Enhancing Patient Adherence to Newly-Prescribed Medicine for Chronic Diseases: A Comprehensive Review and Cost-Effective Approach to Implementing the New Medicine Service in Community Pharmacies in Poland.

New Medicine Service (NMS) components are an important element to improve patient compliance with medical recommendations. NMS provides support to patients prescribed new medicines, helping them to manage long-term conditions. The purpose of this service is to provide patients with advice, guidelines, and educational materials regarding the use of new medicines to increase patient compliance and therapy safety. The NMS has already been introduced in many European countries. This review aims to identify the benefits and potential barriers to implementing the NMS in community pharmacies and to suggest solutions that would increase its effectiveness. Previous studies have primarily shown that the NMS improves patient compliance with therapy, accelerating the expected effects of the therapy. Pharmacist support during implementation of a new drug therapy substantially increases patient safety. As the experience of numerous countries shows, both pharmacists and patients express positive opinions on this service. Therefore, it seems that NMS should be an indispensable part of pharmaceutical patient care in any healthcare system. This article aims to review the implementation of the New Medicine Service (NMS) for community pharmacists in Poland and the provision of a cost-effective approach to improve patient adherence to newly-prescribed medicine for chronic diseases.

The Bioavailability of Drugs-The Current State of Knowledge.

Drug bioavailability is a crucial aspect of pharmacology, affecting the effectiveness of drug therapy. Understanding how drugs are absorbed, distributed, metabolized, and eliminated in patients' bodies is essential to ensure proper and safe treatment. This publication aims to highlight the relevance of drug bioavailability research and its importance in therapy. In addition to biochemical activity, bioavailability also plays a critical role in achieving the desired therapeutic effects. This may seem obvious, but it is worth noting that a drug can only produce the expected effect if the proper level of concentration can be achieved at the desired point in a patient's body. Given the differences between patients, drug dosages, and administration forms, understanding and controlling bioavailability has become a priority in pharmacology. This publication discusses the basic concepts of bioavailability and the factors affecting it. We also looked at various methods of assessing bioavailability, both in the laboratory and in the clinic. Notably, the introduction of new technologies and tools in this field is vital to achieve advances in drug bioavailability research. This publication also discusses cases of drugs with poorly described bioavailability, providing a deeper understanding of the complex challenges they pose to medical researchers and practitioners. Simultaneously, the article focuses on the perspectives and trends that may shape the future of research regarding bioavailability, which is crucial to the development of modern pharmacology and drug therapy. In this context, the publication offers an essential, meaningful contribution toward understanding and highlighting bioavailability's role in reliable patient treatment. The text also identifies areas that require further research and exploration.

Acetylsalicylic Acid-Primus Inter Pares in Pharmacology.

Acetylsalicylic acid (ASA) is one of the first drugs to be obtained by synthesis while being the most used. It has experienced the longest lasting commercial success and is considered the most popular drug of the modern era. ASA, originally used as an anti-inflammatory medication, nowadays is predominantly used as an antiplatelet agent for prophylaxis in cardiac patients. Many studies show that the benefits of using ASA far outweigh the potential risk of side effects. With particular emphasis on the possibility of ASA repositioning for new therapies, extending the indications for use beyond the diseases from the spectrum of atherosclerotic diseases, such as cancer, requires shifting the benefit-risk ratio, although very good, even more towards safety. Interesting activities consisting not only of changing the formulation but also modifying the drug molecule seem to be an important goal of the 21st century. ASA has become a milestone in two important fields: pharmacy and medicine. For a pharmacist, ASA is a long-used drug for which individual indications are practically maintained. For a doctor, acetylsalicylic acid is primarily an antiplatelet drug that saves millions of lives of patients with coronary heart disease or after a stroke. These facts do not exempt us from improving therapeutic methods based on ASA, the main goal of which is to reduce the risk of side effects, as well as to extend effectiveness. Modified acetylsalicylic acid molecules already seem to be a promising therapeutic option.

Balloon aortic valvuloplasty for severe aortic stenosis may reduce mitral regurgitation in mid-term follow-up.

Introduction: Mitral regurgitation (MR) is a frequent complication in patients with severe aortic stenosis (AS). Material and methods: Echocardiographic assessment of MR was performed at baseline, at 30 days and at 6 months after balloon aortic valvuloplasty (BAV). Results: Data of 271 patients were included in our final analysis, of which 21.2% (n = 85) had at least moderate MR at baseline (in 19 (22.3%) subjects MR was diagnosed as primary). Both groups showed similar severity of AS, but patients in the MR group had a greater left ventricle (LV) size (p = 0.003 for LVESD, p = 0002 for LVEDD) and slightly lower LV ejection fraction (p = 0.04). Mitral regurgitation parameters significantly improved both at 30 days and 6 months after BAV in the MR group (MR jet area: 7.2 (4.5-9.9) vs. 3.6 (2.3-7.2) cm2, and 7.2 (4.5-9.9) vs. 3.2 (2.1-6.7) cm2; %MR/left atrial area 34.5 (23.4-42.7) vs. 17.5 (9.3-29.5) and 34.5 (23.4-42.7) vs. 14.5 (8.3-24.5), p < 0.001 for all). In multivariate logistic regression analysis, the change at 30 days, from baseline, in the LVESD (OR = 1.87; 95% CI: 1.23-2.87; p < 0.001) and LVEF (OR = 0.95; 95% CI: 0.87-1.01; p < 0.001); MR jet area (OR = 2.2, 95% CI: 1.5-4.6; p < 0.001) and the presence of primary MR (OR = 3.2, 95% CI: 1.04-5.98; p < 0.001) were retained as independent predictors of significant persisting MR at 6 months. Conclusions: Balloon aortic valvuloplasty may reduce MR in mid-term follow-up. Predictors of persistent MR at 6 months after BAV included an increase of LVESD and MR jet area and decrease of LVEF at 30 days.

Antiepileptic Drug Tiagabine Does Not Directly Target Key Cardiac Ion Channels Kv11.1, Nav1.5 and Cav1.2.

Tiagabine is an antiepileptic drug used for the treatment of partial seizures in humans. Recently, this drug has been found useful in several non-epileptic conditions, including anxiety, chronic pain and sleep disorders. Since tachycardia-an impairment of cardiac rhythm due to cardiac ion channel dysfunction-is one of the most commonly reported non-neurological adverse effects of this drug, in the present paper we have undertaken pharmacological and numerical studies to assess a potential cardiovascular risk associated with the use of tiagabine. A chemical interaction of tiagabine with a model of human voltage-gated ion channels (VGICs) is described using the molecular docking method. The obtained in silico results imply that the adverse effects reported so far in the clinical cardiological of tiagabine could not be directly attributed to its interactions with VGICs. This is also confirmed by the results from the isolated organ studies (i.e., calcium entry blocking properties test) and in vivo (electrocardiogram study) assays of the present research. It was found that tachycardia and other tiagabine-induced cardiac complications are not due to a direct effect of this drug on ventricular depolarization and repolarization.

Assessment of Paroxetine Molecular Interactions with Selected Monoamine and γ-Aminobutyric Acid Transporters.

Thus far, many hypotheses have been proposed explaining the cause of depression. Among the most popular of these are: monoamine, neurogenesis, neurobiology, inflammation and stress hypotheses. Many studies have proven that neurogenesis in the brains of adult mammals occurs throughout life. The generation of new neurons persists throughout adulthood in the mammalian brain due to the proliferation and differentiation of adult neural stem cells. For this reason, the search for drugs acting in this mechanism seems to be a priority for modern pharmacotherapy. Paroxetine is one of the most commonly used antidepressants. However, the exact mechanism of its action is not fully understood. The fact that the therapeutic effect after the administration of paroxetine occurs after a few weeks, even if the levels of monoamine are rapidly increased (within a few minutes), allows us to assume a neurogenic mechanism of action. Due to the confirmed dependence of depression on serotonin, norepinephrine, dopamine and γ-aminobutyric acid levels, studies have been undertaken into paroxetine interactions with these primary neurotransmitters using in silico and in vitro methods. We confirmed that paroxetine interacts most strongly with monoamine transporters and shows some interaction with γ-aminobutyric acid transporters. However, studies of the potency inhibitors and binding affinity values indicate that the neurogenic mechanism of paroxetine's action may be determined mainly by its interactions with serotonin transporters.

Paroxetine-Overview of the Molecular Mechanisms of Action.

In the 21st century and especially during a pandemic, the diagnosis and treatment of depression is an essential part of the daily practice of many family doctors. It mainly affects patients in the age category 15-44 years, regardless of gender. Anxiety disorders are often diagnosed in children and adolescents. Social phobias can account for up to 13% of these diagnoses. Social anxiety manifests itself in fear of negative social assessment and humiliation, which disrupts the quality of social functioning. Treatment of the above-mentioned disorders is based on psychotherapy and pharmacotherapy. Serious side effects or mortality from antidepressant drug overdose are currently rare. Recent studies indicate that paroxetine (ATC code: N06AB), belonging to the selective serotonin reuptake inhibitors, has promising therapeutic effects and is used off-label in children and adolescents. The purpose of this review is to describe the interaction of paroxetine with several molecular targets in various points of view including the basic chemical and pharmaceutical properties. The central point of the review is focused on the pharmacodynamic analysis based on the molecular mechanism of binding paroxetine to various therapeutic targets.

Comparison of Bromhexine and its Active Metabolite - Ambroxol as Potential Analgesics Reducing Oxaliplatin-induced Neuropathic Pain - Pharmacodynamic and Molecular Docking Studies.

BACKGROUND: Painful peripheral neuropathy is a dose-limiting adverse effect of the antitumor drug oxaliplatin. The main symptoms of neuropathy: tactile allodynia and cold hyperalgesia, appear in more than 80% of patients on oxaliplatin therapy and are due to the overexpression of neuronal sodium channels (Navs) and neuroinflammation. OBJECTIVE: This study assessed antiallodynic and antihyperalgesic properties of two repurposed drugs with antiinflammatory and Nav-blocking properties (bromhexine and its pharmacologically active metabolite - ambroxol) in a mouse model of neuropathic pain induced by oxaliplatin. Using molecular docking techniques, we predicted targets implicated in the observed in vivo activity of bromhexine. METHODS: Oxaliplatin (a single intraperitoneal dose of 10 mg/kg) induced tactile allodynia and cold hyperalgesia in CD-1 mice and the effectiveness of single-dose or repeated-dose bromhexine and ambroxol to attenuate pain hypersensitivity was assessed in von Frey and cold plate tests. Additionally, Veber analysis and molecular docking experiments of bromhexine on mouse (m) and human (h) Nav1.6-1.9 were carried out. RESULTS: At the corresponding doses, ambroxol was more effective than bromhexine as an antiallodynic agent. However, at the dose of 150 mg/kg, ambroxol induced motor impairments in mice. Repeated-dose bromhexine and ambroxol partially attenuated the development of late-phase tactile allodynia in oxaliplatin-treated mice. Only 7-day administration of bromhexine attenuated the development of late-phase cold hyperalgesia. Bromhexine was predicted to be a strong inhibitor of mNav1.6, mNav1.7, mNav1.9, and hNav1.7-hNav1.9. CONCLUSION: The conversion of bromhexine to other than ambroxol active metabolites should be considered when interpreting some of its in vivo effects. Nav-blocking properties of bromhexine (and previously also predicted for ambroxol) might underlie its ability to attenuate pain caused by oxaliplatin.

Novel mouse GABA uptake inhibitors with enhanced inhibitory activity toward mGAT3/4 and their effect on pain threshold in mice.

γ-Aminobutyric acid (GABA) uptake transporters are membrane transport proteins that are involved in the pathophysiology of a number of neurological disorders. Some types of chronic pain appear to result from the dysfunction of the GABAergic system. The deficiency of mouse GAT1 transporter (mGAT1) abolishes the nociceptive response, which means that mGAT1 inhibition is an appropriate medical approach to achieve analgesia. The mGAT4 transporter is the second most abundant GAT subtype in the brain; however, its physiological role has not yet been fully understood in the central nervous system. In this study, we examined whether the combination of mGAT1 and mGAT3/mGAT4 inhibition in a single molecule might lead to potentially synergistic effects improving analgesic activity to relieve neuropathic pain. To study this hypothesis, new GABA uptake inhibitors were designed, synthesized, and evaluated in terms of their activity and subtype selectivity for mGAT1-4. Among new functionalized amino acid derivatives of serine and GABA analogs, compounds with preferential mGAT3/4 inhibitory activity were discovered. Two selected hits (19b and 31c) were subjected to in vivo tests. We found a statistically significant antiallodynic activity in the von Frey test in diabetic and oxaliplatin-induced neuropathic pain model. The novel compounds (4-hydroxybutanoic, 4-hydroxypentanoic, and 4-aminobutanoic acid derivatives and serine analogs) provide new insights into the structure-activity relationship of mGAT3/mGAT4 inhibitors and indicate a new direction in the search for potential treatment of neuropathic pain of various origin.

Dopamine D2/D3 receptor agonists attenuate PTSD-like symptoms in mice exposed to single prolonged stress.

Medications that enhance dopaminergic neurotransmission can be useful in the pharmacotherapy of posttraumatic stress disorder (PTSD), which manifests as fearful memory retrieval, anxiety and depression. We examined the effects of subchronic (15 days) treatment with select dopaminergic medications, including bromocriptine, modafinil, dihydrexidine, rotigotine and pramipexole, in a mouse model of PTSD induced by single prolonged stress (mSPS). The potential antidepressant-like and anxiolytic effects of the medications were measured by the forced swim test (FST) and the elevated plus maze (EPM) test, respectively. In addition, we studied the effects of these medications on memory retrieval in an auditory fear conditioning (FC) test, on ultrasonic vocalizations (USVs) induced by restraint stress, and on spontaneous locomotor activity (SLA). We report that a single exposure to a severe and complex set of stressors several days before testing increased immobility time in the FST and freezing in the FC paradigm and reduced the time spent in the open arms of the EPM. The stressed mice also displayed increased USVs, especially the short type. While none of the tested dopamine-mimetics exhibited anxiolytic-like effects, rotigotine produced antidepressant-like activity specifically in the mSPS-exposed animals. Moreover, both rotigotine and pramipexole shortened the duration of freezing in the fear conditioning test, but only in the mSPS-exposed mice. This study supports the hypothesis that the activation of dopaminergic D2/D3 receptors may be a promising pharmacotherapy for PTSD.

Studies on the Activity of Selected Highly Lipophilic Compounds toward hGAT1 Inhibition. Part II.

In this paper, we describe the latest results involving molecular modeling and pharmacodynamic studies of the selected highly lipophilic compounds acting by human GABA transporter 1 (hGAT1) inhibition. The chemical interaction of 17 GABA analogues with a model of hGAT1 is described using the molecular docking method. The biological role of GAT1 is related to the regulation of GABA level in the central nervous system and GAT1 inhibition plays an important role in the control of seizure threshold. To confirm that GAT1 can be also a molecular target for drugs used to treat other neurological and psychiatric diseases (e.g., pain and anxiety), in the in vivo part of this study, potential antinociceptive and anxiolytic-like properties of tiagabine, a selective GAT1 inhibitor, are described.

Docking and pharmacodynamic studies on hGAT1 inhibition activity in the presence of selected neuronal and astrocytic inhibitors. Part I.

Inhibition of 4-aminobutanoic acid (GABA) uptake is a strategy for enhancing GABA transmission. The utility of this approach is demonstrated by the successful development of such agents for the treatment of epilepsy and pain. Existing reports on acute brain slice preparations indicate the intersecting of complementary channels and receptors sets between astrocytes and neurons cells. Thorough analysis of astroglial cells by means of molecular and functional studies demonstrated their active modulatory role in intercellular communication. The chemical interactions between sixteen GABA analogues and isoform of hGAT1 is outlined in the light of molecular docking results. In the in vivo part antinociceptive properties of racemic nipecotic acid, its R and S enantiomers and isonipecotic acid, each administered intraperitoneally at 3 fixed doses (10, 30 and 100 mg/kg), were assessed in a thermally-induced acute pain model i.e. the mouse hot plate test. Docking analyses provided complex binding energies, specific h-bond components, and h-bond properties, such as energies, distances and angles. In vivo tests revealed statistically significant antinociceptive properties of isonipecotic acid (10 and 30 mg/kg), R-nipecotic acid (30 and 100 mg/kg) and S-nipecotic acid (100 mg/kg) in mice. The docking data endorse the hypothesis of correlation between the strength of their chemical interactions with hGAT1 and analgesic action of studied compounds.

Time-shifted co-administration of sub-analgesic doses of ambroxol and pregabalin attenuates oxaliplatin-induced cold allodynia in mice.

BACKGROUND: Oxaliplatin-induced cold allodynia is a frequent complication appearing in patients treated with this anti-tumor drug. Since, there are no clear algorithms to overcome this painful condition effectively, it is important to establish novel strategies for its treatment. AIM: In this study, the ability of pregabalin and ambroxol, used as single drugs or in combinations administered in a time-shifted manner to attenuate cold allodynia was assessed in the mouse cold plate test. The hot plate test was additionally used to assess antinociceptive properties of ambroxol in the acute, thermally-induced pain model. Locomotor activity and motor coordination of mice were also evaluated. In silico studies were undertaken to predict potential binding of ambroxol to sodium channel (Nav) subtypes whose overexpression is implicated in the development of oxaliplatin-induced neuropathic pain. KEY FINDINGS: A hyperadditive antiallodynic effect of combined sub-analgesic ambroxol and pregabalin was demonstrated in oxaliplatin-treated mice. This effect was particularly strong when these drugs were given 4 h apart. Both drugs used in combination reduced animals' locomotor activity, but they did not impair motor coordination in the rotarod test. Ambroxol did not show antinociceptive properties in the hot plate test. The molecular docking studies predicted that in mice ambroxol might bind to Nav1.6 and Nav1.9 rather than Nav1.7 and Nav1.8. SIGNIFICANCE: Time-shifted co-administration of sub-analgesic doses of ambroxol and pregabalin effectively attenuates oxaliplatin-induced cold allodynia. Molecular docking model predicts preferential binding of ambroxol to mouse Nav1.6, Nav1.9 channels. This mechanism, if confirmed in vitro, might explain pharmacological activities observed in vivo.

Antidepressant-like activity of venlafaxine and clonidine in mice exposed to single prolonged stress - A model of post-traumatic stress disorder. Pharmacodynamic and molecular docking studies.

BACKGROUND: Post-traumatic stress disorder (PTSD) is a growing issue worldwide characterized by stress and anxiety in response to re-experiencing traumatic events which strongly impair patient's quality of life and social functions. Available antidepressant and anxiolytic drugs are not efficacious in the majority of treated individuals. This necessitates a significant medical demand to develop novel therapeutic strategies for PTSD. EXPERIMENTAL APPROACH: Animal model of PTSD was induced using a mouse single prolonged stress protocol (mSPS). To assess the activity of venlafaxine and clonidine, the forced swim test (FST) was used repeatedly 24h, 3days, 8days, 15days and 25days after mSPS. To get insight into a possible mechanism of anti-PTSD action, molecular docking procedure was utilized for the most active drug. This in silico part comprised molecular docking of enantiomers of venlafaxine to human transporters for serotonin (hSERT), norepinephrine (hNET) and dopamine (hDAT). KEY RESULTS: In mSPS-subjected mice FST revealed the effectiveness of venlafaxine, however in non SPS-subjected mice both venlafaxine and clonidine were active. Molecular docking studies indicated that the affinity of venlafaxine to monoamine transporters is growing in the following rank order: hDAT

Potential role of selected antiepileptics used in neuropathic pain as human GABA transporter isoform 1 (GAT1) inhibitors-Molecular docking and pharmacodynamic studies.

The chemical interaction of nine antiepileptic drugs (tiagabine, gabapentin, pregabalin, lamotrigine, zonisamide, valproic acid, valpromide, vigabatrin, progabide) and two endogenous metabolites (4-aminobutanoic acid, 4-hydroxybutanoic acid) with a model of human GABA transporter 1 (hGAT1) is described using the molecular docking method. To establish the role of hGAT1 in chronic pain, tiagabine, a selective hGAT1 inhibitor, was assessed in the in vivo experiments for its antiallodynic properties in two mouse models of neuropathic pain. Docking analyses performed in this study provided the complex binding energies, specific hydrogen bond components, and hydrogen bond properties such as energies, distances and angles. The data of the docking studies strongly support the assumption that the antiepileptic and analgesic actions of the studied drugs can be at least in part related to the strength of their chemical interactions with hGAT1. In vivo experiments with tiagabine confirmed the involvement of hGAT1 in the regulation of the mechanical nociceptive threshold in neuropathic pain.

Conformational space and vibrational spectra of 2-[(2,4-dimethoxyphenyl)amino]-1,3-thiazolidin-4-one.

In this work we present the results of a study of the X-ray structure of 2-[(2,4-dimethoxyphenyl)amino]-1,3-thiazolidin-4-one. Using the FTIR spectra in solid state and results of ab initio calculations we explain the issue of the tautomerism of this molecule. The compound is shown to exist as the 2-amino tautomer rather 2-imino tautomer. Here we consider eight possible tautomers. On the basis of the vibrational spectra we can eliminate five possible tautomers, as not existing in the solid state. As the most possible tautomeric form we have found keto 2-amino form.