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Background: Essential Tremor (ET) is likely the most frequent movement disorder. In this review, we have summarized the current pharmacological options for the treatment of this disorder and discussed several future options derived from drugs tested in experimental models of ET or from neuropathological data. Methods: A literature search was performed on the pharmacology of essential tremors using PubMed Database from 1966 to July 31, 2019. Results: To date, the beta-blocker propranolol and the antiepileptic drug primidone are the drugs that have shown higher efficacy in the treatment of ET. Other drugs tested in ET patients have shown different degrees of efficacy or have not been useful. Conclusion: Injections of botulinum toxin A could be useful in the treatment of some patients with ET refractory to pharmacotherapy. According to recent neurochemical data, drugs acting on the extrasynaptic GABAA receptors, the glutamatergic system or LINGO-1 could be interesting therapeutic options in the future.

ABSTRACTIntroduction: Several reports suggest a possible association between polymorphisms in the cytochrome P450 2C9 (CYP2C9) gene and the risk for non-steroidal anti-inflammatory drug (NSAID)-related adverse gastrointestinal events, including gastrointestinal bleeding. Because findings were controversial, a systematic review and a meta-analysis of eligible studies on this putative association was conducted.Areas covered: The authors have revised the relationship between CYP2C9polymorphisms and the risk of developing NSAID-related gastrointestinal bleeding, as well as other adverse gastrointestinal events, and performed meta-analyzes. The bias effect and potential sources of heterogeneity between studies was analyzed.Expert opinion: Individuals classified as poor metabolizers after CYP2C9genotyping (activity scores equal to 0 or 0.5) have an increased risk of developing NSAID-related gastrointestinal adverse events with an odds ratio (OR) = 1.86, (p= 0.004) and the OR for subjects with gastrointestinal bleeding is = 1.90, (p= 0.003). Gene-dose effect for variant CYP2C9alleles (p= 0.005 for all gastrointestinal adverse events, and p= 0.0001 for bleeding patients) was observed. Also, there is an allele-specific effect in the association: CYP2C9*2is a poor risk predictor, whereas CYP2C9*3is a highly significant predictor of gastrointestinal adverse events (p= 0.006) and gastrointestinal bleeding (p= 0.0007).

Background: The pathophysiology and neurochemical mechanisms of essential tremor (ET) are not fully understood, because only a few post-mortem studies have been reported, and there is a lack of good experimental model for this disease. Objective: The main aim of this review is to update data regarding the neurochemical features of ET. Alterations of certain catecholamine systems, the dopaminergic, serotonergic, GABAergic, noradrenergic, and adrenergic systems have been described, and are the object of this revision. Methods: For this purpose, we performed a literature review on alterations of the neurotransmitter or neuromodulator systems (catecholamines, gammaaminobutyric acid or GABA, excitatory amino acids, adenosine, T-type calcium channels) in ET patients (both post-mortem or in vivo) or in experimental models resembling ET. Results and Conclusion: The most consistent data regarding neurochemistry of ET are related with the GABAergic and glutamatergic systems, with a lesser contribution of adenosine and dopaminergic and adrenergic systems, while there is not enough evidence of a definite role of other neurotransmitter systems in ET. The improvement of harmaline-induced tremor in rodent models achieved with T-type calcium channel antagonists, cannabinoid 1 receptor, sphingosine-1-phosphate receptor agonists, and gap-junction blockers, suggests a potential role of these structures in the pathogenesis of ET.

ABSTRACTIntroduction: Several studies suggested a possible association between certain polymorphisms in the N-acetyl-transferase 2(NAT2) gene (which encodes a very important enzyme involved in xenobiotic metabolism) and the risk for Parkinson’s disease (PD). As the results of studies on this issue are controversial, we conducted a systematic review and a meta-analysis of eligible studies on this putative association.Areas covered: The authors revised the relationship between NAT2polymorphisms and the risk of developing PD using several databases, and performed a meta-analysis using the software Meta-Disc1.1.1. In addition heterogeneity between studies was analyzed. A description of studies regarding gene-gene interactions and gene-environmental interactions involving NAT2polymorphisms is also made.Expert opinion: Despite several recent meta-analyses showing an association between several polymorphisms in genes related with detoxification mechanisms such as cytochromeP4502D6 (CYP2D6), and glutathione transferases M1and T1(GSTM1, and GSTT1), data on NAT2gene polymorphisms obtained from the current meta-analysis do not support a major association with PD risk, except in Asian populations. However, data from many studies are incomplete and therefore insufficient data exists to draw definitive conclusions. Several studies suggesting gene-gene and gene-environmental factors involving NAT2gene in PD risk await confirmation.

Several single-nucleotide polymorphisms (SNPs) in the catechol-O-methyltransferase(COMT) gene have been associated with the risk of developing Parkinson’s disease (PD). We conducted a systematic review and a meta-analysis including all the studies published on PD risk related with COMTSNPs (mainly rs4680). We also reviewed the possible relationship of COMTSNPs with clinical, neuropharmacological, neurochemical, and neuroimaging features of PD.

A recent genome-wide association study and other replication studies have suggested that the rs3794087 single nucleotide polymorphism in the solute carrier family 1 – glial affinity glutamate transporter-member 2 (SLC1A2) gene is associated with an increased risk for essential tremor (ET), and a replication study in an Asian cohort has shown a decreased risk for ET associated with the rs3794087T allele. We tried to replicate this association in a White Spanish population.

Advances in sequencing technologies, such as next-generation sequencing (NGS), represent an opportunity to perform genetic testing in a clinical scenario. In this study, we developed and tested a method for the detection of mutations in the large BRCA1and BRCA2tumor suppressor genes, using long-range PCR (LR-PCR) and NGS, in samples from individuals with a personal and/or family history of breast and/or ovarian cancer. Eleven LR-PCR fragments, between 3000 and 15,300 bp, containing all coding exons and flanking splice junctions of BRCA1and BRCA2, were obtained from DNA samples of five individuals carrying mutations in either BRCA1or BRCA2. Libraries for NGS were prepared using an enzymatic (Nextera technology) method. We analyzed five individual samples in parallel by NGS and obtained complete coverage of all LR-PCR fragments, with an average coding sequence depth for each nucleotide of 30 reads, running from ×7 (in exon 22 of BRCA1) to ×150. We detected and confirmed 100% of the mutations that predispose to the risk of cancer, together with other genomic variations in BRCA1and BRCA2. Our approach demonstrates that genomic LR-PCR, together with NGS, using the GS Junior 454 System platform, is an effective method for patient sample analysis of BRCA1and BRCA2genes. In addition, this method could be performed in regular molecular genetics laboratories.

Information on CYP2B6allele frequencies and detrimental genotypes in mixed human populations is scarce. The aim of this study was to analyze the frequencies and haplotypes of nonsynonymous CYP2B6single nucleotide polymorphisms (SNPs) in a Colombian population.

Oxidative stress and iron deposition is related to Parkinson's disease (PD). Heme oxygenase 2 (HMOX2) catalyzes the cleavage of the heme ring to form biliverdin with release of iron and carbon monoxide. This study aims to analyze variations in the HMOX2gene in patients with PD.

Some clinical and experimental data suggest a possible role of -aminobutyrate (GABA)-ergic mechanisms in the pathophysiology of essential tremor (ET). We studied the allelic and genotype frequencies of the single nucleotide polymorphisms, such as GABRA4-L26M(Leu26Met, rs2229940), GABRE-S102A(Ser26Ala, rs1139916), and GABRQ-I478F(Ile26Phe, rs3810651), in 200 patients with familial ET and 250 healthy controls using TaqMan genotyping. GABRA4-L26M, GABRE-S102A, and GABRQ-I478Fgenotype and allelic frequencies did not differ significantly between patients with ET and controls, and were unrelated to the age at onset of tremor or sex. The GABRQ-478Fallele seemed to be related to improvement of tremor with ethanol use among men (odds ratio=2.32, 95 confidence interval=0.26–4.3, P=0.007, Pc=0.021). The results of this study suggest that the single nucleotide polymorphisms studied in the GABRA4, GABRE, and GABRQgenes are not related to the risk for familial ET.

Metamizole is a NSAID that has been banned in several countries because of its toxicity. It is often involved in selective hypersensitivity reactions and most hypersensitivity patients develop anaphylaxis. Metamizole is rapidly metabolized, and metabolic profiles are related to genetic factors. We analyzed whether genetic determinants of metamizole metabolism influence the risk of developing hypersensitivity in 265 patients diagnosed with hypersensitivity to metamizole and 362 healthy individuals who tolerated metamizole. Slow acetylation is associated with an increased risk of developing selective hypersensitivity to metamizole [odds ratio for slow alleles=2.17 (95% confidence interval=1.44–3.27); P=0.00016], and particularly anaphylaxis [odds ratio=4.77 (95% confidence interval=2.28–9.98); P=0.000006], with a significant gene–dose effect. The association was not identified in patients with cross-hypersensitivity. Cytochrome P450 2C9 (CYP2C9) and cytochrome P450 2C19 (CYP2C19) genotypes did not influence risk association. Our findings raise the hypothesis of genetically determined metabolic variability as a risk factor for developing anaphylaxis with metamizole.

The isozymes CYP1A2, CYP2D6, and CYP3A4/5 are involved in the majority of all cytochrome P450– mediated drug biotransformations. In this study we investigated the inhibition profiles of CYP1A2 (substrate: caffeine) CYP2D6 (substrate: dextromethorphan), and CYP3A4/5 (substrate: dextrorphan) by cimetidine, ranitidine, and the novel H2-receptor antagonist ebrotidine in human liver microsomes. The inhibitory effect of the drugs on the enzymes activities were as follows: CYP1A2: cimetidine >> ranitidine = ebrotidine; CYP2D6: cimetidine >>> ranitidine = ebrotidine; CYP3A4/5: ebrotidine > cimetidine >>> ranitidine. The inhibition of CYP3A4/5 enzyme activity by ebrotidine was competitive. To test whether the inhibitory effect of ebrotidine in CYP3A activity was also found in vivo, we analyzed the biodisposition of midazolam in 8 healthy volunteers. Midazolam biodisposition was significantly reduced when administered together with cimetidine (P < .05), whereas no significant inhibition was observed with ebrotidine or ranitidine compared with placebo. Psychomotor performance analysis revealed no significant effect of the observed reduction on midazolam biodisposition. We concluded that patients who are receiving treatment with drugs metabolized through CYP3A may experience enhanced drug effects as a result of pharmacokinetic interaction when treated concomitantly with cimetidine. In contrast, the effect of ranitidine or ebrotidine on CYP3A activity in vivo seems to have little clinical significance.

The polymorphic human cytochrome P450 2A6 (CYP2A6) metabolises a number of drugs, activates a variety of precarcinogens and constitutes the major nicotine C‐oxidase. A relationship between CYP2A6genotype and smoking habits, as well as incidence of lung cancer, has been proposed. Two defective alleles have hitherto been identified, one of which is very common in Asian populations. Among Caucasians, an additional defective and frequently distributed allele (CYP2A6*3) has been suggested to play a protective role against nicotine addiction and cigarette consumption. Here, we have re‐evaluated the genotyping method used for the CYP2A6*3allele and found that a gene conversion in the 3′ flanking region of 30–40% of CYP2A6*1alleles results in genotype misclassification. In fact, no true CYP2A6*3alleles were found among 100 Spaniards and 96 Chinese subjects. In one Spanish poor metaboliser of the CYP2A6 probe drug coumarin, we found two novel defective alleles. One, CYP2A6*5, encoded an unstable enzyme having a G479L substitution and the other was found to carry a novel type of CYP2A6gene deletion (CYP2A6*4D). The results imply the presence of numerous defective as well as active CYP2A6alleles as a consequence of CYP2A6/CYP2A7gene conversion events. We conclude that molecular epidemiological studies concerning CYP2A6 require validated genotyping methods for accurate detection of all known defective CYP2A6alleles.

The arylamine N-acetyltransferase (NAT2) polymorphism has been related to the risk of developing non-insulin-dependent diabetes mellitus (NIDDM). Several studies suggested an excess of rapid acetylators among NIDDM patients. This may be explained by an increased risk to develop NIDDM among subjects with the rapid acetylator capacity, or by changes in the acetylator status due to the disease or drug therapy. In order to elucidate this controversial topic, we have studied by a mutation-specific polymerase chain amplification (PCR) method the occurrence of seven point mutations at the coding region of the NAT2 gene in genomic DNA from 111 patients with NIDDM and 217 healthy controls. In addition, we have studied by the combined use of PCR and restriction fragment length polymorphism the occurrence of seven allelic variants of the CYP2D6 gene in the same subjects. In contrast to previous phenotyping studies, no relationship was found between NAT2 polymorphism and NIDDM or its complications such as nephropathy or neuropathy. The CYP2D6 genotype was similar between cases and controls. Our findings do not provide a genetic basis for any association of NIDDM and NAT2 polymorphism, suggesting that any excess of subjects with the rapid acetylator phenotype among patients with NIDDM should be secondary to the disease or concomitant drug therapy.

The fact that CYP2D6 is not only expressed in liver but also in brain and the clinical association of this cytochrome with Parkinson's disease suggests the possibility of existence of some endogenous substrate, and among these perhaps one or more neurotransmitters could be metabolized by CYP2D6. In this study we explored such a possibility by studying the modulation of CYP2D6 activity by several neurotransmitters. Our findings confirm the occurrence of a competitive inhibition of dextromethorphan O-demethylation in the presence of tryptamine, with a Kivalue of 44.6 µM. Tryptamine was metabolized in human liver microsomes by an enzyme activity with a Kmof 3.6 ± 0.9 µM. Such activity is NADPH dependent and is inhibited by quinidine and CYP2D6- specific substrates. The product of the reaction is tryptophol. These results suggest that tryptamine may be an endogenous substrate of CYP2D6

The prevalence and distribution of seven point mutations at the coding region of the highly polymorphic NAT2 gene were studied in 1008 chromosomes from healthy Spanish subjects. Most of the genes studied (78.4) had one or more mutations, distributed in seventeen allelic variants of the NAT2 gene. Three alleles were present at high frequencies, namely NAT25B (41.6), NAT26A (23.6) and NAT24 (21.6). The frequencies for the rest of alleles were NAT212A (2.5), NAT26B (2.0), NAT213 (1.9), NAT25A (1.5), NAT27B (1.2), NAT212C (1.0), NAT25C (0.8), NAT214C (0.8), NAT214A (0.6), NAT25D (0.3), NAT212B (0.2), and NAT214D (0.1). In addition, we identified two new allelic variants with mutations at 191A 341C 803G (0.1) and 282T 59OA 803G (0.3) which to our knowledge are described here for the first time. No other combination of mutations was identified, including the previously described allelic variants NAT214B, NAT214E, NAT25E and NAT27A. The phenotype predictive capacity of simplified PCR tests including analyses for mutations at 341C and 590A, and more sophisticated tests analysing seven mutations revealed that, in the population studied, the analysis of these two mutations is enough to predict as rapid acetylators over 99.5 subjects with two rapid genes, and about 94 subjects with one rapid gene. Given a prevalence of poor acetylators of about 55 subjects, the simplified analysis would predict the phenotype in about 97.5 subjects.