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Genomic ERBB2/ERBB3 mutations promote PD-L1-mediated immune escape in gallbladder cancer: a whole-exome sequencing analysis.

Gut. 2018 Jun 28;:

Authors: Li M, Liu F, Zhang F, Zhou W, Jiang X, Yang Y, Qu K, Wang Y, Ma Q, Wang T, Bai L, Wang Z, Song X, Zhu Y, Yuan R, Gao Y, Liu Y, Jin Y, Li H, Xiang S, Ye Y, Zhang Y, Jiang L, Hu Y, Hao Y, Lu W, Chen S, Gu J, Zhou J, Gong W, Zhang Y, Wang X, Liu X, Liu C, Liu H, Liu Y, Liu Y

Abstract
OBJECTIVES: Patients with gallbladder carcinoma (GBC) lack effective treatment methods largely due to the inadequacy of both molecular characterisation and potential therapeutic targets. We previously uncovered a spectrum of genomic alterations and identified recurrent mutations in the ErbB pathway in GBC. Here, we aimed to study recurrent mutations of genes and pathways in a larger cohort of patients with GBC and investigate the potential mechanisms and clinical significance of these mutations.
DESIGN: We performed whole-exome sequencing (WES) in 157 patients with GBC. Functional experiments were applied in GBC cell lines to explore the oncogenic roles of ERBB2/ERBB3 hotspot mutations, their correlation with PD-L1 expression and the underlying mechanisms. ERBB inhibitors and a PD-L1 blocker were used to evaluate the anticancer activities in co-culture systems in vitro and in vivo.
RESULTS: WES identified ERBB2 and ERBB3 mutations at a frequency of 7%-8% in the expanded cohort, and patients with ERBB2/ERBB3 mutations exhibited poorer prognoses. A set of in vitro and in vivo experiments revealed increased proliferation/migration on ERBB2/ERBB3 mutation. Ectopic expression of ERBB2/ERBB3 mutants upregulated PD-L1 expression in GBC cells, effectively suppressed normal T-cell-mediated cytotoxicity in vitro through activation of the PI3K/Akt signalling pathway and contributed to the growth and progression of GBC in vivo. Treatment with an ERBB2/ERBB3 inhibitor or a PD-L1 monoclonal antibody reversed these immunosuppressive effects, and combined therapy revealed promising therapeutic activities.
CONCLUSIONS: ERBB2/ERBB3 mutations may serve as useful biomarkers in identifying patients who are sensitive to ERBB2/ERBB3 inhibitors and PD-L1 monoclonal antibody treatment.
TRIAL REGISTRATION NUMBER: NCT 02442414;Pre-results.

PMID: 29954840 [PubMed - as supplied by publisher]

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Analysis of Circulating Cell-Free DNA Identifies Multiclonal Heterogeneity of BRCA2 Reversion Mutations Associated with Resistance to PARP Inhibitors.

Cancer Discov. 2017 09;7(9):999-1005

Authors: Quigley D, Alumkal JJ, Wyatt AW, Kothari V, Foye A, Lloyd P, Aggarwal R, Kim W, Lu E, Schwartzman J, Beja K, Annala M, Das R, Diolaiti M, Pritchard C, Thomas G, Tomlins S, Knudsen K, Lord CJ, Ryan C, Youngren J, Beer TM, Ashworth A, Small EJ, Feng FY

Abstract
Approximately 20% of metastatic prostate cancers harbor mutations in genes required for DNA repair by homologous recombination repair (HRR) such as BRCA2 HRR defects confer synthetic lethality to PARP inhibitors (PARPi) such as olaparib and talazoparib. In ovarian or breast cancers, olaparib resistance has been associated with HRR restoration, including by BRCA2 mutation reversion. Whether similar mechanisms operate in prostate cancer, and could be detected in liquid biopsies, is unclear. Here, we identify BRCA2 reversion mutations associated with olaparib and talazoparib resistance in patients with prostate cancer. Analysis of circulating cell-free DNA (cfDNA) reveals reversion mutation heterogeneity not discernable from a single solid-tumor biopsy and potentially allows monitoring for the emergence of PARPi resistance.Significance: The mechanisms of clinical resistance to PARPi in DNA repair-deficient prostate cancer have not been described. Here, we show BRCA2 reversion mutations in patients with prostate cancer with metastatic disease who developed resistance to talazoparib and olaparib. Furthermore, we show that PARPi resistance is highly multiclonal and that cfDNA allows monitoring for PARPi resistance. Cancer Discov; 7(9); 999-1005. ©2017 AACR.See related commentary by Domchek, p. 937See related article by Kondrashova et al., p. 984See related article by Goodall et al., p. 1006This article is highlighted in the In This Issue feature, p. 920.

PMID: 28450426 [PubMed - indexed for MEDLINE]

Efficacy and safety of the combination fluticasone propionate plus salmeterol in asthmatic preschoolers: An observational study.

J Asthma. 2018 Jun 29;:1-8

Authors: Hatziagorou E, Kouroukli E, Galogavrou M, Papanikolaou D, Terzi DD, Anagnostopoulou P, Kirvassilis F, Panagiotakos DB, Tsanakas J

Abstract
BACKGROUND: Inhaled Corticosteroids (ICS) are the cornerstone of asthma management in pediatric patients. However, in some cases, asthma is not adequately controlled on ICS alone. Long-acting beta2-agonists (LABA) are one of the available additional therapies but their use has rarely been studied among children younger than 5 years.
OBJECTIVE: The aim of this observational study was to evaluate the efficacy and safety of the combination of fluticasone propionate and salmeterol (FP/SA) in asthmatic children younger than 5 years of age.
METHODS: A retrospective study of 796 children under the age of 5 years (2.87 ± 1.22 years, 64.2% males), who were treated with FP/SA was conducted. Hospitalization rates, frequency of wheezing, exercise induced asthma, nocturnal wheeze and drug-related side-effects were recorded through children's medical records.
RESULTS: The children had previously received short-acting β2-agonists (73%), ICS (17%), montelukast (1%), and ICS with montelukast (2%). Mean duration of therapy with FP/SA was 12.45 ± 9.14 months. After adjusting for age, gender, and duration of treatment, a 89% reduction was recorded in annual hospitalization rates (from 27.13% before treatment to 3.01% after FP/SA therapy, p < 0.001), a 71% reduction in incidence of exercise-induced asthma (36.8% vs. after 10.6%, p < 0.001), a 81% reduction in nocturnal asthma (33.7% vs. after: 6.4%, p < 0.001), as well as in frequency of wheezing (p < 0.01),. No previous treatment carry-on effect was observed. No major drug-related side-effects occurred in the study group.
CONCLUSIONS: Combination therapy (FP/SA) is well-tolerated and highly effective in asthmatic children under the age of 5 years.

PMID: 29958011 [PubMed - as supplied by publisher]

Efficacy and Safety of Estradiol Valerate/Dienogest for the Management of Heavy Menstrual Bleeding: A Multicenter, Double-Blind, Randomized, Placebo-Controlled, Phase III Clinical Trial.

J Womens Health (Larchmt). 2018 Jun 29;:

Authors: Yu Q, Zhou Y, Suturina L, Jaisamrarn U, Lu D, Parke S

Abstract
BACKGROUND: To investigate the efficacy and safety of estradiol valerate (EV)/dienogest (DNG) for the management of heavy menstrual bleeding (HMB) in Asian and non-Asian women desiring contraception.
MATERIALS AND METHODS: In this multicenter, double-blind, phase III study, women were randomized 2:1 to receive EV/DNG or placebo tablets daily for seven 28-day cycles. The primary endpoint was the absolute change in menstrual blood loss (MBL) volume between the run-in and efficacy phases (90 days each). Secondary endpoints included the proportion of women with successful treatment (i.e., no episodes of MBL ≥80 mL and a decrease of <50% in MBL), percent change in MBL from the run-in phase, and change in hemoglobin and serum ferritin levels. Adverse events (AEs) were monitored throughout the study.
RESULTS: Of the 341 women (mean age 34.7 ± 7.7 years; 309 Asians, 32 non-Asians) randomized, 270 completed the study. Mean reduction in MBL volume from run-in phase was significantly greater with EV/DNG than placebo (366.75 mL vs. 149.14 mL; p < 0.0001), with ∼52% and 12% of women, respectively, experiencing successful treatment. Percent decrease in MBL volume from the run-in phase was significantly greater with EV/DNG than placebo (63.5% vs. 24.8%; p < 0.0001). Hemoglobin and serum ferritin levels were increased with EV/DNG compared with placebo. Study drug-related AEs were reported in 16.3% and 8.2% of women with EV/DNG and placebo, respectively, none of which were of severe intensity.
CONCLUSIONS: EV/DNG may be a safe and effective option in the treatment of HMB in Asian and non-Asian women who desire contraception.

PMID: 29957101 [PubMed - as supplied by publisher]

A randomized, open-label, crossover study evaluating bioequivalence of two N-acetylcysteine 2% oral solution formulations in healthy subjects
.

Int J Clin Pharmacol Ther. 2018 Jun 29;:

Authors: Donath F, Armogida M, Shneyer L

Abstract
OBJECTIVE: N-acetylcysteine is a mucolytic agent used to treat bronchopulmonary diseases associated with airway mucus hypersecretion. The bioequivalence of a new oral N-acetylcysteine 2% formulation was evaluated relative to an appropriate reference product.
MATERIALS AND METHODS: This open-label, randomized, crossover study assessed the bioequivalence of a new N-acetylcysteine 2% oral solution compared to an approved reference N-acetylcysteine 2% oral solution in healthy subjects in terms of pharmacokinetics, including area under the plasma concentration vs. time curve of N-acetylcysteine plasma concentrations from time 0 to the last measurable sampling time point and the maximum postdose concentration. Bioequivalence was concluded if the 90% confidence intervals for the ratio of the geometric means of the two pharmacokinetic parameters with baseline correction were entirely within the range of 80 - 125%.
RESULTS: 46 participants were randomized. The ratios of the geometric means for the test vs. reference treatment, with baseline correction, were 1.0961 (90% confidence interval: 1.0228, 1.1746) for area under the plasma concentration curve of test N-acetylcysteine plasma concentrations and 1.0938 (90% confidence interval: 1.0142, 1.1796) for maximum postdose concentration; both were within the predefined range to demonstrate bioequivalence. Most treatment-emergent adverse events were mild or moderate and not considered study drug related.
CONCLUSION: The new N-acetylcysteine 2% oral solution was found to be bioequivalent to the marketed reference formulation. Treatments were generally safe and well tolerated.
.

PMID: 29956648 [PubMed - as supplied by publisher]

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Reversible pancytopenia caused by severe copper deficiency in a patient with Wilson disease.

Med J Aust. 2018 Jun 02;209(1):1112

Authors: Mohamed M, Johnston A, Maclaine Cross A, Sharma A

PMID: 29954304 [PubMed - in process]

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Adverse Event Profile of Pyrimethamine-Based Therapy in Toxoplasmosis: A Systematic Review.

Drugs R D. 2017 Dec;17(4):523-544

Authors: Ben-Harari RR, Goodwin E, Casoy J

Abstract
INTRODUCTION: Approximately a third of the population worldwide is chronically infected with Toxoplasma gondii. Pyrimethamine-based regimens are recommended for the treatment of toxoplasmosis.
OBJECTIVE: The aim was to evaluate the safety profile of pyrimethamine-based treatment for the three main Toxoplasma manifestations: toxoplasmic encephalitis (TE), ocular toxoplasmosis, and congenital toxoplasmosis.
METHODS: PubMed, Cochrane Library, and Google Scholar databases were searched through August 1, 2016. Randomized, observational, prospective/retrospective, and cohort studies were eligible. Thirty-one studies were included with a total of 2975 patients. Of these, 13 were in congenital toxoplasmosis (n = 929), 11 in ocular toxoplasmosis (n = 1284), and seven in TE (n = 687). Across manifestations, adverse event (AE)-related treatment discontinuation and/or change in therapy involved ≤37% of patients and occurred in >55% of studies: 100% for ocular toxoplasmosis, 57.1% for TE, and 61.5% for congenital toxoplasmosis. The most commonly observed AEs were bone marrow suppression, dermatologic, and gastrointestinal (GI). The prevalence of bone marrow suppression-related AEs was ≤50% in congenital toxoplasmosis, ≤42.7% in TE, and ≤9.0% in ocular toxoplasmosis. The frequency of GI and dermatologic AEs were ≤100 and ≤11.1%, respectively, for ocular toxoplasmosis, ≤10.7 and ≤17.9% for TE, and ≤10.8 and ≤2.1% for congenital toxoplasmosis. Steven-Johnson syndrome was reported in two patients with ocular toxoplasmosis and one with TE.
CONCLUSION: The AE profile associated with pyrimethamine-based treatments differed by each manifestation of toxoplasmosis and within a given manifestation. Hematologic AEs occurred across all manifestations indicating the importance of monitoring the blood of patients administered pyrimethamine-based regimens.

PMID: 28879584 [PubMed - indexed for MEDLINE]

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Benzodiazepines and Z-Drugs: An Updated Review of Major Adverse Outcomes Reported on in Epidemiologic Research.

Drugs R D. 2017 Dec;17(4):493-507

Authors: Brandt J, Leong C

Abstract
Various adverse events resulting from, or associated with, benzodiazepine and/or Z-drug use have been extensively reported on and discussed in great detail within the biomedical literature. It is widely accepted that motor vehicle accidents and falls leading to fractures in older adults are major adverse events that have been shown to occur more frequently in users of sedative-hypnotic medication, especially of the benzodiazepine and related Z-drug variety. However, the last few years have seen increasing reports in the literature raising the issue of benzodiazepine and Z-drug exposure in the development of other serious medical issues including dementia, infections, respiratory disease exacerbation, pancreatitis, and cancer. This article provides an overview and interpretation on the current state of evidence regarding each of these associations and proposes what gaps in the evidence for drug-exposure-harm associations need to be addressed in the future for the purpose of evaluating causality of harm as it relates to these drugs.

PMID: 28865038 [PubMed - indexed for MEDLINE]

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[Systematic review of Kudiezi injection drug safety].

Zhongguo Zhong Yao Za Zhi. 2017 Jun;42(12):2380-2390

Authors: Gao SS, Cui RZ, Xie YM, Liao X, Gao XY, Wang JD

Abstract
To systematically evaluate the safety of Kudiezi injection. Databases such as Cochrane library, Medline, EMbase, Web of Science, Clinical Trials, CBM, CNKI, VIP, Wanfang and Chinese Clinical Trial Register were searched to collect the literature on all the study types of Kudiezi injection. Two researchers screened literature, assessed quality and extracted data according to inclusion and exclusion criteria. All studies were assessed by using internationally recognized methodological quality assessment tools or reporting quality evaluation criteria; Meta-analysis of adverse drug reaction/adverse events (ADR/AE) of Kudiezi injection was performed by using Stata 12.0 software. There were 411 clinical studies included, out of which 315 studies were analyzed finally. 18 072 patients in total used kudiezi injection, and there were 330 cases with ADRs and 13 cases with AEs. The most common ADR related system was the central and peripheral nervous system, with a weighted incidence of 2.9% [95%CI(0.022, 0.036)]. From the current evidence, the overall safety of Kudiezi injection was acceptable. Although data could be collected from all kinds of published reports, there are lack of mechanism experiments or observational studies with large samples of Kudiezi injection. Therefore, it is necessary to carry out further research on the safety of Kudiezi injection. Meanwhile, off label use of Kudiezi injection is common, so it is urgent for relevant governmental departments to formulate drug use specifications and provide better guidance for clinical drug use.

PMID: 28822197 [PubMed - indexed for MEDLINE]

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Intrauterine therapy of cytomegalovirus infection with valganciclovir: review of the literature.

Med Microbiol Immunol. 2017 Oct;206(5):347-354

Authors: Seidel V, Feiterna-Sperling C, Siedentopf JP, Hofmann J, Henrich W, Bührer C, Weizsäcker K

Abstract
Congenital cytomegalovirus (CMV) infection is the leading cause for sensorineural hearing loss and mental retardation in children without genetic diseases worldwide. There is little evidence guiding therapeutic strategies during pregnancy when intrauterine fetal CMV infection is confirmed. We provide a systematic review of the use of ganciclovir (GCV) or VGCV during pregnancy discussing safety of its use for mother and fetus and describe two cases of intrauterine therapy of fetal CMV infection with valganciclovir (VGCV). A PubMed database search was done up to November 16, 2016 without any restrictions of publication date or journal, using the following keywords: "valganciclovir" or "ganciclovir" and "pregnan*". Furthermore, citations were searched and expert references were obtained. Reported cases were considered if therapy was in humans and initiation of treatment of the CMV infection was during pregnancy. In total, seven case reports were retrieved which described GCV or VGCV use during pregnancy for fetal or maternal CMV infection. In the four cases of treatment for maternal CMV infection, no negative effects on the fetus were reported. Three cases of GCV administration to pregnant woman with the intention of fetal treatment after proven fetal infection were found. We additionally present two cases of VGCV treatment in pregnancy from our center of tertiary care. VGCV seems to be a safe treatment for congenital CMV infection for the mother and the fetus. Therapeutic concentrations can be achieved in the fetus by oral intake of the mother and CMV replication can be suppressed. Larger studies are needed to evaluate this therapeutic intervention and the long-term effects.

PMID: 28733760 [PubMed - indexed for MEDLINE]

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Physicians' Non-Uniform Approach to Prescribing Drugs to Older Patients - A Qualitative Study.

Basic Clin Pharmacol Toxicol. 2017 Dec;121(6):505-511

Authors: Christensen LD, Petersen J, Andersen O, Kaae S

Abstract
Multi-morbidity and polypharmacy are common in older patients and increase their susceptibility to adverse drug events and hospitalizations. Rational drug prescription is critical; however, little is known about physicians' perspectives on how to prescribe drugs for older patients. The aim of this study was to explore physicians' approach to prescribe drugs to older patients, including identifying the drugs that physicians perceive to be risk drugs for older patients and comparing them with established lists of potentially inappropriate medications. Short semi-structured interviews were conducted with 50 medical specialists in 23 different specialities throughout Denmark who had contact with older patients. Content analysis was performed to identify the relevant themes. Regardless of their medical or surgical background and how often they prescribed drugs for older patients in daily work, all physicians expressed a cautious approach when prescribing risk drugs. Despite their shared caution, physicians had different strategies for prescribing drugs to older patients. The following strategies were identified: (1) 'Start low, go slow', (2) 'Trial and error', (3) 'Dose reduction', and (4) 'Never prescribe'. The most frequently mentioned risk drugs considered to cause hospitalization were vitamin K antagonists, opioids and diuretics; these drugs are relatively highly consistent with established lists of PIMs. Physicians were relatively knowledgeable about risk drugs. Although the physicians agreed that a cautious approach was needed when prescribing drugs for older people, there was no consensus about how to best accomplish this in practice.

PMID: 28640946 [PubMed - indexed for MEDLINE]

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Reliability and Validity of the Short Version of Udvalg for Kliniske Undersogelser in Antipsychotic Treatment.

Psychiatr Q. 2017 Dec;88(4):787-796

Authors: Chen KP, Lung FW

Abstract
The aim of this study was to develop a reliable and valid short version of the Udvalg for Kliniske Undersogelser (UKU) to efficiently evaluate the side effects of antipsychotics in patients with schizophrenia. This multi-site study included 10 hospitals, which included 331 inpatients and outpatients diagnosed with schizophrenia. UKU, Clinical Global Impression-Severity (CGI-S), Personal and Social Performance (PSP) and dosage of paliperidone were collected. The predictive validity of the UKU-short version, as well as that of the CGI-S, PSP and paliperidone dosages, was analyzed using structural equation modeling (SEM), latent growth models (LGM), and confirmatory factor analysis to test its content and construct validity. The UKU-short included nine-items of sedation, reduced sleep, rigidity, tremor, akathisia, headache, reduced salivation, constipation and orthostatic dizziness, and has good construct and content validity over time. Confirmatory factor analysis showed good construct validity, with the psychic, neurological and autonomic side effect dimensions having correlations between 0.60 and 0.71. The predictive validity of the short-version UKU for psychiatric symptoms (CGI-S), quality of life (PSP) and dosage showed that the effects of drug dosage were negligible, and only neurological side effects were associated with psychiatric symptoms and quality of life. The UKU-short showed good content, construct and predictive validity. It is a more time-efficient instrument than the original UKU. This study only included patients treated with paliperidone, larger scale studies is needed to validate the UKU-short in detection of side effects in routine clinical practice to prevent non-adherence in patients with schizophrenia.

PMID: 28150091 [PubMed - indexed for MEDLINE]

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Related Articles

CYP3A and CYP2C19 activity in urine in relation to CYP3A4, CYP3A5, and CYP2C19 polymorphisms in Russian peptic ulcer patients taking omeprazole.

Pharmgenomics Pers Med. 2018;11:107-112

Authors: Denisenko NP, Sychev DA, Sizova ZM, Smirnov VV, Ryzhikova KA, Sozaeva ZA, Grishina EA

Abstract
Background: Proton pump inhibitors (PPIs) are metabolized by cytochrome P450. CYP2C19 is the main isoenzyme for the majority of PPI, whereas CYP3A family is a secondary enzyme for PPI biotransformation.
Purpose: The aim of the study was to find if CYP3A4*22, CYP3A5*3, CYP2C19*2, CYP2C19*3, and CYP2C19*17 genotypes are connected with CYP3A and CYP2C19 activities in Russian peptic ulcer patients taking omeprazole.
Patients and methods: Forty-eight gastric or duodenal ulcer patients (15 men, 33 women; mean age 55.0±15.3 years, age range 18-91 years) from Moscow region of Russia were enrolled. Peripheral venous blood was collected for DNA extraction, and real-time polymerase chain reaction was performed for CYP3A5*3 A6986G (rs776746), CYP3A4*22 C>T in intron 6 (rs35599367), CYP2C19*2G681A (rs4244285), CYP2C19*3G636A (rs4986893), and CYP2C19*17C-806T (rs12248560) polymorphism analyses. Urine samples of patients were collected in the morning between 6 and 9 am before food or drug intake. Urine cortisol and 6β-hydroxycortisol concentrations (for CYP3A activity) and omeprazole and 5-hydroxyomeprazole concentrations (for CYP2C19 activity) were measured using high-performance liquid chromatography/mass spectroscopy.
Results: We found a connection between CYP2C19 genotypes and CYP3A activity. Median metabolic ratios 6β-hydroxycortisol/cortisol (25%-75% percentiles) were 2.84 (1.99-4.39) for CYP2C19 extensive metabolizers (EMs), 2.51 (1.86-4.73) for CYP2C19 ultra-rapid metabolizers (UMs), and 1.45 (1.12-2.16) for CYP2C19 intermediate metabolizers (IMs) + poor metabolizers (PMs). A statistically significant difference in CYP3A activity (Mann-Whitney test) was found between CYP2C19 EMs vs CYP2C19 IMs+PMs (p=0.006), between CYP2C19 UMs vs CYP2C19 IMs+PMs (p=0.018), and in multiple comparison Kruskal-Wallis test (p=0.014).
Conclusion: In CYP2C19 IMs+PMs, CYP3A activity was significantly lower than in CYP2C19 EMs and UMs.

PMID: 29950882 [PubMed]