Breast Cancer Res Treat. 2023 Mar 30. doi: 10.1007/s10549-023-06913-3. Online ahead of print.

NO ABSTRACT

PMID:36997749 | DOI:10.1007/s10549-023-06913-3

Behav Brain Res. 2023 Mar 28:114411. doi: 10.1016/j.bbr.2023.114411. Online ahead of print.

ABSTRACT

Kratom (M. speciosa Korth) is an herbal plant native to Southeast Asia. The leaves have been widely used to alleviate pain and opioid withdrawal symptoms. However, the increasing trend of recreational use of kratom among youth is concerning because substance abuse may render the adolescent brain more susceptible to neuropathological processes, causing dramatic consequences that persist into adulthood. Therefore, the present study aimed to investigate the long-term effects of mitragynine, the main alkaloid and lyophilized kratom decoction (LKD) exposure during adolescence on cognitive behaviours and brain metabolite profiles in adult rats. Adolescent male Sprague-Dawley rats were given mitragynine (3, 10 or 30mg/kg) or LKD orally for 15 consecutive days during postnatal days 31-45 (PND31-45). Behavioural testing was performed during adulthood (PND70-84) and the brains were subjected to metabolomic analysis. The results show that a high dose of mitragynine impaired long-term object recognition memory. Social behaviour and spatial learning were not affected, but both mitragynine and LKD impaired reference memory. Brain metabolomic study revealed several altered metabolic pathways that may be involved in the cognitive behavioural effects of LKD and mitragynine exposure. These pathways include arachidonic acid, taurine and hypotaurine, pantothenate and CoA biosynthesis, and tryptophan metabolism, while the N-isovalerylglycine was identified as the potential biomarker. In summary, adolescent kratom exposure can cause long-lasting cognitive behavioural deficits and alter brain metabolite profiles that are still evident in adulthood. This finding also indicates that the adolescent brain is vulnerable to the impact of early kratom use.

PMID:36997094 | DOI:10.1016/j.bbr.2023.114411

Mini Rev Med Chem. 2023 Mar 28. doi: 10.2174/1389557523666230328153417. Online ahead of print.

ABSTRACT

Compounds from plants that are used in traditional medicine may have medicinal properties. It is well known that plants belonging to the genus Aconitum are highly poisonous. Utilizing substances derived from Aconitum sp. has been linked to deadly negative effects. In addition to their toxicity, the natural substances derived from Aconitum species may have a range of biological effects on humans, such as analgesic, anti-inflammatory, and anti-cancer characteristics. Multiple in silico, in vitro, and in vivo studies have demonstrated the effectiveness of their therapeutic effects. In this review, the clinical effects of natural compounds extracted from Aconitum sp., focusing on aconite-like alkaloids, are investigated particularly by bioinformatics tools such as the quantitative structure-activity relationship method, molecular docking, and predicted pharmacokinetic and pharmacodynamic profiles. The experimental and bioinformatics aspects of aconitine's pharmacogenomic profile are discussed. Our review could help shed light on the molecular mechanisms of Aconitum sp. compounds. The effects of several aconite-like alkaloids such as aconitine, methyllycacintine, or hypaconitine on specific molecular targets, including voltage-gated sodium channels, CAMK2A and CAMK2G during anaesthesia, or BCL2, BCL-XP, and PARP-1 receptors during cancer therapy, are evaluated. According to the reviewed literature, aconite and aconite derivatives have a high affinity for the PARP-1 receptor. The toxicity estimations for aconitine indicate hepatotoxicity and hERG II inhibitor activity; however, this compound is not predicted to be AMES toxic or a hERG I inhibitor. The efficacy of aconitine and its derivatives in treating many illnesses has been proven experimentally. Toxicity occurs as a result of the large ingested dose; however, a valuable component of the usage of this drug in future research is based on the small quantity of an active compound that fulfils a therapeutic role.

PMID:36994982 | DOI:10.2174/1389557523666230328153417

medRxiv. 2023 Mar 17:2023.03.15.23287166. doi: 10.1101/2023.03.15.23287166. Preprint.

ABSTRACT

BACKGROUND: GLP1R agonists provide multiple benefits to patients with type 2 diabetes, including improved glycemic control, weight loss, and decreased risk of major adverse cardiovascular events. Because drug responses vary among individuals, we initiated investigations to identify genetic variants associated with the magnitude of drug responses.

METHODS: Exenatide (5 mcg, sc) or saline (0.2 mL, sc) was administered to 62 healthy volunteers. Frequently sampled intravenous glucose tolerance tests were conducted to assess the impact of exenatide on insulin secretion and insulin action. This pilot study was designed as a crossover study in which participants received exenatide and saline in random order.

RESULTS: Exenatide increased first phase insulin secretion 1.9-fold (p=1.9x10-9) and accelerated the rate of glucose disappearance 2.4-fold (p=2x10-10). Minimal model analysis demonstrated that exenatide increased glucose effectiveness (Sg) by 32% (p=0.0008) but did not significantly affect insulin sensitivity (Si). The exenatide-induced increase in insulin secretion made the largest contribution to inter-individual variation in exenatide-induced acceleration of glucose disappearance while inter-individual variation in the drug effect on Sg contributed to a lesser extent (β=0.58 or 0.27, respectively).

CONCLUSIONS: This pilot study provides validation for the value of an FSIGT (including minimal model analysis) to provide primary data for our ongoing pharmacogenomic study of pharmacodynamic effects of semaglutide ( NCT05071898 ). Three endpoints provide quantitative assessments of GLP1R agonist effects on glucose metabolism: first phase insulin secretion, glucose disappearance rates, and glucose effectiveness.

REGISTRATION: NCT02462421 (clinicaltrials.gov) Funding: American Diabetes Association (1-16-ICTS-112); National Institute of Diabetes and Digestive and Kidney Disease (R01DK130238, T32DK098107, P30DK072488).

PMID:36993363 | PMC:PMC10055582 | DOI:10.1101/2023.03.15.23287166

Vaccines (Basel). 2023 Mar 2;11(3):572. doi: 10.3390/vaccines11030572.

ABSTRACT

Immunogenicity after SARS-CoV-2 vaccination is known to be impaired in liver transplant (LT) recipients, but the results after the application of a third dose show significant improvement in seroconversion rates. In the general population, the antibody response wanes over the course of time after two doses of the vaccination, but seems to be more robust after the application of three doses. Still, the durability of the antibody response in LT recipients who receive a third dose of SARS-CoV-2 vaccination has not been analyzed yet. We therefore assessed antibody responses in a total of 300 LT recipients and observed antibody titers for six months each after patients had received the second and the third doses of the vaccination, explicitly excluding all patients who had suffered from SARS-CoV-2 infection. The initial antibody response was compared to a control group of 122 healthcare workers. After the application of two doses of the vaccination, 74% of LT recipients (158 out of 213) developed antibodies against SARS-CoV-2; this result depended significantly on whether the patients were taking the medication mycophenolate mofetil, and on the age of the patients. Antibody titers declined significantly within six months from 407 BAU/mL (IQR: 0-1865) to 105 BAU/mL (IQR: 0-145) (p ≤ 0.001), but increased after the application of the third vaccine dose in 92% of patients (105 out of 114), showing an antibody response (p ≤ 0.001). After a further six-month period, despite showing a decline from 2055 BAU/mL (IQR: 500 to >2080) to 1805 BAU/mL (IQR: 517 to >2080), the waning of antibody titers was not significant (p = 0.706), and antibody durability appeared to be more robust than that after the second dose. In conclusion, our study confirms the high efficacy of the application of a third dose of SARS-CoV-2 vaccination in LT recipients, and a reasonably sustained humoral response with superior durability in comparison to antibody kinetics after the application of the second dose of the vaccination.

PMID:36992156 | DOI:10.3390/vaccines11030572

Int J Clin Pharm. 2023 Mar 29. doi: 10.1007/s11096-023-01565-1. Online ahead of print.

ABSTRACT

BACKGROUND: Numerous genotype-guided warfarin dosing algorithms have been developed to individualize warfarin doses, but they can only explain 47-52% of the variability.

AIM: This study aimed to develop new warfarin algorithms suitable to predict the stable warfarin dose for the Chinese population and to compare their prediction performance with those of the most commonly used algorithms.

METHOD: Multiple linear regression analysis with the warfarin optimal dose (WOD), logarithm (log) WOD, 1/WOD, and [Formula: see text], respectively, as the dependent variables were performed to deduce a new warfarin algorithm (NEW-Warfarin). WOD was the stable dose that maintained the international normalized ratio (INR) within the target range (2.0-3.0). Three major genotype-guided warfarin dosing algorithms were selected and compared against NEW-Warfarin predictive performance using the mean absolute error (MAE). Furthermore, patients were divided into five groups according to warfarin indications [atrial fibrillation (AF), pulmonary embolism (PE), cardiac-related disease (CRD), deep vein thrombosis (DVT), and other diseases (OD)]. Multiple linear regression analyses were also performed for each group.

RESULTS: The regression equation with [Formula: see text] as the dependent variable had the highest coefficient of determination (R2 = 0.489). The NEW-Warfarin had the best predictive accuracy compared to the three algorithms selected. Group analysis, according to indications, showed that the R2 of the five groups were PE (0.902) > DVT (0.608) > CRD (0.569) > OD (0.436) > AF (0.424).

CONCLUSION: Dosing algorithms based on warfarin indications are more suitable for predicting warfarin doses. Our research provides a novel strategy to develop indication-specific warfarin dosing algorithms to improve the efficacy and safety of warfarin prescribing.

PMID:36991222 | DOI:10.1007/s11096-023-01565-1

Sci Rep. 2023 Mar 29;13(1):5121. doi: 10.1038/s41598-023-32260-w.

NO ABSTRACT

PMID:36991146 | DOI:10.1038/s41598-023-32260-w

Mol Psychiatry. 2023 Mar 29. doi: 10.1038/s41380-022-01909-9. Online ahead of print.

ABSTRACT

Lithium (Li) is one of the most effective drugs for treating bipolar disorder (BD), however, there is presently no way to predict response to guide treatment. The aim of this study is to identify functional genes and pathways that distinguish BD Li responders (LR) from BD Li non-responders (NR). An initial Pharmacogenomics of Bipolar Disorder study (PGBD) GWAS of lithium response did not provide any significant results. As a result, we then employed network-based integrative analysis of transcriptomic and genomic data. In transcriptomic study of iPSC-derived neurons, 41 significantly differentially expressed (DE) genes were identified in LR vs NR regardless of lithium exposure. In the PGBD, post-GWAS gene prioritization using the GWA-boosting (GWAB) approach identified 1119 candidate genes. Following DE-derived network propagation, there was a highly significant overlap of genes between the top 500- and top 2000-proximal gene networks and the GWAB gene list (Phypergeometric = 1.28E-09 and 4.10E-18, respectively). Functional enrichment analyses of the top 500 proximal network genes identified focal adhesion and the extracellular matrix (ECM) as the most significant functions. Our findings suggest that the difference between LR and NR was a much greater effect than that of lithium. The direct impact of dysregulation of focal adhesion on axon guidance and neuronal circuits could underpin mechanisms of response to lithium, as well as underlying BD. It also highlights the power of integrative multi-omics analysis of transcriptomic and genomic profiling to gain molecular insights into lithium response in BD.

PMID:36991131 | DOI:10.1038/s41380-022-01909-9

Adv Exp Med Biol. 2023;1422:121-142. doi: 10.1007/978-3-031-21547-6_4.

ABSTRACT

Cilia are evolutionarily conserved organelles that can be found on virtually every cell. They appear as hair-like structures emanating from the cellular surface either as single or as bundles of cilia. There, they sense external stimuli and translate them into intracellular signals. Motile cilia beat for the generation of locomotion of unicellular organisms or fluid flow in certain body cavities of vertebrate organisms. Defects in cilia are detrimental and account for the development of ciliopathies, one of the fastest-growing family of afflictions. In the past decade, membrane lipids, such as cholesterol and phosphoinositides, have emerged as essential elements in both the signal transduction via cilia and the building of cilia itself. Here, we summarize the current knowledge on the impact of cholesterol and phosphoinositides on cilium biology.

PMID:36988879 | DOI:10.1007/978-3-031-21547-6_4

Basic Clin Pharmacol Toxicol. 2023 Mar 29. doi: 10.1111/bcpt.13867. Online ahead of print.

ABSTRACT

Although switching to antipsychotic monotherapy improves patient outcomes in schizophrenia, antipsychotic deprescribing is rarely performed and its use varies between countries, as do psychotropic prescribing patterns. This study aimed to determine factors associated with antipsychotic deprescribing at discharge after a psychiatric hospitalisation and to compare psychotropic prescribing patterns between Belgium and Québec, Canada. Data on adult inpatients with schizophrenia were collected retrospectively in seven hospitals. At discharge, the number of antipsychotics had decreased in 22.2% of the 63 Canadian patients and 9.9% of the 516 Belgian patients. A number of factors increased the likelihood of antipsychotic deprescribing: a hospitalisation in the Canadian hospital (aOR=4.13, 95% CI 1.48-11.5), living in a residential facility (aOR=2.51, 95% CI 1.05-4.39), ≥2 previous antipsychotic trials (aOR=15.38, 95% CI 3.62-65.36), having an antipsychotic side effect (aOR=1.86, 95% CI 1.01-3.44), and being in a general hospital (aOR=2.28, 95% CI 1.09-4.75). Patients on a long-acting injectable antipsychotic (aOR=0.51, 95% CI 0.26-0.98), with prior clozapine use (aOR=0.36, 95% CI 0.13-0.95), greater antipsychotic exposure (aOR=0.35, 95% CI 0.2-0.61) and more hypno-sedatives (aOR=0.65, 95% CI 0.43-0.98), were less likely to be deprescribed. Specific deprescribing interventions could target patients who are less likely to be deprescribed.

PMID:36988426 | DOI:10.1111/bcpt.13867

Pharmaceutics. 2023 Feb 25;15(3):766. doi: 10.3390/pharmaceutics15030766.

ABSTRACT

Biological drugs, especially those targeting anti-tumour necrosis factor α (TNFα) molecule, have revolutionized the treatment of patients with non-infectious uveitis (NIU), a sight-threatening condition characterized by ocular inflammation that can lead to severe vision threatening and blindness. Adalimumab (ADA) and infliximab (IFX), the most widely used anti-TNFα drugs, have led to greater clinical benefits, but a significant fraction of patients with NIU do not respond to these drugs. The therapeutic outcome is closely related to systemic drug levels, which are influenced by several factors such as immunogenicity, concomitant treatment with immunomodulators, and genetic factors. Therapeutic drug monitoring (TDM) of drug and anti-drug antibody (ADAbs) levels is emerging as a resource to optimise biologic therapy by personalising treatment to bring and maintain drug concentration within the therapeutic range, especially in those patients where a clinical response is less than expected. Furthermore, some studies have described different genetic polymorphisms that may act as predictors of response to treatment with anti-TNFα agents in immune-mediated diseases and could be useful in personalising biologic treatment selection. This review is a compilation of the published evidence in NIU and in other immune-mediated diseases that support the usefulness of TDM and pharmacogenetics as a tool to guide clinicians' treatment decisions leading to better clinical outcomes. In addition, findings from preclinical and clinical studies, assessing the safety and efficacy of intravitreal administration of anti-TNFα agents in NIU are discussed.

PMID:36986627 | DOI:10.3390/pharmaceutics15030766

Nutrients. 2023 Mar 21;15(6):1525. doi: 10.3390/nu15061525.

ABSTRACT

The objective of this systematic review was to provide a compilation of all the literature available on the association between single-nucleotide polymorphisms (SNPs) in the genes involved in the metabolic pathway of vitamin D and overall survival (OS) and progression-free survival (PFS) in patients with non-small cell lung cancer (NSCLC). This systematic review was conducted in accordance with the PRISMA guidelines. It included all the literature published up to 1 November 2022 and was carried out in four databases (Medline [PubMed], Scopus, Web of Science, and Embase), using the PICO strategy, with relevant keywords related to the objective. The quality of the studies included was evaluated with an assessment tool derived from the Strengthening the Reporting of Genetic Association Studies (STREGA) statement. Six studies were included in this systematic review. Our findings showed that the BsmI (rs1544410), Cdx-2 (rs11568820), FokI (rs2228570), ApaI (rs7975232), TaqI (rs731236), rs4646536, rs6068816, rs7041, and rs10741657 SNPs in the genes that play a part in vitamin D synthesis (CYP2R1, CYP27B1), transport (GC), and metabolism (CYP24A1), as well as in the vitamin D receptor (VDR), are associated with OS and/or PFS in patients with NSCLC. The SNPs in VDR have been the most extensively analyzed. This systematic review summed up the available evidence concerning the association between 13 SNPs in the main genes involved in the vitamin D metabolic pathway and prognosis in NSCLC. It revealed that SNPs in the VDR, CYP27B1, CYP24A1, GC, and CYP2R1 genes could have an impact on survival in this disease. These findings suggest the identification of prognostic biomarkers in NSCLC patients. However, evidence remains sparse for each of the polymorphisms examined, so these findings should be treated with caution.

PMID:36986255 | DOI:10.3390/nu15061525

Nutrients. 2023 Mar 17;15(6):1462. doi: 10.3390/nu15061462.

ABSTRACT

High-sugar diet-induced prediabetes and obesity are a global current problem that can be the result of glucose or fructose. However, a head-to-head comparison between both sugars on health impact is still lacking, and Lactiplantibacillus plantarum dfa1 has never been tested, and has recently been isolated from healthy volunteers. The mice were administered with the high glucose or fructose preparation in standard mouse chaw with or without L. plantarum dfa1 gavage, on alternate days, and in vitro experiments were performed using enterocyte cell lines (Caco2) and hepatocytes (HepG2). After 12 weeks of experiments, both glucose and fructose induced a similar severity of obesity (weight gain, lipid profiles, and fat deposition at several sites) and prediabetes condition (fasting glucose, insulin, oral glucose tolerance test, and Homeostatic Model Assessment for Insulin Resistance (HOMA score)). However, fructose administration induced more severe liver damage (serum alanine transaminase, liver weight, histology score, fat components, and oxidative stress) than the glucose group, while glucose caused more prominent intestinal permeability damage (FITC-dextran assay) and serum cytokines (TNF-α, IL-6, and IL-10) compared to the fructose group. Interestingly, all of these parameters were attenuated by L. plantarum dfa1 administration. Because there was a subtle change in the analysis of the fecal microbiome of mice with glucose or fructose administration compared to control mice, the probiotics altered only some microbiome parameters (Chao1 and Lactobacilli abundance). For in vitro experiments, glucose induced more damage to high-dose lipopolysaccharide (LPS) (1 µg/mL) to enterocytes (Caco2 cell) than fructose, as indicated by transepithelial electrical resistance (TEER), supernatant cytokines (TNF-α and IL-8), and glycolysis capacity (by extracellular flux analysis). Meanwhile, both glucose and fructose similarly facilitated LPS injury in hepatocytes (HepG2 cell) as evaluated by supernatant cytokines (TNF-α, IL-6, and IL-10) and extracellular flux analysis. In conclusion, glucose possibly induced a more severe intestinal injury (perhaps due to LPS-glucose synergy) and fructose caused a more prominent liver injury (possibly due to liver fructose metabolism), despite a similar effect on obesity and prediabetes. Prevention of obesity and prediabetes with probiotics was encouraged.

PMID:36986190 | DOI:10.3390/nu15061462

J Pers Med. 2023 Mar 8;13(3):489. doi: 10.3390/jpm13030489.

ABSTRACT

For patients with type 2 diabetes, metformin is the most often recommended drug. However, there are substantial individual differences in the pharmacological response to metformin. To investigate the effect of transporter polymorphisms on metformin pharmacokinetics in an environment free of confounding variables, we conducted our study on healthy participants. This is the first investigation to consider demographic characteristics alongside all transporters involved in metformin distribution. Pharmacokinetic parameters of metformin were found to be affected by age, sex, ethnicity, and several polymorphisms. Age and SLC22A4 and SLC47A2 polymorphisms affected the area under the concentration-time curve (AUC). However, after adjusting for dose-to-weight ratio (dW), sex, age, and ethnicity, along with SLC22A3 and SLC22A4, influenced AUC. The maximum concentration was affected by age and SLC22A1, but after adjusting for dW, it was affected by sex, age, ethnicity, ABCG2, and SLC22A4. The time to reach the maximum concentration was influenced by sex, like half-life, which was also affected by SLC22A3. The volume of distribution and clearance was affected by sex, age, ethnicity and SLC22A3. Alternatively, the pharmacokinetics of metformin was unaffected by polymorphisms in ABCB1, SLC2A2, SLC22A2, or SLC47A1. Therefore, our study demonstrates that a multifactorial approach to all patient characteristics is necessary for better individualization.

PMID:36983671 | DOI:10.3390/jpm13030489

J Pers Med. 2023 Mar 4;13(3):471. doi: 10.3390/jpm13030471.

ABSTRACT

The inadequate efficacy and adverse effects of antipsychotics severely affect the recovery of patients with schizophrenia spectrum disorders (SSD). We report the evidence for associations between pharmacogenetic (PGx) variants and antipsychotics outcomes, including antipsychotic response, antipsychotic-induced weight/BMI gain, metabolic syndrome, antipsychotic-related prolactin levels, antipsychotic-induced tardive dyskinesia (TD), clozapine-induced agranulocytosis (CLA), and drug concentration level (pharmacokinetics) in SSD patients. Through an in-depth systematic search in 2010-2022, we identified 501 records. We included 29 meta-analyses constituting pooled data from 298 original studies over 69 PGx variants across 39 genes, 4 metabolizing phenotypes of CYP2D9, and 3 of CYP2C19. We observed weak unadjusted nominal significant (p < 0.05) additive effects of PGx variants of DRD1, DRD2, DRD3, HTR1A, HTR2A, HTR3A, and COMT (10 variants) on antipsychotic response; DRD2, HTR2C, BDNF, ADRA2A, ADRB3, GNB3, INSIG2, LEP, MC4R, and SNAP25 (14 variants) on weight gain; HTR2C (one variant) on metabolic syndrome; DRD2 (one variant) on prolactin levels; COMT and BDNF (two variants) on TD; HLA-DRB1 (one variant) on CLA; CYP2D6 (four phenotypes) and CYP2C19 (two phenotypes) on antipsychotics plasma levels. In the future, well-designed longitudinal naturalistic multi-center PGx studies are needed to validate the effectiveness of PGx variants in antipsychotic outcomes before establishing any reproducible PGx passport in clinical practice.

PMID:36983653 | DOI:10.3390/jpm13030471

J Pers Med. 2023 Feb 26;13(3):416. doi: 10.3390/jpm13030416.

ABSTRACT

Metoprolol is a medication commonly utilized in select patients to achieve a reduction in heart rate, systolic blood pressure, or other indications. A majority of metoprolol metabolism occurs via CYP2D6. Decreased expression of the CYP2D6 enzyme increases the concentration of metoprolol. Current pharmacogenomics guidelines by the Dutch Pharmacogenomics Working Group recommend slower titrations and dose decreases to minimize adverse effects from poor metabolizers or normal metabolizers taking concomitant medications that are strong inhibitors of CYP2D6 (phenoconverters). This study aimed to evaluate adverse effects such as bradycardia, hypotension, and syncope in patients who are expected to have absent CYP2D6 enzyme activity due to drug-drug or drug-gene interactions. The secondary aims of this study were to evaluate heart rate measurements for the included participants. Retrospective data were collected for individuals with CYP2D6 genotyping results obtained for clinical purposes. Three categories (CYP2D6 normal metabolizers, poor metabolizers, and phenoconverters) were assigned. A total of 325 participants were included. There was no statistically significant difference found in the primary composite outcome between the three metabolizer groups (p = 0.054). However, a statistically significant difference was identified in the incidences of bradycardia between the poor metabolizers and the normal metabolizers or phenoconverters (p < 0.0001). The average heart rates were 2.8 beats per minute (bpm) and 2.6 bpm lower for the poor metabolizer and phenoconverter groups, respectively, compared to the normal metabolizers (p < 0.0001 for both comparisons). This study further supports the role of genetic testing in precision medicine to help individualize patient care as CYP2D6 poor metabolizers taking metoprolol were found to have an increase in bradycardia. Additional research is needed to clarify the dose relationship in this drug-gene interaction.

PMID:36983598 | DOI:10.3390/jpm13030416

J Pers Med. 2023 Feb 25;13(3):411. doi: 10.3390/jpm13030411.

ABSTRACT

Research in the field of psychopharmacology is ongoing to develop novel compounds which can revolutionize the treatment of psychiatric disorders. The concept of bench-to-bedside is a tedious process, transforming the initial research performed in the laboratories into novel treatment options. Schizophrenia (SCZ) is a chronic psychiatric illness with significant morbidity and mortality. SCZ not only presents with psychotic symptoms including hallucinations and delusions but also with negative and cognitive symptoms. The negative symptoms include the diminished ability to express emotions, loss of pleasure, and motivation with minimal social interactions. Conventional antipsychotics primarily target positive symptoms with minimal therapeutic benefits for negative and cognitive symptoms along with metabolic side effects. Researchers have explored novel targets to develop new compounds to overcome the above limitations. The glutamatergic system has provided new hope in treating schizophrenia by targeting negative and cognitive symptoms. Other receptor modulators, including serotonergic, phosphodiesterase, trans-amine-associated receptors, etc., are novel targets for developing new compounds. Future research is required in this field to explore novel compounds and establish their efficacy and safety for the treatment of schizophrenia. Last but not least, pharmacogenomics has effectively utilized genetic information to develop novel compounds by minimizing the risk of failure of the clinical trials and enhancing efficacy and safety.

PMID:36983593 | DOI:10.3390/jpm13030411

J Pers Med. 2023 Feb 22;13(3):385. doi: 10.3390/jpm13030385.

ABSTRACT

Huntington's disease (HD) is an autosomal dominant progressive brain disorder, caused by a pathological expansion of a CAG repeat that encodes the huntingtin gene. This genetic neurodegenerative rare disease is characterized by cognitive, motor, and neuropsychiatric manifestations. The aim of the treatment is symptomatic and addresses the hyperkinetic disorders (chorea, dystonia, myoclonus, tics, etc.) and the behavioural and cognitive disturbances (depression, anxiety, psychosis, etc.) associated with the disease. HD is still a complex condition in need of innovative and efficient treatment. The long-term goal of pharmacogenetic studies is to use genotype data to predict the effective treatment response to a specific drug and, in turn, prevent potential undesirable effects of its administration. Chorea, depression, and psychotic symptoms have a substantial impact on HD patients' quality of life and could be better controlled with the help of pharmacogenetic knowledge. We aimed to carry out a review of the available publications and evidence related to the pharmacogenetics of HD, with the objective of compiling all information that may be useful in optimizing drug administration. The impact of pharmacogenetic information on the response to antidepressants and antipsychotics is well documented in psychiatric patients, but this approach has not been investigated in HD patients. Future research should address several issues to ensure that pharmacogenetic clinical use is appropriately supported, feasible, and applicable.

PMID:36983567 | DOI:10.3390/jpm13030385

Int J Mol Sci. 2023 Mar 22;24(6):5974. doi: 10.3390/ijms24065974.

ABSTRACT

High blood pressure (HBP) is the leading risk factor for cardiovascular disease (CVD) and all-cause mortality worldwide. The progression of the disease leads to structural and/or functional alterations in various organs and increases cardiovascular risk. Currently, there are significant deficiencies in its diagnosis, treatment, and control. Vitamin D is characterized by its functional versatility and its involvement in countless physiological processes. This has led to the association of vitamin D with many chronic diseases, including HBP and CVD, due to its involvement in the regulation of the renin-angiotensin-aldosterone system. The aim of this study was to evaluate the effect of 13 single nucleotide polymorphisms (SNPs) related to the vitamin D metabolic pathway on the risk of developing HBP. An observational case-control study was performed, including 250 patients diagnosed with HBP and 500 controls from the south of Spain (Caucasians). Genetic polymorphisms in CYP27B1 (rs4646536, rs3782130, rs703842, and rs10877012), CYP2R1 rs10741657, GC rs7041, CYP24A1 (rs6068816, and rs4809957), and VDR (BsmI, Cdx2, FokI, ApaI, and TaqI) were analyzed by real-time PCR using TaqMan probes. Logistic regression analysis, adjusted for body mass index (BMI), dyslipidemia, and diabetes, showed that in the genotypic model, carriers of the GC rs7041 TT genotype were associated with a lower risk of developing HBP than the GG genotype (odds ratio (OR) = 0.44, 95% confidence interval (CI): 0.41-0.77, p = 0.005, TT vs. GG). In the dominant model, this association was maintained; carriers of the T allele showed a lower risk of developing HBP than carriers of the GG genotype (OR = 0.69, 95% CI: 0.47-1.03; TT + TG vs. GG, p = 0.010). Finally, in the additive model, consistent with previous models, the T allele was associated with a lower risk of developing HBP than the G allele (OR = 0.65, 95% CI: 0.40-0.87, p = 0.003, T vs. G). Haplotype analysis revealed that GACATG haplotypes for SNPs rs1544410, rs7975232, rs731236, rs4646536, rs703842, and rs10877012 were associated with a marginally significant lower risk of developing HBP (OR = 0.35, 95% CI: 0.12-1.02, p = 0.054). Several studies suggest that GC 7041 is associated with a lower active isoform of the vitamin D binding protein. In conclusion, the rs7041 polymorphism located in the GC gene was significantly associated with a lower risk of developing HBP. This polymorphism could therefore act as a substantial predictive biomarker of the disease.

PMID:36983047 | DOI:10.3390/ijms24065974

Int J Mol Sci. 2023 Mar 15;24(6):5607. doi: 10.3390/ijms24065607.

ABSTRACT

Osteosarcoma (OS) is the most common malignant bone tumor in children and adolescents. In recent decades, OS treatment has reached a plateau and drug resistance is still a major challenge. Therefore, the present study aimed to analyze the expression of the genes related to pharmacogenetics in OS. The expression of 32 target genes in 80 paired specimens (pre-chemotherapeutic primary tumor, post-chemotherapeutic primary tumor and pulmonary metastasis) obtained from 33 patients diagnosed with OS were analyzed by the real-time PCR methodology. As the calibrators (control), five normal bone specimens were used. The present study identified associations between the OS outcome and the expression of the genes TOP2A, DHFR, MTHFR, BCL2L1, CASP3, FASLG, GSTM3, SOD1, ABCC1, ABCC2, ABCC3, ABCC5, ABCC6, ABCC10, ABCC11, ABCG2, RALBP1, SLC19A1, SLC22A1, ERCC1 and MSH2. In addition, the expression of the ABCC10, GGH, GSTM3 and SLC22A1 genes were associated with the disease event, and the metastasis specimens showed a high expression profile of ABCC1, ABCC3 and ABCC4 genes and a low expression of SLC22A1 and ABCC10 genes, which is possibly an important factor for resistance in OS metastasis. Therefore, our findings may, in the future, contribute to clinical management as prognostic factors as well as possible therapeutic targets.

PMID:36982681 | DOI:10.3390/ijms24065607