Br J Clin Pharmacol. 2023 Jan 7. doi: 10.1111/bcp.15658. Online ahead of print.

ABSTRACT

OBJECTIVES: Since Fc-gamma receptors (FcgRs) are involved in the degradation of IgG complexes, we assessed whether a modification in FcgRs' affinity to Fc portion, caused by single nucleotide polymorphisms such as rs1801274-R131H FcgRIIa, rs396991-F158V FcgRIIIa and NA1/NA2-FcgRIIIb, might impact clearance of therapeutic monoclonal antibodies and thus, serum drug levels and the development of anti-drug antibodies.

METHODS: A cross sectional, multicentral and non-interventional study was conducted in Tunisian RA patients treated with rituximab (RTX), etanercept (ETA), infliximab (IFX) and adalimumab (ADL). Serum drug level (SDL) of the different biologics and ADA against them were measured. All patients were genotyped for the three FCGR SNPs.

RESULTS: A total of 81 patients were included: 47 were under TNF-inhibitors (18 ETA, 13 ADL and 16 IFX) and 34 were under RTX. Regardless of the type of biotherapy, SDL was in therapeutic range, in 35 patients (43.2%) of whom only one was treated with RTX. Fourteen patients (22.2%) developed ADA but none of the patients treated with ETA had detectable ADA levels. There was no association between SDL positivity and FCGR polymorphisms. However, the high affinity FCGR2A 131 H/H receptor was statistically more prevalent in patients with detectable ADA treated with ADL, IFX and RTX (p=0.018). The same result was obtained in mAb TNFi subgroup (n=29, p=0.022) as well as in patients treated only with IFX (n=16, p=0.029).

CONCLUSION: Our work supports the hypothesis of an impact of FCGR SNPs on biologics' immunogenicity, particularly FCGR R131H polymorphism, but further studies with larger cohorts needs to be undertaken to confirm these results.

PMID:36609675 | DOI:10.1111/bcp.15658

Tumori. 2023 Jan 6:3008916221147944. doi: 10.1177/03008916221147944. Online ahead of print.

ABSTRACT

BACKGROUND: Trifluridine/tipiracil and regorafenib are indicated for metastatic colorectal cancer (mCRC) patients' refractory to standard chemotherapy. No prognostic or predictive biomarkers are available for these agents.

METHODS: We assessed messenger ribonucleic acid (mRNA) expression of four biomarkers implicated in the mechanism of action of trifluridine/tipiracil (TK-1 and TP) and regorafenib (Ang-2 and Tie-2) in baseline plasma-derived microvesicles of chemo-refractory mCRC patients treated with these agents (trifluridine/tipiracil cohort and regorafenib cohort), to explore their prognostic and predictive role.

RESULTS: Baseline characteristics of the two cohorts were not different. Ang-2 mRNA was not detectable. Only TK-1 expression measured as a continuous variable was associated with progression-free survival (HR=1.09, 95%CI: 0.99-1.21; p=0.07) and overall survival (HR=1.11, 95%CI: 1.00-1.22; p=0.04), confirmed at multivariate analysis for progression-free survival (p=0.02) with a positive trend for overall survival (p=0.08). Baseline mRNA levels of TK-1, TP and Tie-2 were not predictive of trifluridine/tipiracil and regorafenib benefit.

CONCLUSION: Baseline mRNA levels of TK-1, TP and Tie-2 on plasma-derived microvesicles were not predictive of trifluridine/tipiracil and regorafenib benefit. Future studies should analyze the early modulation of these biomarkers to assess their potential predictive role.

PMID:36609197 | DOI:10.1177/03008916221147944

Neuropharmacology. 2023 Jan 3:109410. doi: 10.1016/j.neuropharm.2022.109410. Online ahead of print.

ABSTRACT

Bipolar disorder (BD) is characterized by manic and depressive mood episodes and loss of brain gray matter. Lithium has antimanic and neuroprotective properties, but only 30% BD patients respond to lithium pharmacotherapy. Dopamine signaling has been implicated in BD and may contribute to lithium response. Methamphetamine (METH) stimulates dopamine release and models the clinical features of mania but has never been used to study cell death in BD patient neurons. We used BD patient derived neuronal progenitor cells (NPCs) to determine whether the vulnerability to cell death differed in samples from lithium responder (Li-R) and non-responder (Li-NR) BD patients and healthy controls following METH exposure in vitro. We hypothesized that NPCs from Li-R and Li-NR would differ in vulnerability to METH, dopamine signaling and neuroprotection from lithium. Following METH, NPCs from controls and Li-NR showed significantly greater cell loss compared to Li-R. Pre-treatment of NPCs with the D1 dopamine receptor antagonist SCH 23390 reversed the neurotoxic effects of METH. In Li-R NPCs, expression of phosho-ERK1/2 was significantly increased. In Li-NR NPCs, phospho-AKT, D1 and D2 dopamine receptor proteins were significantly increased. Pre-treatment of NPCs with lithium before METH reversed the neurotoxic effects of METH in control NPCs, whereas Li-NR showed less protective benefit. Li-R cells showed decreased levels of cell death after METH and comparatively high viability, and lithium treatment did not increase viability any further. This novel NPC model of mania reveals differences in cell death that could help identify mechanisms of lithium response in BD.

PMID:36608815 | DOI:10.1016/j.neuropharm.2022.109410

Arh Hig Rada Toksikol. 2023 Jan 7;73(4):303-307. doi: 10.2478/aiht-2022-73-3663. eCollection 2022 Dec 1.

ABSTRACT

Uridine diphosphate glucuronosyltransferase-2B7 (UGT2B7), enzyme responsible for the elimination of a number of xenobiotics through glucuronidation, is expressed in the gut, kidneys, intestines, and brain. However, data on the frequency of UGT2B7 polymorphisms in the Croatian population are limited. The aim of this study was to assess the frequency of the UGT2B7 c.-161C>T (rs7668258) polymorphism in the Croatian population and to compare it with reported frequencies in other populations. This polymorphism is in complete linkage disequilibrium with the UGT2B7 c.802C>T (UGT2B7*2, rs7439366) variant, which is important in clinical medicine. The study reports data of 501 participants from University Hospital Centre Zagreb. All data were collected and analysed retrospectively. Genotyping was performed by real-time polymerase chain reaction (PCR) using the TaqMan® Drug Metabolism Genotyping Assay for UGT2B7 c.-161C>T (rs7668258). We found that 120 (23.95 %) participants were carriers of the UGT2B7 c.-161CC genotype and 255 (50.9 %) were heterozygous carriers (UGT2B7 c.-161CT), while 126 (25.15 %) were homozygous carriers of the variant allele (UGT2B7 c.-161TT). The frequency of the variant UGT2B7 c.-161C>T allele in this study was T=0.506. The frequency of the UGT2B7 c.-161C>T allelic variants and genotypes in the Croatian population is similar to other European populations.

PMID:36607721 | DOI:10.2478/aiht-2022-73-3663

Expert Opin Drug Metab Toxicol. 2023 Jan 6. doi: 10.1080/17425255.2022.2166486. Online ahead of print.

ABSTRACT

INTRODUCTION: Clopidogrel is the only antiplatelet agent whose activity is significantly affected by CYP2C19 polymorphism.

AREAS COVERED: This review has summarized the available evidence on the clinically significant association between CYP2C19 polymorphism and clopidogrel-based therapy; reviewed the current recommendations for clinical use of CYP2C19 genotype test results in patients on clopidogrel treatment; and discussed possible pitfalls of routine application, and future perspectives of antiplatelets pharmacogenetics.

EXPERT OPINION: The available body of evidence, reflected in several meta-analyses and high-quality clinical practice guidelines, shows that the presence of CYP2C19 LOF alleles, especially CYP2C19*2, correlates with impaired activation of clopidogrel and variable platelet inhibition, followed by minimal or no antiplatelet effect, and higher risk of treatment failure. In combination with other known risk factors, CYP2C19 genetic testing could be very valuable in predicting low clopidogrel efficacy. At the same time, it could be very successful in selecting patients who will most probably benefit from the clopidogrel-based therapy, thus decreasing the pool of those who might need more expensive and otherwise riskier antiplatelet alternatives.

PMID:36606363 | DOI:10.1080/17425255.2022.2166486

Addiction. 2023 Jan 5. doi: 10.1111/add.16126. Online ahead of print.

ABSTRACT

BACKGROUND AND AIMS: Previous findings have been equivocal as to whether a single nucleotide polymorphism (rs2832407) in GRIK1, which encodes a glutamate receptor subunit, moderates the effects of topiramate treatment for drinking reduction. We leveraged intensive longitudinal data to provide greater precision and allow an examination of intermediate outcomes addressing this question. We used data from a randomized controlled trial (RCT) to test the hypotheses that topiramate treatment reduces daily heavy drinking, desire to drink, and positive alcohol expectancies and that these effects are stronger in rs2832407*C-allele homozygotes.

DESIGN: Secondary data analysis of a randomized controlled trial SETTING: University of Pennsylvania Treatment Research Center in the United States of America PARTICIPANTS/CASES: Participants were 164 individuals (70% male, mean age=51.5, 36% rs2832407*C-allele homozygotes) who sought to reduce or stop drinking. Intervention and Comparator Participants were assigned to medication (topiramate or placebo), with stratification by genotype group (CC vs. AA/AC) and treatment goal (reduce versus abstain).

MEASUREMENTS: Over the 12-week treatment period, participants completed daily interactive voice response (IVR) surveys.

FINDINGS: On any given day during treatment, participants who received topiramate had lower odds of IVR-reported heavy drinking (odds ratio [OR]=0.257, b (standard error [SE])=-1.351 (0.334), p<0.001) and lower levels of desire to drink (b (SE)=-0.323 (0.122), p=0.001) and positive alcohol expectancies (b (SE)=-0.347 (0.138), p=0.013) than those who received placebo. Participants who received topiramate also reported greater reductions in positive alcohol expectancies over the first 2 weeks of treatment than those who received placebo (b (SE)=-0.028(0.008), p=0.001), but topiramate did not impact the daily rate of change in heavy drinking or desire to drink. Genotype did not moderate the effects of topiramate on any outcomes examined (ps>0.05).

CONCLUSIONS: Topiramate is an effective medication for individuals seeking to reduce heavy drinking. The effects are not moderated by the single nucleotide polymorphism rs2832407.

PMID:36606295 | DOI:10.1111/add.16126

Malays Fam Physician. 2022 Nov 25;17(3):22-32. doi: 10.51866/rv.208. eCollection 2022 Nov 30.

ABSTRACT

INTRODUCTION: Patient education is an integral component of diabetes mellitus care. The emergence of different methods and characteristics of patient education has led to varying outcomes of quality of life (QoL). Herein, we systematically searched for published studies reporting patient education and its methods and characteristics for improving the QoL of patients with type 2 diabetes mellitus (T2DM).

METHOD: In this scoping review, eligible studies from six databases (PubMed, Scopus, Cochrane Library, Springer Link, Science Direct and Google Scholar) were identified. The keywords used in the search strategies were as follows: health education, health promotion, patient education, diabetes care, QoL, diabetes mellitus and type 2 diabetes mellitus. Two reviewers independently screened all references and full-text articles retrieved to identify articles eligible for inclusion.

RESULTS: A total of 203 articles were identified in the initial search. Of them, 166 were excluded after screening the titles and abstracts. Further full-text screening led to the subsequent removal of 22 articles, leaving 15 articles eligible for data extraction.

CONCLUSION: There is a broad array of methods of patient education for improving the QoL of patients with T2DM. Self-management education with supplementary supervision and monitoring effectively improves QoL. Future studies must emphasise the application of holistic education covering psychological distress, diet plan, and physical health.

PMID:36606173 | PMC:PMC9809450 | DOI:10.51866/rv.208

Biomed Rep. 2022 Oct 31;17(6):99. doi: 10.3892/br.2022.1582. eCollection 2022 Dec.

ABSTRACT

In precision medicine, multiple factors are involved in clinical decision-making because of ethnic and racial genetic diversity, family history and other health factors. Although advanced techniques have evolved, there is still an economic obstacle to pharmacogenetic (PGx) implementation in developing countries. The aim of the present study was to provide an alternative pipeline that roughly estimate patient carrier type and prescreen out wild-type samples before sequencing or genotyping to determine genetic status. Fast co-amplification at lower denaturation temperature (COLD)-PCR was used to differentiate genetic variant non-carriers from carriers. The majority of drugs are hepatically cleared by cytochrome P450 (CYP) enzymes and genes encoding CYP enzymes are highly variable. Of all the CYPs, CYP2 family of CYP2C9, CYP2C19, and CYP2D6 isoforms have clinically significant impact on drugs of PGx testing. Therefore, five variants associated with these CYPs were selected for preliminary testing with this novel pipeline. For fast COLD-PCR, the optimal annealing temperature and critical denaturation temperature were determined and evaluated via Sanger sequencing of 27 randomly collected samples. According to precise Tc, to perform in a single-reaction is difficult. However, in this study, this issue was resolved by combination of precise Tc using 10+10+20 cycles. The results showed 100% sensitivity and specificity, with perfect agreement (κ=1.0) compared with Sanger sequencing. The present study provides a prescreening platform by introducing multiplex fast COLD-PCR as a pharmacoeconomic implementation. Our study just present in five variants which are not enough to describe patient metabolic status. Therefore, other actional genetic variants are still needed to cover the actual patient's genotypes. Nevertheless, the proposed method can well-present its efficiency and reliability for serving as a PGx budget platform in the future.

PMID:36606140 | PMC:PMC9808490 | DOI:10.3892/br.2022.1582

Pharmgenomics Pers Med. 2022 Dec 30;15:1029-1035. doi: 10.2147/PGPM.S389197. eCollection 2022.

ABSTRACT

Vincristine-induced peripheral neuropathy (VIPN) is a common adverse effect of vincristine (VCR) for which there is no preventative or curative treatment. Here, we report a case of a patient suffering from severe VCR-related neurotoxicity. To explore the possible causes of severe VIPN in this patient, a set of genes involved in VCR metabolism, transport or are related to the cytoskeleton, microtubules, and inherited neurological diseases gene polymorphisms were examined via pharmacogenetic analyses. The genotyping results revealed the presence of a complex pattern of polymorphisms in CYP3A5, ABCC2, SYNE2, BAHD1, NPSR1, MTNR1B, CEP72, miR-4481 and miR-3117. A comprehensive understanding of all the pharmacogenetic risk factors for VIPN may explain the occurrence of severe neurotoxicity in our patient. This case brings to light the potential importance of pharmacogenetic testing in clinical practice. It also exemplifies the importance of developing early-detection strategies to optimize treatment regimens through prior risk stratification while reducing adverse drug reactions and personalizing therapy.

PMID:36605068 | PMC:PMC9809358 | DOI:10.2147/PGPM.S389197

Saudi Pharm J. 2022 Dec;30(12):1765-1772. doi: 10.1016/j.jsps.2022.10.005. Epub 2022 Oct 12.

ABSTRACT

INTRODUCTION: Possessing a correct and comprehensive foundation on the science of pharmacogenomics (PGx) is an important prerequisite for pharmacists to successfully apply pharmacogenomic testing to patient care. While some work has addressed general PGx knowledge among pharmacists, little research has specifically focused on PGx foundational knowledge. This study examines the level of foundational knowledge of PGx and interest in learning about PGx among community pharmacists and first-year pharmacy students at Beirut Arab University (BAU), Beirut, Lebanon.

METHODS: A cross-sectional survey was self-administered to community pharmacists within a random sample of community pharmacies in Beirut, Lebanon, and to first-year BAU pharmacy students. The knowledge component of the instrument consisted of 25 items, each worth one point, addressing fundamental PGx information. The validity and internal consistency of the designed instrument were tested among the study population. Correlation analysis was carried out between aggregate knowledge and key variables for participating pharmacists.

RESULTS: Of 150 approached pharmacists, 137 (91 %) participated and of 132 pharmacy students, 131 (99 %) participated. The average knowledge score for community pharmacists was 15 (Standard Deviation = 4) out of a possible total of 25 with the total number of correct answers ranging from 8 to 24 out of 25 questions. The average score for pharmacy students was 17 (Standard Deviation = 5) out of a possible total of 25 with the total number of correct answers ranging from 5 to 24. Pharmacists' age and years of practice were associated with a lower aggregate knowledge score (r = -0.20; p < 0.05 and r = -0.21; p < 0.05), respectively. Pharmacists' interest in learning about PGx varied whereas 62 % were either interested or very interested in learning about PGx. Students' interest, however, was higher with 70 % being either interested or very interested. Specific PGx topics of interest to participants were highlighted.

CONCLUSION: This study identified areas where PGx foundational knowledge was acceptable and others where significant opportunities for improvement exist. These results add to the rapidly expanding field of pharmacogenomics education and practice in relation to pharmacy. In particular, these findings have significant implications for planning pharmacogenomics-related educational activities targeting current and future pharmacists.

PMID:36601506 | PMC:PMC9805969 | DOI:10.1016/j.jsps.2022.10.005

Front Cardiovasc Med. 2022 Dec 19;9:1016126. doi: 10.3389/fcvm.2022.1016126. eCollection 2022.

ABSTRACT

BACKGROUND: Dyslipidemia is a major cause of arteriosclerotic cardiovascular disease (ASCVD), and low-density lipoprotein cholesterol (LDL-C) is the profile to be reduced to prevent disease progression. Small dense low-density lipoprotein cholesterol (sdLDL-C) has been proven to be a more effective biomarker than LDL-C for ASCVD primary and secondary prevention. CYP2C19 is an important drug metabolism gene. This study aimed to investigate the relationship between sdLDL-C and coronary artery disease (CAD) risk factors and explore the influence of CYP2C19 metabolizer phenotypes on the sdLDL-C lowering efficacy of statins.

METHODS: This study recruited 182 patients with CAD and 200 non-CAD controls. Baseline laboratory indices of fasting blood were detected, including blood lipids, glucose, and creatinine. In addition, LDL-C subfractions were separated and quantified. Gene polymorphisms of SLCO1B1 and CYP2C19 were detected in patients with CAD. The LDL-C subfractions levels of patients with CAD were followed up after statin drug treatment.

RESULTS: Total cholesterol, LDL-C, LDLC-2, LDLC-3, LDLC-4, LDLC-5, LDLC-6, LDLC-7, and sdLDL-C levels of patients with CAD were significantly higher than those in non-CAD controls. Meanwhile, sdLDL-C (AUC = 0.838) and LDLC-4 (AUC = 0.835) performed outstandingly in distinguishing patients with CAD from controls. Based on CYP2C19 metabolizer phenotypes, 113 patients with CAD were divided into the extensive metabolizer (EM, n = 49), intermediate metabolizer (IM, n = 52), and poor metabolizer (PM, n = 12) groups. The patients with IM and PM metabolizer phenotypes had better sdLDL-C lowering efficacy after taking statin drugs than patients with EM phenotype (P = 0.0268, FDR = 0.0536). The SLCO1B1 genotype had no significant impact on the efficacy of statins (P = 0.1611, FDR = 0.1611).

CONCLUSION: sdLDL-C and LDLC-4 outperformed other blood lipids such as LDL-C for CAD risk screening. CYP2C19 metabolizer phenotypes had the potential to predict the efficacy of statins in lowering sdLDL-C.

PMID:36601065 | PMC:PMC9806256 | DOI:10.3389/fcvm.2022.1016126

Sci Adv. 2023 Jan 4;9(1):eabn9793. doi: 10.1126/sciadv.abn9793. Epub 2023 Jan 4.

ABSTRACT

During embryonic development, mutually antagonistic signaling cascades determine gonadal fate toward a testicular or ovarian identity. Errors in this process result in disorders of sex development (DSDs), characterized by discordance between chromosomal, gonadal, and anatomical sex. The absence of an appropriate, accessible in vitro system is a major obstacle in understanding mechanisms of sex-determination/DSDs. Here, we describe protocols for differentiation of mouse and human pluripotent cells toward gonadal progenitors. Transcriptomic analysis reveals that the in vitro-derived murine gonadal cells are equivalent to embryonic day 11.5 in vivo progenitors. Using similar conditions, Sertoli-like cells derived from 46,XY human induced pluripotent stem cells (hiPSCs) exhibit sustained expression of testis-specific genes, secrete anti-Müllerian hormone, migrate, and form tubular structures. Cells derived from 46,XY DSD female hiPSCs, carrying an NR5A1 variant, show aberrant gene expression and absence of tubule formation. CRISPR-Cas9-mediated variant correction rescued the phenotype. This is a robust tool to understand mechanisms of sex determination and model DSDs.

PMID:36598988 | DOI:10.1126/sciadv.abn9793

Per Med. 2023 Jan 4. doi: 10.2217/pme-2022-0135. Online ahead of print.

NO ABSTRACT

PMID:36598111 | DOI:10.2217/pme-2022-0135

Curr Pharm Des. 2023 Jan 3. doi: 10.2174/1381612829666230103161824. Online ahead of print.

ABSTRACT

¬¬A dipeptide mimetic of the BDNF loop 4, bis (N-monosuccinyl-L-seryl-L-lysine) hexamethylenediamide, GSB-106, was designed and synthesized by V.V. Zakusov Research Institute of Pharmacology. The compound activated in vitro TrkB, MAPK/ERK, PI3K/AKT, and PLCγ, like full-length BDNF. In vivo, GSB-106 exhibited antidepressant-like, neuroprotective and neuroregenerative properties. The aim of this work was to study the effects of GSB-106 on depressive-like behavior, cognitive impairments, as well as on hippocampal neuroplasticity in an experimental model of ischemic stroke. </P> <P> Methods. Male Wistar rats were subjected to 60 minutes of transient middle cerebral artery occlusion (MCAO). Dipeptide GSB-106 was administered intraperitoneally at a dose of 0.1 mg/kg/day for 21 days after surgery. 30-40 days after MCAO, the depressive-like state in the forced swimming test and memory impairment in the novel object recognition test were assessed. Then, the content of CREB, as a neuroplasticity marker, was assessed in the ipsilateral hippocampus. </P> <P> Results. Rats in MCAO group showed depression-like behavior (increase in immobility time in the forced swimming test by 28% compared to sham group), impairments in short-term and long-term memory (decrease in the discrimination index in the novel object recognition test by 70% and 50%, respectively), and a decrease in immunoreactivity to CREB (cAMP response element-binding protein) in the hippocampus by 36% as compared with the sham group. GSB-106 completely prevented the behavior impairments and counteracted the reduction of immunoreactivity to CREB in the hippocampus. </P> <P> Conclusion. The BDNF dipeptide mimetic GSB-106 is promising for further development as a drug for the treatment of poststroke neuropsychiatric disorders.

PMID:36597610 | DOI:10.2174/1381612829666230103161824

Heliyon. 2022 Dec 30:e12746. doi: 10.1016/j.heliyon.2022.e12746. Online ahead of print.

ABSTRACT

Knowledge regarding the sustainability of immune responses after COVID-19 vaccination is important, e.g., to decide whom and when to booster. Thus, we analyzed antibody titers in firefighters six months after vaccination with the mRNA-based vaccine Comirnaty. SARS-CoV-2 spike-binding antibodies (bAb) were quantified and compared to peak responses determined in healthcare workers (HCW). For the firefighters, neutralizing antibodies (nAb) were also analyzed. Six months after the second vaccine dose, all analyzed firefighters had detectable bAb, and 91% exhibited nAb titers above 1:16. However, actual titers six months after vaccination were over 12-fold lower than in the HCW control group four weeks after vaccination. bAb and nAb responses showed a significant correlation, and age correlated inversely with antibody responses. Unexpectedly, participants with a body mass index over 25 had higher neutralization titers after six months. All participants with very low neutralization titers were offered booster vaccination. The booster vaccination improved the extent and sustainability of antibody responses.

PMID:36597483 | PMC:PMC9801692 | DOI:10.1016/j.heliyon.2022.e12746

Expert Opin Drug Metab Toxicol. 2023 Jan 3:1-17. doi: 10.1080/17425255.2022.2160317. Online ahead of print.

ABSTRACT

INTRODUCTION: CYP2D6 contributes to the metabolism of approximately 20-25% of drugs. However, CYP2D6 is highly polymorphic and different alleles can lead to impacts ranging from null to increase in activity. Moreover, there are commonly used drugs that potently inhibit the CYP2D6, thus causing 'phenoconversion' which can convert the genotypic normal metabolizer into phenotypic poor metabolizer. Despite growing literature on the clinical implications of non-normal CYP2D6 genotype and phenoconversion on patient-related outcomes, implementation of CYP2D6 pharmacogenetics and phenoconversion to guide prescribing is rare. This review focuses on providing the clinical importance of CYP2D6 pharmacogenetics and phenoconversion in precision medicine and summarizes the challenges and approaches to implement these into clinical practice.

AREAS COVERED: A literature search was performed using PubMed and clinical studies documenting the effects of CYP2D6 genotypes and/or CYP2D6 inhibitors on pharmacokinetics, pharmacodynamics or treatment outcomes of CYP2D6-metabolized drugs, and studies on implementation challenges and approaches.

EXPERT OPINION: Considering the extent and impact of genetic polymorphisms of CYP2D6, phenoconversion by the comedications, and contribution of CYP2D6 in drug metabolism, CYP2D6 pharmacogenetics is essential to ensure drug safety and efficacy. Utilization of proper guidelines incorporating both CYP2D6 pharmacogenetics and phenoconversion in clinical care assists in optimizing drug therapy.

PMID:36597259 | DOI:10.1080/17425255.2022.2160317

J Psychiatry Neurosci. 2023 Jan 3;48(1):E11-E12. doi: 10.1503/jpn.220154. Print 2023 Jan-Feb.

NO ABSTRACT

PMID:36596590 | DOI:10.1503/jpn.220154

Oncologist. 2023 Jan 3:oyac252. doi: 10.1093/oncolo/oyac252. Online ahead of print.

ABSTRACT

BACKGROUND: Side effects of immune checkpoint inhibitors (ICIs), called immune-related adverse events (irAEs), closely resemble primary autoimmune or rheumatic diseases. We aimed to understand the clinical utility of rheumatic autoantibodies (rhAbs) for diagnosing irAEs.

PATIENTS AND METHODS: Patients without pre-existing autoimmune disease (pAID) who had cancer treated with ICI(s) treatment from 1/1/2011 to 12/21/2020 and a rhAb checked were retrospectively identified. Logistic regression assessed associations between autoantibodies and irAEs, cancer outcome, and survival. Specificity, sensitivity, and positive/negative predictive values (PPV, NPV) were estimated for key rhAbs and ICI-arthritis. Kaplan-Meier analyzed objective response rate (ORR) and overall survival (OS).

RESULTS: A total of 2662 patients were treated with≥1 ICIs. One hundred and thirty-five without pAID had ≥ 1 rhAb tested. Of which 70/135(52%) were female; median age at cancer diagnosis was 62 years with most common cancers: melanoma (23%) or non-small cell lung cancer (21%), 96/135 (75%) were anti-PD1/PDL1 treated. Eighty had a rhAb ordered before ICI, 96 after ICI, and 12 before and after. Eighty-two (61%) experienced an irAE, 33 (24%) with rheumatic-irAE. Pre-ICI RF showed significant association with rheumatic-irAEs (OR = 25, 95% CI, 1.52-410.86, P = .024). Pre- and post-ICI RF yielded high specificity for ICI-arthritis (93% and 78%), as did pre- and post-ICI CCP (100% and 91%). Pre-ICI RF carried 93% NPV and pre-ICI CCP had 89% PPV for ICI-arthritis. No variables were significantly correlated with ORR. Any-type irAE, rheumatic-irAE and ICI-arthritis were all associated with better OS (P = .000, P = .028, P = .019).

CONCLUSIONS: Pre-ICI RF was associated with higher odds of rheumatic-irAEs. IrAEs had better OS; therefore, clinical contextualization for rhAbs is critical to prevent unnecessary withholding of lifesaving ICI for fear of irAEs.

PMID:36595378 | DOI:10.1093/oncolo/oyac252

Ann Acad Med Singap. 2022 Dec;51(12):752-754.

NO ABSTRACT

PMID:36592143

Adv Nanobiomed Res. 2022 Aug;2(8):2200037. doi: 10.1002/anbr.202200037. Epub 2022 Jul 19.

ABSTRACT

Red blood cells (RBCs) are natural carriers for sustained drug delivery, imaging, and in vivo sensing. One of the popular approaches to functionalize RBCs is through lipophilic anchors, but the structural requirements for anchor stability and in vivo longevity remain to be investigated. Using fluorescent lipids with the same cyanine 3 (Cy3) headgroup but different lipid chain and linker, the labeling efficiency of RBCs and in vivo stability are investigated. Short-chain derivatives exhibited better insertion efficiency, and mouse RBCs are better labeled than human RBCs. Short-chain derivatives demonstrate low retention in vivo. Derivatives with ester bonds are especially unstable, due to removal and degradation. On the other hand, long-chain, covalently linked derivatives show remarkably long retention and stability (over 80 days half life in the membrane). The clearance organs are liver and spleen with evidence of lipid transfer to the liver sinusoidal endothelium. Notably, RBCs modified with PEGylated lipid show decreased macrophage uptake. Some of the derivatives promote binding of antibodies in human plasma and mouse sera and modest increase in complement deposition and hemolysis, but these do not correlate with in vivo stability of RBCs. Ultra-stable anchors can enable functionalization of RBCs for drug delivery, imaging, and sensing.

PMID:36591390 | PMC:PMC9797212 | DOI:10.1002/anbr.202200037