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Alopecia as a disease condition can be a symptom of other ailments, the body’s reaction to medications, hormonal changes, nutritional deficiencies, hygiene negligence, too intense or frequent cosmetic procedures, or it can constitute an independent disease syndrome. Depending on the individual genetic traits, alopecia may also be inherited. Usually, there is no one universal cause for this disease to occur. Properly conducted diagnosis of the problem and individually selected therapeutic substances can help to deal with this problem or at least delay hair loss associated with the physiological aging process. One of the treatments that are used to support the treatment or prevention of alopecia is needle mesotherapy. It is a local treatment that delivers healing substances having stimulating, regenerating, and nourishing effects directly to the skin or hair follicles. The medicinal substances administered during the needle mesotherapy treatment include peptides, biotin, minoxidil, d-panthenol, vitamins, and minerals, alone or in the form of mixtures, as well as platelet-rich plasma and stem cells. The effects of needle mesotherapy in alopecia are visible after a single treatment when hair loss stops. On the other hand, the thickening and regrowth of new hair are visible after a series of treatments. The full course of therapy depends on the type of alopecia, a patient’s condition, and its comorbidities. It usually consists of four to eight treatments performed at two-week intervals. In the case of alopecia, they are visible after two months, and to maintain the effect, a reminder treatment is recommended after six months. Not all people can undergo such a procedure. The main contraindications include: (1) pregnant and lactating women; (2) children and persons under the age of 18; (3) people who are allergic to any of the ingredients of the administered preparation; (4) people with skin lesions, skin diseases, active infections (bacterial, viral, fungal) or susceptibility to streptococcal infections (recurrent strep throat); (5) people taking drugs: immunosuppressants, anticoagulants, non-steroidal anti-inflammatory drugs, high doses of glucocorticosteroids; (6) patients with decompensated diabetes, neoplastic, mental, rheumatic diseases, or other autoimmune disorders. Needle mesotherapy is very popular in cosmetology and aesthetic medicine clinics. This innovative method is a proven and relatively safe procedure in the fight against various skin conditions, including alopecia. Keywords: excessive hair loss, alopecia, needle mesotherapy, platelet-rich plasma, biomimetic peptides, stem cells.

The current pharmaceutical market lacks therapeutic agents designed to modulate behavioral disturbances associated with dementia. To address this unmet medical need, we designed multifunctional ligands characterized by a nanomolar affinity for clinically relevant targets that are associated with the disease pathology, namely, the 5-HT2A/6/7 and D2 receptors. Compounds that exhibited favorable functional efficacy, water solubility, and metabolic stability were selected for more detailed study. Pharmacological profiling revealed that compound 11 exerted pronounced antidepressant activity (MED 0.1 mg/kg), outperforming commonly available antidepressant drugs, while compound 16 elicited a robust anxiolytic activity (MED 1 mg/kg), exceeding comparator anxiolytics. In contrast to the existing psychotropic agents tested, the novel chemotypes did not negatively impact cognition. At a chronic dose regimen (25 days), 11 did not induce significant metabolic or adverse blood pressure disturbances. These promising therapeutic-like activities and benign safety profiles make the novel chemotypes potential treatment options for dementia patients.

Background The presence of depressive and anxiety symptoms in patients with schizophrenia may have an important impact on treatment and compliance. Hence, interventions addressing such comorbidity in schizophrenia should be explored. One target may be a serotonergic 5-HT 6 receptor (5-HT 6R) since its ligands displayed antidepressant- and anxiolytic-like activities in preclinical experiments. Methods Acute and chronic (21 days) administration of haloperidol or risperidone in combination with a selective 5-HT 6R agonist (WAY-181187) or antagonist (SB-742457) to rats was performed for detecting antidepressant- and anxiolytic-like behaviors. In addition, the level of brain-derived neurotrophic factor (BDNF) protein and its gene expression in hippocampus and prefrontal cortex were determined. Results Both single and chronic administration of WAY-181187 with haloperidol produced antidepressant- and anxiolytic-like activities. SB-742457 did not provide full benefits in terms of improvement of haloperidol-induced adverse mood effects. However, the administration of SB-742457 with risperidone triggered its anxiolytic-like activity. Both 5-HT 6R ligands evoked no changes in haloperidol-induced effects on BDNF level. WAY-181187 induced repression of the BDNF gene while SB-742457 increased its expression in both structures. 5-HT 6R ligands, when combined with risperidone, did not change BDNF protein level and increased gene expression in the hippocampus, while they elevated BDNF level and potentiated gene expression in the prefrontal cortex. Conclusion The combined administration of WAY-181187 and haloperidol provided the greatest benefits, which were manifested by antidepressant-like effects and suppression of the anxiogenic-like properties. The combined administration of risperidone with both agonist and antagonist resulted only in an anxiolytic-like effect. It seems that the anxiolytic-like effects induced by haloperidol or risperidone with the addition of 5-HT 6R ligands are task-specific. The data on BDNF protein and gene expression did not fully correspond with the behavioral outcomes, and thus it appears that other factors/mechanisms are involved in the observed antidepressant- and/or anxiolytic-like effects.

Background: Our previous studies showed that xanthone derivatives with N-(2-methoxyphenyl)piperazine fragment have an affinity to the 5-HT1A receptor and show antidepressant-like properties in rodents. In this study, we tested three xanthone derivatives, HBK-1 (R, S) and its enantiomers, in which we increased the distance between the piperazine and xanthone fragments by using a hydroxypropoxy linker. We hypothesized that this would increase the binding to the 5-HT1A receptor and consequently, pharmacological activity. Aims: We aimed to assess the in vitro and in vivo pharmacological activity of the xanthone derivatives. Methods: We evaluated the in vitro affinity for serotonin 5-HT1A and 5-HT2A receptors and serotonin transporter. We also determined the intrinsic activity at the 5-HT1A receptor. We investigated the antidepressant-like properties and safety after acute administration (dose range: 1.25–20 mg/kg) using the forced swim, tail suspension, locomotor activity, rotarod and chimney tests in mice. We also evaluated the basic pharmacokinetic parameters. Results: Our results indicated that the compounds showed a high affinity for the 5-HT1A receptor but very weak antagonistic properties in the Ca2+ mobilization assay; however, they showed significant agonistic properties in the β-arrestin recruitment assay. In both behavioural tests the studied xanthone derivatives showed antidepressant-like activity. Pre-treatment with p-chlorophenylalanine or WAY-100635 abolished their antidepressant-like activity. None of the compounds caused motor impairments at antidepressant-like doses. The racemate penetrated the blood–brain barrier and had a relatively high bioavailability after intraperitoneal administration. Conclusions: Xanthone derivatives with N-(2-methoxyphenyl)piperazine fragment and hydroxypropoxy linker show increased binding to the 5-HT1A receptor and may represent an attractive putative treatment candidate for depression.

Alzheimer’s Disease (AD) is a chronic neurodegenerative disorder characterized by cognitive impairments such as memory loss, decline in language skills, and disorientation that affects over 46 million people worldwide. Patients with AD also suffer from behavioral and psychological symptoms of dementia that deteriorate their quality of life and lead to premature death. Currently available drugs provide modest symptomatic relief but do not reduce pathological hallmarks (senile plaques and neurofibrillary tangles) and neuroinflammation, both of which are integral parts of dementia. A large body of evidence indicates that impaired signaling pathways of cyclic-3′,5′- Adenosine Monophosphate (cAMP) and cyclic-3′,5′-guanosine Monophosphate (cGMP) may contribute to the development and progression of AD. In addition, Phosphodiesterase (PDE) inhibitors, commonly known as cAMP and/or cGMP modulators, were found to be involved in the phosphorylation of tau; aggregation of amyloid beta; neuroinflammation; and regulation of cognition, mood, and emotion processing. The purpose of this review was to update the most recent reports on the development of novel multifunctional ligands targeting PDE as potential drugs for both symptomatic and disease-modifying therapy of AD. This review collected the chemical structures of representative multifunctional ligands, results of experimental in vitro and in vivo pharmacological studies, and current opinions regarding the potential utility of these compounds for the comprehensive therapy of AD. Finally, the multiparameter predictions of drugability of the representative compounds were calculated and discussed.

Novel 1-(1-benzoylpiperidin-4-yl)methanamine derivatives with high affinity and selectivity for serotonin 5-HT1A receptors were obtained and tested in four functional assays: ERK1/2 phosphorylation, adenylyl cyclase inhibition, calcium mobilization, and β-arrestin recruitment. Compounds 44 and 56 (2-methylaminophenoxyethyl and 2-(1H-indol-4-yloxy)ethyl derivatives, respectively) were selected as biased agonists with highly differential "signaling fingerprints" that translated into distinct in vivo profiles. In vitro, 44 showed biased agonism for ERK1/2 phosphorylation and, in vivo, it preferentially exerted an antidepressant-like effect in the Porsolt forced swimming test in rats. In contrast, compound 56 exhibited a first-in-class profile: it preferentially and potently activated β-arrestin recruitment in vitro and potently elicited lower lip retraction in vivo, a component of "serotonergic syndrome". Both compounds showed promising developability properties. The presented 5-HT1A receptor-biased agonists, preferentially targeting various signaling pathways, have the potential to become drug candidates for distinct central nervous system pathologies and possessing accentuated therapeutic activity and reduced side effects.

Critically ill patients are at high risk of developing a life-threatening infection leading to severe shock and, as a consequence, multi-organ failure and even death. Optimal antimicrobial therapy, especially in the first 48 hours, is crucial to increasing patients' chances of survival. However, effective drug dosing is problematic because pathophysiological changes associated with the critical state of a disease affect their pharmacokinetic properties, mainly those drugs that are hydrophilic in nature. Concentrations of these drugs may be elevated in critically ill patients, mainly because of decreased renal clearance due to renal failure/damage. Conversely, antimicrobial concentrations may decrease due to increased volume of distribution and increased renal clearance, caused by the systemic inflammatory response syndrome, capillary leakage, reduced drug binding, intravenous fluids and inotropic drugs used. The frequency of simultaneous occurrence of numerous complications that may affect pharmacokinetic properties of drugs is excessively complicated by predicting their therapeutic concentrations. In general, situations where antimicrobial concentrations in serum of critically ill patients are too low dominate in clinical settings. And obtaining inappropriate plasma concentrations of patients is clinically important because it leads to ineffective eradication of pathogenic microorganisms and a lack of clinical improvement. In addition, too low drug levels trigger the development of multi-drug resistance, which is not only a medical but also a socio-economic problem. One of the major solutions to this problem seems to be the widespread use of plasma drug monitoring for individual adjustment of the dosage of antimicrobial drugs in a particular patient's clinical condition. However, despite the successful implementation of the beta-lactam antibiotic monitoring program in critically ill patients in Poland, several problems remain to be solved, such as insufficient documentation of the advantage of such a procedure and its clinical success, the lack of necessary technical preparation and specialist knowledge of medical staff in hospitals, which has an impact for the time of determining the concentration of antibacterial drugs in the patient plasma, even the possibility of monitoring drug concentration therapy does not solve the problem of obtaining the most optimal pharmacokinetic-pharmacodynamic indicators that determine the dosage selection. One solution, though not without its drawbacks, is to use population models to calculate the dosage of antimicrobial drugs. These models should take into account the state of mechanical ventilation, diagnostic category and glomerular filtration of the patient. However, also in such model preparation, there are problems such as the state of patients' kidney function, which may show large fluctuations and require frequent monitoring of creatinine, which is associated with additional work and time input, capillary leak affecting the value of distribution volume. The above pathophysiological changes significantly impede the development of appropriate models that would be adequate for use in optimization of the antimicrobial dosage in critically ill patients.

Neuropsychiatric symptoms (NPS), such as psychosis, depression and anxiety are frequently observed among patients with dementia. NPS is treated by off-label psychotropic medications that are only modestly effective in dementia patients, with a high risk of adverse events and cognitive decline. Considering the above, there is an unmet need for a well-tolerated and effective therapy of NPS in dementia. We designed and synthesized a library of dual-acting compounds as phosphodiesterase type-10A inhibitors and serotonin 5-HT

Tetrabenazine, a preferential inhibitor of the vesicular monoamine transporter type 2, depletes the brain monoamines dopamine, serotonin and norepinephrine. Tetrabenazine and deutetrabenazine (Austedo ®) are used to treat chorea associated with Huntington's disease. However, both compounds are known to aggravate Parkinsonism and depression observed in Huntington's disease patients. NLX-112 (a.k.a. befiradol/F13640) is a highly selective, potent and efficacious serotonin 5-HT 1A agonist. In animal models, it has robust efficacy in combating other iatrogenic motor disorders such as L-DOPA-induced dyskinesia and has marked antidepressant-like activity in rodent tests. In the present study, we investigated, in rats, the efficacy of NLX-112 to counteract tetrabenazine-induced catalepsy (a model of Parkinsonism) and tetrabenazine-induced potentiation of immobility in the forced swim test (FST, a model to detect antidepressant-like activity). The prototypical 5-HT 1A agonist, (±)8-OH-DPAT, and the 5-HT 1A partial agonist/dopamine D2 receptor blocker, buspirone, were used as comparators. Both NLX-112 and (±)8-OH-DPAT (0.16-2.5 mg/kg p.o. or s.c., respectively) abolished catalepsy induced by tetrabenazine (2 mg/kg i.p.). In comparison, buspirone (0.63-5.0 mg/kg p.o.) was ineffective and even tended to potentiate tetrabenazine-induced catalepsy at 0.63 mg/kg. In the FST, NLX-112 and (±)8-OH-DPAT (0.63 mg/kg) strongly reduced immobility when administered alone but also significantly opposed potentiation of immobility induced by tetrabenazine (1.5 mg/kg i.p.). Buspirone (0.63 and 2.5 mg/kg p.o.) had no effect by itself or against tetrabenazine. These results strongly suggest that selective and highly efficacious 5-HT 1A agonists, such as NLX-112, may be useful in combating tetrabenazine-induced Parkinsonism and/or depression in Huntington's disease patients.

Among the serotonin receptors, one of the most recently discovered 5-HT6 subtype is an important protein target and its ligands may play a key role in the innovative treatment of cognitive disorders. However, none of its selective ligands have reached the pharmaceutical market yet. Recently, a new chemical class of potent 5-HT6 receptor agents, the 1,3,5-triazine-piperazine derivatives, has been synthesized. Three members, the ortho and meta dichloro- (1,2) and the unsubstituted phenyl (3) derivatives, proved to be of special interest due to their high affinities (1,2) and selectivity (3) toward 5-HT6 receptor. Thus, a broader pharmacological profile for 1–3, including comprehensive screening of the receptor selectivity and drug-like parameters in vitro as well as both, pharmacokinetic and pharmacodynamic properties in vivo, have been investigated within this study. A comprehensive analysis of the obtained results indicated significant procognitive-like activity together with beneficial drug-likeness in vitro and pharmacokinetics in vivo profiles for both, (RS)-4-[1-(2,3-dichlorophenoxy)propyl]-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (2) and (RS)-4-(4-methylpiperazin-1-yl)-6-(1-phenoxypropyl)-1,3,5-triazin-2-amine (3), but insensibly predominant for compound 2. Nevertheless, both compounds (2 and 3) seem to be good Central Nervous System drug candidates in search for novel therapeutic approach to dementia diseases, based on the 5-HT6 receptor target.

The contemporary theory of the inflammatory-immunological pathomechanism of atherosclerosis includes the participation of interleukin-1β (Il), Il-6, Il-10, Il-12, RANTES, and homocysteine in this process. The knowledge on the direct effect of hyperhomocysteinemia on inflammatory-state-related atherosclerosis is rather scarce. Our study is the first to account for the effects of homocysteine on the secretion of Il-10 and RANTES in vitro conditions. For this purpose, human mitogen-stimulated peripheral blood mononuclear cells (PBMNCs) were cultured in vitro and exposed to homocysteine at high concentrations. Subsequently, the concentrations of cytokines were assayed in the cell culture supernatant using flow cytofluorimetry. It has been shown that, in the presence of homocysteine, the secretion of IL-1, IL-6 and RANTES by PBMNCs was increased, whereas IL-10 concentration was significantly lower than that of the supernatant derived from a mitogen-stimulated cell culture without homocysteine. The secretion of Il-12 by PBMNCs exposed exclusively to mitogen, did not differ from homologous cells also treated with homocysteine. Therefore, in our opinion, high-concentration homocysteine affects the progression of atherosclerosis by increasing the secretion of proinflammatory cytokines secreted by PBMNCs, such as Il-1β, Il-6, RANTES, and by attenuating the secretion of Il-10.

Schizophrenia is a chronic psychiatric disorder that affects about 1 in 100 people around the world and results in persistent emotional and cognitive impairments. Untreated schizophrenia leads to deterioration in quality of life and premature death. Although the clinical efficacy of dopamine D2 receptor antagonists against positive symptoms of schizophrenia supports the dopamine hypothesis of the disease, the resistance of negative and cognitive symptoms to these drugs implicates other systems in its pathophysiology. Many studies suggest that abnormalities in glutamate homeostasis may contribute to all three groups of schizophrenia symptoms. Scientific considerations also include disorders of gamma-aminobutyric acid-ergic and serotonergic neurotransmissions as well as the role of the immune system. The purpose of this review is to update the most recent reports on the discovery and development of non-dopaminergic agents that may reduce positive, negative, and cognitive symptoms of schizophrenia, and may be alternative to currently used antipsychotics. This review collects the chemical structures of representative compounds targeting metabotropic glutamate receptor, gamma-aminobutyric acid type A receptor, alpha 7 nicotinic acetylcholine receptor, glycine transporter type 1 and glycogen synthase kinase 3 as well as results of in vitro and in vivo studies indicating their efficacy in schizophrenia. Results of clinical trials assessing the safety and efficacy of the tested compounds have also been presented. Finally, attention has been paid to multifunctional ligands with serotonin receptor affinity or phosphodiesterase inhibitory activity as novel strategies in the search for dedicated medicines for patients with schizophrenia.

This research allowed us to find the first highly potent 5-HT

In this study, a series of compounds derived from 4-methoxy-1H-isoindole-1,3(2H)-dione, potential ligands of phosphodiesterase 10A and serotonin receptors, were investigated as potential antipsychotics. A library of 4-methoxy-1H-isoindole-1,3(2H)-dione derivatives with various amine moieties was synthesized and examined for their phosphodiesterase 10A (PDE10A)-inhibiting properties and their 5-HT1A and 5-HT7 receptor affinities. Based on in vitro studies, the most potent compound, 18 (2-[4-(1H-benzimidazol-2-yl)butyl]-4-methoxy-1H-isoindole-1,3(2H)-dione), was selected and its safety in vitro was evaluated. In order to explain the binding mode of compound 18 in the active site of the PDE10A enzyme and describe the molecular interactions responsible for its inhibition, computer-aided docking studies were performed. The potential antipsychotic properties of compound 18 in a behavioral model of schizophrenia were also investigated.

In the light of recent lines of evidence, 5-HT

A series of 2-pyrimidinyl-piperazinyl-alkyl derivatives of 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione has been synthesized in an attempt to discover a new class of psychotropic agents. Compounds were evaluated for their in vitro affinity for serotonin 5-HT1A , 5-HT7 , and phosphodiesterases PDE4 and PDE10. The most potent compound 2-pyrimidinyl-1-piperazinyl-butyl-imidazo[2,1-f]purine-2,4-dione (4b) behaved as strong and selective antagonist of 5-HT1A . Molecular modeling studies revealed differences in binding mode between compound 4b and buspirone, which might reflect variation of the ligands' affinity and potency in the 5-HT1A receptor. Compound 4b in silico models demonstrated drug-likeness properties and, contrary to buspirone, showed a metabolic stability in mouse liver microsomes system. Experimentally obtained value of apparent permeability coefficient Papp for 4b in parallel artificial permeability assay indicates the possibility of binding weakly to plasma proteins and high intestinal absorption fraction. Evaluation of the antidepressant- and anxiolytic-like activities of 4b revealed both activities at the same dose of 1.25 mg/kg and seemed to be specific. The antidepressant and/or anxiolytic properties of 4b may be related to its first-pass effect.

Introduction: Cardiovascular risk in the course of diabetes depends greatly on glycemic variability which is even more significant than chronic hyperglycemia. Optimal management of diabetes involves a multidisciplinary approach focused in particular on decreasing the risk of atherosclerosis. Therefore, our purpose was to evaluate the impact of dapagliflozin on glucose excursions and related proatherogenic changes in the aortic wall. Methods and materials: Animal model of type 2 diabetes rich-fat/STZ rats was used. Wistar rats were randomized into 3 groups: dapagliflozin-treated with glucose excursions, placebo-treated with glucose excursions and placebo-treated with stable diabetes. Dapagliflozin was administered once a day, 1 mg/kg, for 8 consecutive weeks. Glucose levels were measured twice a week at fasting and postprandially. The samples of aortas were taken for histopathological and immunochemistry examinations at the end of the experiment. The derangement in the aortic wall and the distribution of CD68+ cells in the aorta were considered early signs of atherosclerosis. Results: Dapagliflozin reduced glucose excursion to the level characteristic for stable, well-controlled diabetes. It was related to a significant decrease in histopathological changes which were observed in the placebo-treated rats with glucose variability. Dapagliflozin significantly reduced also the accumulation of CD68+ macrophages in the aortic adventitia. Conclusion: Dapagliflozin provides not only mere beneficial regulation of metabolic status with the depletion of glucose variability, but is also helpful in the prevention of early atherosclerosis related to the course of diabetes type 2. Keywords: Atherosclerosis, Cardiovascular disease, Type 2 diabetes, Glucose excursions, Dapagliflozin

Objectives We quantified the impact of antibiotics prescribed in primary care for urinary tract infections (UTIs) on intestinal colonization by ciprofloxacin-resistant (CIP-RE) and extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL-PE), while accounting for household clustering. Methods Prospective cohort study from January 2011 to August 2013 at primary care sites in Belgium, Poland and Switzerland. We recruited outpatients requiring antibiotics for suspected UTIs or asymptomatic bacteriuria (exposed patients), outpatients not requiring antibiotics (non-exposed patients), and one to three household contacts for each patient. Faecal samples were tested for CIP-RE, ESBL-PE, nitrofurantoin-resistant Enterobacteriaceae (NIT-RE) and any Enterobacteriaceae at baseline (S1), end of antibiotics (S2) and 28 days after S2 (S3). Results We included 300 households (205 exposed, 95 non-exposed) with 716 participants. Most exposed patients received nitrofurans (86; 42%) or fluoroquinolones (76; 37%). CIP-RE were identified in 16% (328/2033) of samples from 202 (28%) participants. Fluoroquinolone treatment caused transient suppression of Enterobacteriaceae (S2) and subsequent two-fold increase in CIP-RE prevalence at S3 (adjusted prevalence ratio (aPR) 2.0, 95% CI 1.2–3.4), with corresponding number-needed-to-harm of 12. Nitrofurans had no impact on CIP-RE (aPR 1.0, 95% CI 0.5–1.8) or NIT-RE. ESBL-PE were identified in 5% (107/2058) of samples from 71 (10%) participants, with colonization not associated with antibiotic exposure. Household exposure to CIP-RE or ESBL-PE was associated with increased individual risk of colonization: aPR 1.8 (95% CI 1.3–2.5) and 3.4 (95% CI 1.3–9.0), respectively. Conclusions These findings support avoidance of fluoroquinolones for first-line UTI therapy in primary care, and suggest potential for interventions that interrupt household circulation of resistant Enterobacteriaceae .

Introduction: Paliperidone is approved in the United States and Europe for the short- and long-term treatment of schizophrenia in adults and adolescents as well as for the acute treatment of schizoaffective disorder either as monotherapy or adjunctive therapy to mood stabilizers and/or antidepressants. It is recommended in patients with hepatic impairment and evokes less drug-drug interactions.Areas covered: This review article focuses on the preclinical discovery of paliperidone, the major active metabolite of risperidone. It provides details regarding paliperidone's pharmacological and neurochemical mechanisms, and their contribution to therapeutic benefits and adverse effects, based on the available literature with respect to the preclinical and clinical findings and product labels.Expert opinion: Paliperidone exhibits a high affinity and antagonistic activity toward D2 and 5-HT2A receptors, followed by 5-HT7, H1, α1, and α2 receptors. In preclinical studies, paliperidone produces antidepressant, anxiolytic, mood-stabilizing, analgesic actions, and affects the endocannabinoid system. It is also known to evoke procognitive, antioxidant, and anti-inflammatory activities. Its positive activity on neurogenesis, neuronal, and synaptic plasticity deserves to be emphasized. The clinical superiority of paliperidone is based primarily on the available formulations of the drug rather than in the subtle differences in its pharmacokinetic/pharmacodynamic properties compared to risperidone.

Purpose Alpha-lipoic acid (ALA), widely known as an antioxidant, modifies also serum levels of angiogenic factors in type 2 diabetic patients. These pharmacological activities may influence the status of the cardiovascular system. Taking into consideration that diabetes is related to the increased cardiovascular risk we investigated several effects of ALA on angiogenic factors in the myocardium and in the aortal wall using a rat model of type 2 diabetes. Methods Diabetes was induced in Wistar rats by a fat-rich diet and by intraperitoneal injection of a small dose of streptozotocin (30 mg/kg). Animals were divided into 3 groups: ALA-treated type 2 diabetes rat model, placebo-treated type 2 diabetes rat model and placebo-treated non-diabetic rats. ALA was administered orally once a day, 20 mg/kg, for 8 consecutive weeks. mRNA VEGF, VEGF-R1 and VEGF-R2 expression was measured in the myocardium and the aortal wall, simultaneously with circulating VEGF and circulating endothelial cells (cEC) and endothelial progenitor cells (cEPC). Results ALA induced pro-angiogenic effect in the myocardium of rats with diabetes increasing mRNA VEGF expression and decreasing mRNA VEGFR-1 expression, while in the aortal wall ALA increased mRNA VEGFR-2 and VEGFR-1 expression. cVEGF in the ALA-treated group was higher comparing to both control groups. It was revealed that cEC percentage in the ALA-treated group was decreased with no effect on the percentage of cEPC. Conclusions In summary, the current data provide novel findings about potential beneficial effects of ALA on angiogenic factors in the cardiovascular system, especially on myocardium, in the course of type 2 diabetes.

The effect of some antidepressants co-administered with EMD386088 in the modified forced swim test in rats was investigated. Additionally, the pharmacokinetics, metabolic stability, and the effect of EMD386088 on P450 cytochromes were determined. Intraperitoneal (i.p.) coadministration of EMD386088 (2.5 mg/kg) and imipramine (15 mg/kg), reboxetine (5 mg/kg), moclobemide (10 mg/kg), or bupropion (10 mg/kg) evoked significant antidepressant-like activity, whereas no effect was observed after joint administration of EMD386088 with s-citalopram (10 mg/kg). Pharmacokinetic in vivo investigation showed a rapid absorption of EMD386088 (2.5 and 5 mg/kg) with t 1/2 = 67 min (t max = 5 min). Large volume of distribution (V d/F = 102 L/kg) indicated its penetration into peripheral compartments. The most active coadministration of EMD386088 (2.5 mg/kg) with imipramine (15 mg/kg) resulted in slower absorption of the compound (C max = 60 min) and decrease in the volume of distribution (V d/F = 32.2 L/kg). EMD386088 penetrates the blood–brain barrier with a high brain/plasma ratio of about 19 (2.5 mg/kg) and 7.5 for coadministration with imipramine. The in silico and in vitro studies on EMD386088 metabolic stability showed the dehydrogenation of tetrahydropyridine moiety as its main metabolic pathway. EMD386088 did not influence on CYP3A4 activity, and it has been classified as a very weak CYP2D6 inhibitor (IC 50 = 2.25 μM). The results obtained from the forced swim test in rats indicate that an activation of 5HT6 receptor may facilitate antidepressant-like activity of some antidepressants. The pharmacokinetic results suggest that the interaction between EMD386088 and imipramine could not have been pharmacokinetic in nature.

The work describes a discovery of new chemical family of potent ligands for the 5-HT6 serotonin receptors. During the search for new histamine H4 receptor antagonists among 1,3,5-triazine derivatives, compound 2 (4-benzyl-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine) was found. Compound 2, weakly active for the H4 receptor but fitted in 3/4 of pharmacophore features of the 5-HT6R ligand, occurred to be a moderate 5-HT6R agent, useful as a lead structure for further modifications. A series of new derivatives (3–19) of the lead 2 was synthesized, evaluated in the radioligand binding assay (RBA) and explored in comprehensive molecular modelling, including both pharmacophore- and structure-based approaches with docking to the homology model of 5-HT6R. The most active compounds displayed a potent affinity for the 5-HT6R in the nanomolar range (Ki = 20–30 nM), some of them (4, 11 and 19) were tested in the rat forced swim test that revealed their antidepressant-like effect. SAR-analysis on the basis of both, RBA and docking results, indicated that action on the receptor is related to the hydrophobicity and the size of aromatic moiety substituted by a methylene linker at the position 4 of 1,3,5-triazine.

Among serotonin receptors, the 5-HT6 subtype is the most controversial and the least known in the field of molecular mechanisms. The 5-HT6R ligands can be pivotal for innovative treatment of cognitive impairment, but none has reached pharmacological market, predominantly, due to insufficient &ldquo, druglikeness&rdquo, properties. Recently, 1,3,5-triazine-piperazine derivatives were identified as a new chemical family of potent 5-HT6R ligands. For the most active triazine 5-HT6R agents found (1&ndash, 4), a wider binding profile and comprehensive in vitro evaluation of their drug-like parameters as well as behavioral studies and an influence on body mass in vivo were investigated within this work. Results indicated the most promising pharmacological/druglikeness profiles for 4-((1H-indol-3-yl)methyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (3) and 4-((2-isopropyl-5-methylphenoxy)methyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (4), which displayed a significant procognitive action and specific anxiolytic-like effects in the behavioral tests in vivo together with satisfied pharmaceutical and safety profiles in vitro. The thymol derivative (4) seems to be of higher importance as a new lead candidate, due to the innovative, non-indole and non-sulfone structure with the best 5-HT6R binding properties.

The purpose of this study has been to determine the effect of acute consumption of noni and chokeberry juices vs. energy drinks on blood pressure, heart rate, and blood glucose. The subjects divided into 4 groups, which consumed three portions of noni or chokeberry juices (30 mL or 200 mL, respectively) and energy drink (ED) or water (200 mL) at one-hour intervals. All participants had their blood pressure (BP), both systolic and diastolic BP (SBP and DBP), as well as heart rate (HR) and blood glucose (BG), measured. Consumption of noni juice caused a significant decrease in SBP and DBP of 5.0% and 7.5%, respectively, while, the consumption of chokeberry juice slightly decreased only DBP by 3.6%. On the contrary, consumption of three portions of EDs caused a significant increase in DBP by 14.7%. The BG of participants consuming noni juice decreased by 7.3%, while the consumption of EDs increased BG by as much as 15.8%. Acute consumption of noni juice contributed to a significantly decreased SBP, DBP, and HR as well as a mild reduction of BG. Consumption of chokeberry juice caused only a slight reduction of DBP. Contrary to juices, EDs consumption resulted in an increase of blood pressure (especially DBP) and blood glucose. The results of the study showed that noni juice may be effective in lowering blood pressure and blood sugar levels, but there is a need to continue research on the long-term effect of this juice.

Alzheimer’s Disease (AD) is a chronic and progressive neurodegenerative disorder that affects over 46 million people worldwide. It is characterized by a decline in cognitive abilities, including memory and thinking skills. AD patients also suffer from behavioral and psychological symptoms of dementia of which depression is the most prevalent. Currently available drugs provide modest symptomatic relief and do not reduce pathological hallmarks (senile plaques and neurofibrillary tangles) and neuroinflammation, both of which are integral parts of AD. Studies suggest that AD is a type of diabetes manifested in the brain. Although AD and diabetes are currently classified as separate disease entities, they share common pathophysiological mechanisms, one of them is an increased level of cytokines involved in the inflammation and the regulation of metabolic, regenerative, and neural processes. The purpose of this review was to update the most recent reports on the discovery and development of antidiabetic agents as promising drugs for the symptomatic and diseasemodifying treatment of AD. We collected the results of in vitro and in vivo studies, and recent reports from clinical trials suggesting the utility of antidiabetic agents in memory-enhancing therapy of AD. Their beneficial effects on chronic neuroinflammation, pathological hallmarks, and neuropsychiatric symptoms co-occurring with cognitive deficits are also presented. Antidiabetic agents refer to the diabetic and inflammatory hypotheses of AD and provide hope to find an effective drug for comprehensive therapy of the disease.

The aim of the present study was to investigate and compare the effects of acute and chronic (21-day) administration of agonist (WAY-181187) and antagonist (SB-742457) of the 5-hydroxytryptamine 6 receptor (5-HT