it starts with the characteristic of the peptides and considers its following aspects: mechanisms of cellular internalization, interaction with cancer-modified membranes, selectivity against tumor tissue. Also, CPPs with anticancer activity have been distinguished and summarized with their mechanisms of action. With respect to the conjugates, the preclinical studies (in vitro, in vivo) indicated that they possess several merits in comparison to the parent drugs. They concerned not only better cellular internalization but also other improvements in pharmacokinetics (e.g. access to the brain tissue) and pharmacodynamics (e.g. overcoming drug resistance). The anticancer activity of the conjugates was usually superior to that of the unconjugated drug. Certain anticancer CPPs and conjugates entered clinical trials.

Tachykinin antagonists ameliorate surgically induced impairment of gastrointestinal motility in rats.

The protective effects of tachykinin receptor antagonists: SR140333 (NK1 receptor), SR48968 (NK2 receptor), and SB222200 (NK3 receptor) were tested in rats against a surgically induced postoperative inhibition of gut motility, a common complication of abdominal surgery. The small intestinal transit of Evans blue was measured 24-h post-surgery in untreated rats and animals subjected to skin incision, laparotomy, or laparotomy followed by gut evisceration and manipulation. Surgical procedures were conducted under diethyl ether anesthesia. In comparison to untreated and ether-anesthetized rats, animals undergoing skin incision, laparotomy, or laparotomy with gut evisceration and manipulation showed a significant decrease in the intestinal transit of Evans blue. The pretreatment with NK1 (3-100 µg/kg), NK2 (3-30 µg/kg), and NK3 (10-300 µg/kg) blockers before surgery ameliorated the inhibitory effects of gut manipulation in a dose-dependent manner. Moreover, the submaximal and maximal doses of NK3 antagonists showed a trend toward reversing not only the inhibition caused by gut manipulation but also laparotomy. An additive effect of combining submaximal doses of NK1-3 blockers was observed in animals pretreated with NK1  + NK2 compared to single-agent NK1 and NK2 . Additionally, doublets: NK1  + NK3 or NK2  + NK3 and a triplet: NK1  + NK2  + NK3 proved to be more effective than NK2 antagonist alone. In contrast, NK1-3 blockers have not markedly affected the intestinal propulsion in untreated rats or animals subjected to skin incision or laparotomy. NK1-3 blockers ameliorated the suppressed small-bowel gut motility 24 post-surgery. Combined pretreatment with NK1-3 antagonists provided selective, additive benefits compared to single agents.

Protective effect of nicotinamide and L-arginine against monocrotaline-induced pulmonary hypertension in rats: gender dependence.

BACKGROUND: The purpose of this paper was to examine the effects of nicotinamide (ND) and L-arginine (L-ARG) on pulmonary vascular and heart changes induced by pulmonary hypertension in rats in a gender-dependent way. METHODS: Experiments were performed on male (M) and female (F) rats. PAH was induced via monocrotaline injection (sc, 60/kg B.W.) on day one of the 23-day observational period. After that, the animals were sacrificed, hearts removed and weighed and the papillary muscles isolated to measure force of contraction (Fc). Morphological changes of pulmonary vessels were also examined. RESULTS: Mixed diet supplementation with L-ARG + ND prevented highly significant right ventricle enlargement induced by PAH in both, male and female rats. Weight ratios between the right ventricle (RV) on one side and the left ventricle with septum on the other (LV + S) decreased from 0.46 ± 0.016 g to 0.29 ± 0.006 g in males and from 0.63 ± 0.03 g to 0.24 ± 0.008 g in females, n = 6, p < 0.001. Additionally, PAH increased basal contractility in female groups, and each of the diet allocations (L-ARG, ND, and mixed) were found to restore contractility to control values. All diet protocols in male and female restored decreased responsiveness of the myocardium to norepinephrine in hearts obtained from rats with PAH and prevented vascular changes observed in pulmonary hypertension (thickness of blood vessels and cell infiltration). CONCLUSION: Our study suggests that L-arginine, nicotinamide or both play a positive role in right ventricle function or the process reducing pulmonary vascular remodeling especially in a gender-independent way.

Publisher Correction: Transportan 10 improves the pharmacokinetics and pharmacodynamics of vancomycin.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Pharmaceutical care in the neonatal intensive care unit: Perspectives of Polish medical and pharmacy students.

INTRODUCTION: The concepts of ward-based pharmaceutical care as well as collaborative practice are still relatively novel in Poland, particularly in specialty areas of practice such as the neonatal intensive care unit (NICU). The purpose of this study was to identify the opinions and perceptions of Polish medical and pharmacy students towards the provision of pharmaceutical care services in the NICU as well as pharmacist integration into the ward-based multi-disciplinary NICU treating team. METHODS: A cross-sectional, mixed-method survey was distributed among medical and pharmacy students at a large Polish medical university. RESULTS: A total of 147 students completed the survey (74 pharmacy and 73 medical). Overall, there were statistically significant differences between the perspectives of medical and pharmacy students towards the provision of pharmaceutical care services in the NICU. For 11 out of 15 proposed clinical roles, a significantly lower proportion of medical students (M) agreed that pharmacists should perform these in the NICU compared to pharmacy students (P). These roles included participation in ward rounds (P = 82.4%, M = 38.4%, p < 0.001), therapeutic drug monitoring (P = 98.6%, M = 78.1%, p < 0.001), and monitoring total parenteral nutrition (P = 87.8%, M = 37%, p ≤ 0.001). CONCLUSIONS: Further investigation is needed to develop educational strategies directed at clinical, patient-centered, collaborative roles, particularly for specialty areas of practice such as the NICU, that have the potential to facilitate the provision of a more advanced and comprehensive level of pharmaceutical care.

Transportan 10 improves the pharmacokinetics and pharmacodynamics of vancomycin.

In the presented study, transportan 10 (TP10), an amphipathic cell penetrating peptide (CPP) with high translocation activity, was conjugated with vancomycin (Van), which is known for poor access to the intracellular bacteria and the brain. The antibacterial activity of the conjugates was tested on selected clinical strains of methicillin-resistant Staphylococcus aureus (MRSA) and Enterococcus sp. It turned out that all of them had superior antimicrobial activity in comparison to that of free Van, which became visible particularly against clinical MRSA strains. Furthermore, one of the conjugates was tested against MRSA - infected human cells. With respect to them, this compound showed high bactericidal activity. Next, the same conjugate was screened for its capacity to cross the blood brain barrier (BBB). Therefore, qualitative and quantitative analyses of the conjugate's presence in the mouse brain slices were carried out after its iv administration. They indicated the conjugate's presence in the brain in amount >200 times bigger than that of Van. The conjugates were safe with respect to erythrocyte toxicity (erythrocyte lysis assay). Van in the form of a conjugate with TP10 acquires superior pharmacodynamic and pharmacokinetic.

Perspectives of Hospital Pharmacists Towards Biosimilar Medicines: A Survey of Polish Pharmacy Practice in General Hospitals.

INTRODUCTION: There has been a significant increase in the volume of biosimilar medicines recently due to the expiries of patent protections of biologic medicines. Biosimilars are considered new medicines, and their usage in therapy is often associated with uncertainty from the perspectives of physicians, pharmacists and patients. OBJECTIVES: The purpose of this study was to identify hospital pharmacist opinions towards these new medicines and investigate their usage in practice. METHODS: A paper-based, self-administered questionnaire was distributed to Polish hospital pharmacists. RESULTS: Biosimilars were used in 77% of surveyed hospitals, whereas originator biologics were utilised within 90% of settings. The former medicines were found to consist of less than one-third of the entire course of biological pharmacotherapy used within Polish hospitals. A total of 88% of hospital pharmacists were concerned that the new drugs were not identical with the biologic versions, 48% with their immunogenicity and 44% with other pharmacokinetic properties. The majority of respondents (87%) stated that the most important advantage of biosimilars related to decreased costs. Furthermore, according to participants, pharmacist-led substitution is not appropriate. CONCLUSION: Due to the numerous concerns relating to the usage of biosimilars, their introduction into patient therapy requires special attention from healthcare providers. While pharmacists involved in the distribution of biosimilars are conscious of their impact in decreasing costs of therapy, they do not feel comfortable in recommending their substitution without a physician's permission. There is a need for more precise legal regulations relating to biosimilars, improved communication between physicians and pharmacists, as well as educational initiatives to improve the safe and effective usage of biosimilars.

TP10-Dopamine Conjugate as a Potential Therapeutic Agent in the Treatment of Parkinson's Disease.

Parkinson's disease (PD) is a common progressive neurodegenerative disorder for which the current treatment is not fully satisfactory. One of the major drawbacks of current PD therapy is poor penetration of drugs across the blood-brain barrier (BBB). In recent years, cell-penetrating peptides (CPPs) such as Tat, SynB, or TP10 have gained great interest due to their ability to penetrate cell membranes and to deliver different cargos to their targets including the central nervous system (CNS). However, there is no data with respect to the use of CPPs as drug carriers to the brain for the treatment of PD. In the presented research, the covalent TP10-dopamine conjugate was synthesized and its pharmacological properties were characterized in terms of its ability to penetrate the BBB and anti-parkinsonian activity. The results showed that dopamine (DA) in the form of a conjugate with TP10 evidently gained access to the brain tissue, exhibited low susceptibility to O-methylation reaction by catechol- O-methyltransferase (lower than that of DA), possessed a relatively high affinity to both dopamine D1 and D2 receptors (in the case of D1, a much higher than that of DA), and showed anti-parkinsonian activity (higher than that of l-DOPA) in the MPTP-induced preclinical animal model of PD. The presented results prove that the conjugation of TP10 with DA may be a good starting point for the development of a new strategy for the treatment of PD.

Clinical and conventional pharmacy services in Polish hospitals: a national survey.

BACKGROUND: Pharmacist-led care services within the hospital pharmacy setting have a significant impact on efficient drug management processes. The work of pharmacists is directly associated with the provision of drugs and medical supplies along with additional clinical, administrative, organizational and educational duties. Depending on the country, these practice roles may differ to a significant extent. OBJECTIVE: The aim of this research was to explore the role of the hospital pharmacist and the provision of both clinical and traditional pharmaceutical services for patients and medical staff in Polish general hospitals. SETTING: Hospital pharmacies from all general hospitals in Poland. METHOD: A cross-sectional study was conducted, utilizing an anonymous questionnaire as the research instrument. Heads of hospital pharmacies were requested to participate in this study and complete the questionnaire. The survey was initially piloted to improve the research method. MAIN OUTCOME MEASURE: The types of pharmaceutical services performed in Polish general hospitals. RESULTS: 166 hospital pharmacies took part in this survey. The overall response rate was 60.8 %. The total number of full-time equivalent (FTE) professionals employed within the surveyed hospital pharmacies was approximately 833. The procurement and distribution of drugs were identified as pharmaceutical services performed by most of the participants. The significant majority of pharmacists were also involved in compounding, adverse drug reaction monitoring and rational drug management services. Eleven (7 %) of the responding pharmacists had direct contact with patients and 7 (4 %) pharmacists took part in ward rounds. More precise legal regulations regarding hospital pharmacy practice were measures indicated by most pharmacists as necessary changes required in the hospital pharmacy system. CONCLUSION: Polish hospital pharmacists provide various pharmaceutical services. Their work is closely related with direct provision of drugs. There is an observed inadequate level of clinical services provided in comparison to clinical settings in other countries.

Pharmacoeconomic considerations regarding hospice and palliative care according to pharmacists and hospice managers.

This study focused on pharmacoeconomic issues affecting pharmacists in residential hospices in Poland. We conducted a questionnaire survey among hospice pharmacists and their managers. The results revealed that the amount of money received from the National Health Fund is insufficient for drug purchasing and therefore hospices often raise additional funds from external sources. Because of the limited financing, pharmacists and hospice directors undertake various activities to reduce costs. Generic drug reimbursement, pharmacoeconomic analysis and participating in tenders to purchase drugs are the most common measures undertaken to decrease expenditure.

Tyrosine Kinase Inhibitor as a new Therapy for Ischemic Stroke and other Neurologic Diseases: is there any Hope for a Better Outcome?

The relevance of tyrosine kinase inhibitors (TKIs) in the treatment of malignancies has been already defined. Aberrant activation of tyrosine kinase signaling pathways has been causally linked not only to cancers but also to other non-oncological diseases. This review concentrates on the novel plausible usage of this group of drugs in neurological disorders, such as ischemic brain stroke, subarachnoid hemorrhage, Alzheimer's disease, multiple sclerosis. The drugs considered here are representatives of both receptor and non-receptor TKIs. Among them imatinib and masitinib have the broadest spectrum of therapeutic usage. Both drugs are effective in ischemic brain stroke and multiple sclerosis, but only imatinib produces a therapeutic effect in subarachnoid hemorrhage. Masitinib and dasatinib reduce the symptoms of Alzheimer's disease. In the case of multiple sclerosis several TKIs are useful, including apart from imatinib and masitinib, also sunitinib, sorafenib, lestaurtinib. Furthermore, the possible molecular targets for the drugs are described in connection with the underlying pathophysiological mechanisms in the diseases in question. The most frequent target for the TKIs is PDGFR which plays a pivotal role particularly in ischemic brain stroke and subarachnoid hemorrhage. The collected data indicates that TKIs are very promising candidates for new therapeutic interventions in neurological diseases.

Neuroprotective effect of masitinib in rats with postischemic stroke.

This study evaluated the therapeutic potential of masitinib, an oral tyrosine kinase inhibitor with activity against c-Kit and platelet-derived growth factor receptors (PDGFR), to reduce ischemic brain area and neurological deficit. Using a well-established filament model of ischemic stroke in rats, the responses to oral treatment with masitinib alone or in combination with recombinant tissue plasminogen activator (rt-PA) were compared to those after rt-PA (10 mg/kg intravenously (i.v.)) monotherapy. In both cases, two doses of masitinib were used--25 or 100 mg/kg, twice per day. Ischemic brain area and the neurological deficit were assessed using the triphenyltetrazolium chloride (TTC) method and behavioral neurological tests, respectively. Masitinib, as a single agent, reduced significantly the infarct size, as compared with the stroke control group. Brain ischemic area decreased from 9.14 to 4.36 % (25 mg/kg) or 2.60 % (100 mg/kg). Moreover, a combined treatment of masitinib with rt-PA produced a stronger effect than the one observed after each of the compound alone. The size of the brain ischemic area (rt-PA 1.67 %) was further reduced to 0.83 or 0.7 % at masitinib doses of 25 and 100 mg/kg, respectively. Masitinib reduced significantly brain ischemia induced by experimental stroke and potentiated the therapeutic effect of rt-PA.

[The story of biosimilars--chance or threat?]. / Leki biopodobne--szansa czy zagrozenie?

Patent protection on some key biologic drugs is going to expire soon. Therefore, chances are rising for biopharmaceutical manufacturers to develop and market biosimilars (follow-on biologics). These drugs are approved when similarity to reference biological medicine is proven: in terms of quality, safety or efficacy. In September 2013 European Medicines Agency authorized the first biosimilar monoclonal antibody-infliximab. Doubts considering follow-on biologics are related to their safety and efficacy. The majority of them are associated with the new phenomenon for biological products in clinical use and drug approval processes. These are: extrapolation of indications, immunogenicity and interchangeability. The case of interchangeability poses a threat that it would be impossible to determine which drug is responsible for adverse event, even if brand names and batch numbers of reference and biosimilar products are known. Biosimilar product is authorized if it has shown efficacy and safety in some of indications. When approved, its use will be extrapolated on other indications of the reference product. The aim of following article is to describe some current issues on biosimilars safety, approval procedures and legal solutions in Poland.