Pharmacological Reports最新文献

Background: Emerging evidence indicates that intravenous ketamine is effective in managing treatment-resistant unipolar and bipolar depression. Clinical studies highlight its favorable efficacy, safety, and tolerability profile within a dosage range of 0.5-1.0 mg/kg based on actual body weight. However, data on alternative dosage calculation methods, particularly in relation to body mass index (BMI) and therapeutic outcomes, remain limited.

Methods: This retrospective analysis of an open-label study aims to evaluate dose calculation strategies and their impact on treatment response among inpatients with treatment-resistant major depressive disorder (MDD) (n = 28). The study employed the Boer and Devine formulas to determine lean body mass (LBM) and ideal body weight (IBW), and the Mosteller formula to estimate body surface area (BSA). The calculated doses were then compared with the actual doses administered or converted to a dosage per square meter for both responders and non-responders.

Results: Regardless of treatment response, defined as a reduction of 50% in the Montgomery-Åsberg Depression Rating Scale, the use of alternative ketamine dosing formulas resulted in underdosing compared to the standardized dose of 0.5 mg/kg. Only two participants received higher doses (102.7% and 113.0%) when the Devine formula was applied.

Conclusions: This study suggests that ketamine dosing formulas, alternative to the standardized 0.5 mg/kg based on body weight, may lead to underdosing and potentially impact outcome interpretation. To enhance dosing accuracy, future studies should consider incorporating body impedance analysis and waist-to-hip ratio measurements, as this study did not account for body composition.

Background: Our previous studies indicated that changes in the functioning of the brain glutamatergic system involving the NMDA receptor may affect cytochrome P450 2D (CYP2D) in the brain. Since CYP2D may contribute to the metabolism of neurotransmitters and neurosteroids engaged in the pathology and pharmacology of neuropsychiatric diseases, in the present work we have investigated the effect of compound LY354740, an agonist of glutamatergic metabotropic receptor mGlu_2/3, on brain and liver CYP2D.

Methods: The activity (high performance liquid chromatography with fluorescence detection) and protein levels (Western blotting) of CYP2D were measured in the microsomes from the liver and different brain areas of male Wistar rats after 5 day-treatment with LY354740 (10 mg/kg ip). The results were analyzed statistically using Student's t-test.

Results: Among the investigated brain areas, the highest CYP2D activity was found in the cerebellum and brainstem, which exceeded that in the thalamus, cortex, hippocampus and frontal cortex. The mGlu_2/3 receptor agonist LY354740 administered for five consecutive days significantly increased the protein level and activity of CYP2D in the frontal cortex. Such a tendency was also observed in the other brain areas. LY354740 did not affect the CYP2D activity in the liver.

Conclusions: Repeated administration of the mGlu_2/3 receptor agonist, the compound LY354740 specifically increases the protein level and activity of CYP2D in the frontal cortex, which may accelerate dopamine synthesis via an alternative CYP2D-mediated route in the mesocortical dopaminergic pathway, and thus may contribute to the beneficial pharmacological effect on negative symptoms of schizophrenia.

Background: The study examined the effects of 5-HT₇ receptor activation on GABAergic transmission within the dentate gyrus and plasticity at the glutamatergic perforant path input.

Methods: Immunofluorescence imaging was performed using transverse hippocampal slices from transgenic mice expressing green fluorescent protein (GFP) under the Htr7 promoter. This was followed by whole-cell patch clamp electrophysiological recordings assessing the effects of pharmacologically activating 5-HT₇ receptors on spontaneous inhibitory postsynaptic currents recorded from dentate granule cells and hilar mossy cells-two glutamatergic neuron types present in the dentate gyrus. Extracellular recordings of field excitatory postsynaptic potentials were then performed to assess whether 5-HT₇ receptor activation influenced theta-burst stimulation-evoked plasticity of the perforant path synaptic input.

Results: It was found that parvalbumin and somatostatin interneurons in the dentate gyrus expressed GFP, which suggests they express 5-HT₇ receptors. However, activation of 5-HT₇ receptors had no effect on GABAergic transmission targeting mossy cells or granule cells. There was also no effect of 5-HT₇ receptor activation on perforant path plasticity either with intact or blocked GABA_A receptor signaling.

Conclusion: The presence of 5-HT₇ receptors in a subset of parvalbumin and somatostatin interneurons in the mouse dentate gyrus could mean that they are involved in the inhibitory control of dentate gyrus activity. However, this potential effect was not evident in slice recordings of inhibitory transmission targeting principal cells and did not affect perforant path plasticity. Further experiments are needed to fully elucidate the functional role of these receptors in the dentate gyrus.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for pain relief and inflammation management, but there are challenges related to poor solubility and bioavailability. We explored modifications of ibuprofen (IBU) by forming ionic pairs using amino acid alkyl esters to enhance solubility without compromising the ability to inhibit cyclooxygenase (COX)-1 and COX-2). We comprehensively evaluated the pharmacological properties of the IBU derivatives, focusing on antioxidant activity (based on the ability to scavenge DPPH and ABTS), biocompatibility (using human dermal fibroblasts), and COX inhibitory potential. The antioxidant activity assays significantly enhanced DPPH scavenging activity for several IBU derivatives, particularly [L-SerOiPr][IBU], suggesting potential therapeutic benefits. There was enhanced cell viability with select derivatives, indicating possible stimulatory effects on cellular proliferation. Finally, predominant COX-1 inhibition across derivatives was consistent with IBU's profile. This study provides insights into the pharmacological properties of IBU amino acid derivatives, highlighting their potential as therapeutic agents. Further exploration into structure-activity relationships and in vivo efficacy warranted to advance these derivatives toward clinical applications, offering prospects for novel NSAIDs with enhanced efficacy and reduced side effects.

Introduction: Free fatty acid receptors (FFARs) are G protein-coupled receptors that divide into 4 subtypes; FFAR2 and FFAR3 are activated by short-chain fatty acids, while FFAR1 and FFAR4 - by long-chain fatty acids. Recent studies show the potential involvement of FFARs in the pathophysiology of colorectal cancer (CRC). A decrease in FFAR2 and FFAR4 gene expression is observed in patients with CRC. The aim of our study was to evaluate the anti-cancer effect of FFAR2 and FFAR4 stimulation by selective synthetic agonists in in vitro and in vivo models of CRC.

Materials and methods: FFAR2 agonist, 4-CMTB, and FFAR4 agonist, GSK137647 were used. Cell viability (CCD 841 CoN and SW-480) was determined after 48 h incubation with tested compounds using MTT assay. Real-time qPCR and Western Blot were used to identify changes in FFARs expression. Migration and invasion were characterized by commercially available tests. Colitis-associated CRC (CACRC) mouse model was induced by azoxymethane and dextran sodium sulfate.

Results: 4-CMTB and GSK137647 significantly reduced cancer cell growth as well as migration and invasion capacities. Both synthetic compounds increased FFAR2 and FFAR4 expression in SW-480 cells. Neither 4-CMTB nor GSK137647 influenced the course of AOM/DSS-induced CACRC in mice, however, 4-CMTB elevated FFAR2 protein expression in mouse tissues.

Conclusion: We presented that stimulation of FFAR2 and FFAR4 may inhibit CRC cell viability and migration and that the FFAR2 and FFAR4 expression decreased in CRC can be restored by treatment with respective agonists, indicating new promising pharmacological targets in CRC treatment.

Background: This study examines self-reported sleep alterations in treatment-resistant depression (TRD) inpatients following intravenous ketamine administration.

Methods: This is a post-hoc analysis of a naturalistic observational study, which enrolled 28 inpatients with treatment-resistant major depressive disorder and analyzed self-reported sleep changes (items 1-4; 'insomnia', 'nighttime restlessness', 'early morning waking', 'hypersomnia') in Inventory of Depressive Symptomatology 30-item (IDS SR-30) in responders and non-responders stratified per Montgomery-Åsberg Depression Rating Scale (MADRS) during short-term ketamine treatment.

Results: Responders, as well as non-responders, did not experience significant changes in IDS SR-30 sleep items ('insomnia', 'nighttime restlessness', 'early morning waking', 'hypersomnia') (p's > 0.05) at 7-day follow-up after eight intravenous ketamine infusions as compared to baseline.

Conclusion: Neither responders, nor non-responders reported any significant alterations in sleep patterns during ketamine infusions. These findings are not in line with current literature, as so far modest improvements in sleep during ketamine treatment have been reported. Results should be interpreted with caution, primarily due to the small sample size.

Psychopharmacotherapy of major psychiatric disorders is mostly based on drugs that modulate serotonergic, dopaminergic, or noradrenergic neurotransmission, either by inhibiting their reuptake or by acting as agonists or antagonists on specific monoamine receptors. The effectiveness of this approach is limited by a significant delay in the therapeutic mechanism and self-perpetuating growth of treatment resistance with a consecutive number of ineffective trials. A growing number of studies suggest that drugs targeting glutamate receptors offer an opportunity for rapid therapeutic effect that may overcome the limitations of monoaminergic drugs. In this article, we present a review of glutamate-modulating drugs, their mechanism of action, as well as preclinical and clinical studies of their efficacy in treating mental disorders. Observations of the rapid, robust, and long-lasting effects of ketamine and ketamine encourages further research on drugs targeting glutamatergic transmission. A growing number of studies support the use of memantine and minocycline in major depressive disorder and schizophrenia. Amantadine, zinc, and Crocus sativus extracts yield the potential to ameliorate depressive symptoms in patients with affective disorders. Drugs with mechanisms of action based on glutamate constitute a promising pharmacological group in the treatment of mental disorders that do not respond to standard methods of therapy. However, further research is needed on their efficacy, safety, dosage, interactions, and side effects, to determine their optimal clinical use.

Background: The benefits of pharmacotherapy with sirolimus (SIR) in pediatric transplant recipients are well established. Traditionally, whole blood samples have been used to measure SIR concentrations. Volumetric Absorptive Microsampling (VAMS) is an alternative sampling strategy suitable for Therapeutic Drug Monitoring (TDM). In this study, we developed and validated two liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods for determining SIR concentrations in whole blood (WB) and capillary whole blood samples collected using a VAMS-Mitra™ device.

Methods: We used protein precipitation during WB sample preparation and dispersive liquid-liquid microextraction (DLLME) with methyl tert-butyl ether for VAMS sample preparation to optimise the analyte extraction process. The described validation protocols were cross-validated, confirming the equivalence of the whole-blood and VAMS-based methods. Furthermore, the developed methods were evaluated in two three-level rounds of an external proficiency-testing scheme.

Results: The analytical methods were successfully validated within the calibration range of SIR (0.5-60 ng/ml). The validation parameters met the European Medicines Agency (EMA) and the International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDM&CT) acceptance criteria. No hematocrit (tested in the range of 24.3-64.1%), matrix, or carry-over effects were observed. Cross-validation confirmed the interchangeability between VAMS-LC-MS/MS and WB-LC-MS/MS methods. The developed methods were successfully implemented for SIR determination in 140 clinical samples (70 each of WB and VAMS) from pediatric renal transplant recipients, demonstrating their practicality and reliability.

Conclusion: The VAMS-based method has been rigorously tested and is clinically equivalent to the reference WB-LC-MS/MS method. Additionally, clinical validation confirmed the utility of the presented methods for TDM of the SIR in the pediatric population after renal transplantation.

Background: The treatment of painful diabetic neuropathy is still a clinical problem. The aim of this study was to determine whether astaxanthin, a substance that inhibits mitogen-activated protein kinases, activates nuclear factor erythroid 2-related factor 2 and influences N-methyl-D-aspartate receptor, affects nociceptive transmission in mice with diabetic neuropathy.

Methods: The studies were performed on streptozotocin-induced mouse diabetic neuropathic pain model. Single intrathecal and intraperitoneal administrations of astaxanthin at various doses were conducted in both males and females. Additionally, repeated twice-daily treatment with astaxanthin (25 mg/kg) and morphine (30 mg/kg) were performed. Hypersensitivity was evaluated with von Frey and cold plate tests.

Results: This behavioral study provides the first evidence that in a mouse model of diabetic neuropathy, single injections of astaxanthin similarly reduce tactile and thermal hypersensitivity in both male and female mice, regardless of the route of administration. Moreover, repeated administration of astaxanthin slightly delays the development of morphine tolerance and significantly suppresses the occurrence of opioid-induced hyperalgesia, although it does not affect blood glucose levels, body weight, or motor coordination. Surprisingly, astaxanthin administered repeatedly produces a better analgesic effect when administered alone than in combination with morphine, and its potency becomes even more pronounced over time.

Conclusions: These behavioral results provide a basis for further evaluation of the potential use of astaxanthin in the clinical treatment of diabetic neuropathy and suggest that the multidirectional action of this substance may have positive effects on relieving neuropathic pain in diabetes.

Background: Ethanol disrupts brain activity and memory. There is evidence supporting the beneficial effect of levetiracetam on alcohol consumption. Therefore, the aim of the study was to examine whether levetiracetam has a protective activity against ethanol-induced memory impairment, alterations in selected neurotransmission activities, oxidative stress, and selected essential elements in rats.

Methods: The rats were given levetiracetam (300 mg/kg b.w. po) with ethanol for three weeks prior to behavioral tests. Spatial memory was tested using the Morris water maze, while recognition memory was evaluated using the Novel object recognition test. The GABA and glutamate concentration was determined in three rat brain regions (cerebellum, hippocampus, and cerebral cortex). Serum oxidative stress parameters and selected essential elements concentration (Cu, Mn, Zn, Fe, Mg) in the rat brain were analyzed.

Results: Levetiracetam administered with ethanol improved spatial memory, but did not affect abstinence-induced impairment. The drug also decreased ethanol-induced long-term recognition memory impairment. No alterations in glutamate levels were observed. GABA levels were elevated by levetiracetam in the cerebral cortex and by ethanol in the cerebellum. Ethanol increased catalase activity (CAT) and decreased superoxide dismutase activity (SOD) in the serum. Levetiracetam significantly increased the activity of SOD. Alcohol disrupted the levels of trace elements (Mn, Zn, Mg) in the rat brain. Additionally, levetiracetam alone increased Mg, Fe, and Cu concentrations while all animals receiving the drug also had significantly lower concentrations of Zn.

Conclusions: Levetiracetam had differential effects against ethanol-induced impairments. These findings could have important implications for future levetiracetam treatment in patients.