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Pharmaceutics Jun 2022This systematic review summarizes the impact of pharmacogenetics on the effect and safety of non-steroidal anti-inflammatory drugs (NSAIDs) and antidepressants when used... (Review)
Review
BACKGROUND
This systematic review summarizes the impact of pharmacogenetics on the effect and safety of non-steroidal anti-inflammatory drugs (NSAIDs) and antidepressants when used for pain treatment.
METHODS
A systematic literature search was performed according to the preferred reporting items for systematic reviews and meta-analysis (PRISMA) guidelines regarding the human in vivo efficacy and safety of NSAIDs and antidepressants in pain treatment that take pharmacogenetic parameters into consideration. Studies were collected from PubMed, Scopus, and Web of Science up to the cutoff date 18 October 2021.
RESULTS
Twenty-five articles out of the 6547 initially detected publications were identified. Relevant medication-gene interactions were noted for drug safety. Interactions important for pain management were detected for (1) ibuprofen/; (2) celecoxib/; (3) piroxicam/, ; (4) diclofenac/, , , ; (5) meloxicam/; (6) aspirin/, , and ; (7) amitriptyline/ and ; (8) imipramine/; (9) nortriptyline/, , ; and (10) escitalopram/, , and .
CONCLUSIONS
Overall, a lack of well powered human in vivo studies assessing the pharmacogenetics in pain patients treated with NSAIDs or antidepressants is noted. Studies indicate a higher risk for partly severe side effects for the poor metabolizers and NSAIDs. Further in vivo studies are needed to consolidate the relevant polymorphisms in NSAID safety as well as in the efficacy of NSAIDs and antidepressants in pain management.
PubMed: 35745763
DOI: 10.3390/pharmaceutics14061190 -
American Journal of Physiology.... Feb 2020We reported previously that increased acid sphingomyelinase (ASMase)-catalyzed hydrolysis of sphingomyelin, which leads to increases in ceramide and sphingosine 1...
We reported previously that increased acid sphingomyelinase (ASMase)-catalyzed hydrolysis of sphingomyelin, which leads to increases in ceramide and sphingosine 1 phosphate (S1P), played a key role in the synergistic upregulation of proinflammatory cytokines by palmitic acid (PA), a major saturated fatty acid, and lipopolysaccharide (LPS) in macrophages. Since macrophages are vital players in nonalcoholic steatohepatitis (NASH) and atherosclerosis, we assessed the effect of ASMase inhibition on NASH and atherosclerosis cooperatively induced by high-PA-containing high-fat diet (HP-HFD) and LPS in LDL receptor-deficient (LDLR-/-) mice. LDLR-/- mice were fed HP-HFD, injected with low dose of LPS and treated with or without the ASMase inhibitor amitriptyline. The neutral sphingomyelinase inhibitor GW4869 was used as control. Metabolic study showed that both amitriptyline and GW4869 reduced glucose, lipids, and insulin resistance. Histological analysis and Oil Red O staining showed that amitriptyline robustly reduced hepatic steatosis while GW4869 had modest effects. Interestingly, immunohistochemical study showed that amitriptyline, but not GW4869, strongly reduced hepatic inflammation. Furthermore, results showed that both amitriptyline and GW4869 attenuated atherosclerosis. To elucidate the underlying mechanisms whereby amitriptyline inhibited both NASH and atherosclerosis, but GW4869 only inhibited atherosclerosis, we found that amitriptyline, but not GW4869, downregulated proinflammatory cytokines in macrophages. Finally, we found that inhibition of sphingosine 1 phosphate production is a potential mechanism whereby amitriptyline inhibited proinflammatory cytokines. Collectively, this study showed that amitriptyline inhibited NASH and atherosclerosis through modulation of sphingolipid metabolism in LDLR-/- mice, indicating that sphingolipid metabolism in macrophages plays a crucial role in the linkage of NASH and atherosclerosis.
Topics: Amitriptyline; Aniline Compounds; Animals; Atherosclerosis; Benzylidene Compounds; Blood Glucose; Cytokines; Diet, High-Fat; Down-Regulation; Enzyme Inhibitors; Insulin Resistance; Lipopolysaccharides; Macrophages; Male; Mice; Mice, Knockout; Non-alcoholic Fatty Liver Disease; Receptors, LDL; Sphingolipids; Sphingomyelin Phosphodiesterase
PubMed: 31821039
DOI: 10.1152/ajpendo.00181.2019 -
International Journal of Molecular... Sep 2022Poisoning is a significant cause of injury-related death worldwide. Dialysis is usually ineffective in removing the toxin once it has been absorbed because of drug...
Poisoning is a significant cause of injury-related death worldwide. Dialysis is usually ineffective in removing the toxin once it has been absorbed because of drug protein binding and high volumes of distribution. In this work, we explore whether the addition of liposomes to peritoneal dialysate could extract protein bound amitriptyline. Liposomes were prepared using the thin film hydration method. In the in vitro experiment, 3 mL of 20% albumin with a concentration of 6000 nmol/L amitriptyline in a proprietary dialysis cartridge was dialysed against 125 mL of phosphate-buffered saline with and without 80 mg 1,2-dioleoyl-sn-glycero-3-phosphoglycerol (DOPG) liposomes. In the in vivo arm, peritoneal dialysis was undertaken in 6 rats with pH gradient liposome augmented dialysate after intravenous amitriptyline injection. Peritoneal blood flow was estimated by CO extraction. Total amitriptyline extracted was compared to freely dissolved (non-protein bound) and total amitriptyline perfusing the membrane during the peritoneal dwell. Mean liposome size for DOPG and acidic centre pH gradient liposomes was 119 nm and 430 nm, respectively. In the in vitro experiment, more amitriptyline was extracted into the liposome containing dialysate than the control dialysate (40 +/- 2 nmol/L vs. 27 +/- 1 nmol/L). In the in vivo experiment, the total amitriptyline in dialysate was 5240 +/- 2750 nmol. Mean total free amitriptyline perfusing the peritoneal membrane was 93 +/- 46 nmol. Mean total blood amitriptyline perfusing the peritoneal membrane was 23,920 +/- 6920 nmol. Two of the six animals were excluded due to overestimation of peritoneal blood flow. This exploratory work suggests the addition of liposome nanoparticles to peritoneal dialysate extracted protein bound amitriptyline from blood.
Topics: Albumins; Amitriptyline; Animals; Carbon Dioxide; Dialysis Solutions; Liposomes; Peritoneal Dialysis; Phosphates; Proteins; Proton-Motive Force; Rats; Renal Dialysis
PubMed: 36232875
DOI: 10.3390/ijms231911577 -
Neurology and Therapy Apr 2023Patients with depression require thorough clinical assessment, which should include symptom profile, severity and staging, personality factors, antecedent and concurrent...
Patients with depression require thorough clinical assessment, which should include symptom profile, severity and staging, personality factors, antecedent and concurrent psychiatric comorbidity, physical comorbidity, neurocognitive function, exposure to stressors in early life (e.g. trauma) or recently (e.g. bereavement), and protective factors. The presence of anxiety symptoms in a depressed patient is associated with more severe depression, increased suicidality and worse outcomes compared with non-anxious depression. A network meta-analysis of antidepressant treatments found that agomelatine, citalopram, amitriptyline, escitalopram, mirtazapine, paroxetine, venlafaxine and vortioxetine were all significantly more effective than other antidepressants for the treatment of depression, and that agomelatine, citalopram, escitalopram, fluoxetine, sertraline and vortioxetine were better tolerated than other antidepressants. Agomelatine has been shown to have two major effects-relieving depressive symptoms, and supporting symptomatic and functional recovery-and these benefits have been demonstrated in patients with depression as well as in patients with generalised anxiety disorder, including those with more severe symptoms. Agomelatine has also been shown to be efficacious and well tolerated in patients with depression plus concomitant anxiety symptoms. A pooled analysis of data from six agomelatine studies of depression (three placebo-controlled and three with active comparators-fluoxetine, sertraline and venlafaxine) found that agomelatine was significantly more effective than placebo at relieving the anxiety subscore on the Hamilton Depression Rating Scale, and that the difference between agomelatine and placebo was even more marked in the subgroup of patients with severe anxiety symptoms at baseline. Irrespective of the pharmacotherapy used in patients with depression, the likelihoods of response and remission are increased when pharmacotherapy is combined with psychotherapy, with this approach being more effective than either pharmacotherapy or psychotherapy alone. Persistence with treatment is important, and clinicians should therefore encourage patients to keep trying to obtain relief.
PubMed: 37115460
DOI: 10.1007/s40120-023-00470-z -
Therapeutic Advances in Urology 2021Bladder pain syndrome/interstitial cystitis (BPS/IC) is a debilitating, systemic pain syndrome with a cardinal symptom of bladder related pain with associated systemic... (Review)
Review
Bladder pain syndrome/interstitial cystitis (BPS/IC) is a debilitating, systemic pain syndrome with a cardinal symptom of bladder related pain with associated systemic symptoms. It is characterized by an inflammation that partially or completely destroys the mucus membrane and can extend into the muscle layer; however, the etiology and pathogenesis is still enigmatic. It has been suggested that mast cell activation, defects in the glycosaminoglycan layer, non-functional proliferation of bladder epithelial cells, neurogenic inflammation, microvascular abnormalities in the submucosal layer, autoimmunity and infectious causes may cause BPS/IC. Available treatment options include general relaxation techniques, patient education, behavioral treatments, physical therapy, multimodal pain therapy, oral (amitriptyline, cimetidine, hydroxyzine) and intravesical treatments (heparin, lidocaine, hyaluronic acid and chondroitin sulfate), hydrodistension and other more invasive treatments. Available treatments are mostly not based on a high level of evidence. Lack of understanding of disease mechanisms has resulted in lack of targeted therapies on this area and a wealth of empirical approaches with usually inadequate efficacy. The aim of this article is to review the available evidence on the pathophysiological mechanisms of BPS/IC as they relate to available treatment options.
PubMed: 34178118
DOI: 10.1177/17562872211022478 -
PloS One 2023Half the US population uses drugs with anticholinergic properties. Their potential harms may outweigh their benefits. Amitriptyline is among the most frequently... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Half the US population uses drugs with anticholinergic properties. Their potential harms may outweigh their benefits. Amitriptyline is among the most frequently prescribed anticholinergic medicinal products, is used for multiple indications, and rated as strongly anticholinergic. Our objective was to explore and quantify (anticholinergic) adverse drug reactions (ADRs) in patients taking amitriptyline vs. placebo in randomized controlled trials (RCTs) involving adults and healthy individuals.
METHODS
We searched electronic databases from their inception until 09/2022, and clinical trial registries from their inception until 09/2022. We also performed manual reference searches. Two independent reviewers selected RCTs with ≥100 participants of ≥18 years, that compared amitriptyline (taken orally) versus placebo for all indications. No language restrictions were applied. One reviewer extracted study data, ADRs, and assessed study quality, which two others verified. The primary outcome was frequency of anticholinergic ADRs as a binary outcome (absolute number of patients with/without anticholinergic ADRs) in amitriptyline vs. placebo groups.
RESULTS
Twenty-three RCTs (mean dosage 5mg to 300mg amitriptyline/day) and 4217 patients (mean age 40.3 years) were included. The most frequently reported anticholinergic ADRs were dry mouth, drowsiness, somnolence, sedation, fatigue, constitutional, and unspecific anticholinergic ADRs. Random-effects meta-analyses showed anticholinergic ADRs had a higher odd's ratio for amitriptyline versus placebo (OR = 7.41; [95% CI, 4.54 to 12.12]). Non-anticholinergic ADRs were as frequent for amitriptyline as placebo. Meta-regression analysis showed anticholinergic ADRs were not dose-dependent.
DISCUSSION
The large OR in our analysis shows that ADRs indicative of anticholinergic activities can be attributed to amitriptyline. The low average age of participants in our study may limit the generalizability of the frequency of anticholinergic ADRs in older patients. A lack of dose-dependency may reflect limited reporting of the daily dosage when the ADRs occurred. The exclusion of small studies (<100 participants) decreased heterogeneity between studies, but may also have reduced our ability to detect rare events. Future studies should focus on older people, as they are more susceptible to anticholinergic ADRs.
REGISTRATION
PROSPERO: CRD42020111970.
Topics: Adult; Aged; Humans; Amitriptyline; Cholinergic Antagonists
PubMed: 37018325
DOI: 10.1371/journal.pone.0284168 -
Pharmaceutics Mar 2021Neuropathic pain in humans results from an injury or disease of the somatosensory nervous system at the peripheral or central level. Despite the considerable progress in... (Review)
Review
Neuropathic pain in humans results from an injury or disease of the somatosensory nervous system at the peripheral or central level. Despite the considerable progress in pain management methods made to date, peripheral neuropathic pain significantly impacts patients' quality of life, as pharmacological and non-pharmacological methods often fail or induce side effects. Topical treatments are gaining popularity in the management of peripheral neuropathic pain, due to excellent safety profiles and preferences. Moreover, topical treatments applied locally may target the underlying mechanisms of peripheral sensitization and pain. Recent studies showed that peripheral sensitization results from interactions between neuronal and non-neuronal cells, with numerous signaling molecules and molecular/cellular targets involved. This narrative review discusses the molecular/cellular mechanisms of drugs available in topical formulations utilized in clinical practice and their effectiveness in clinical studies in patients with peripheral neuropathic pain. We searched PubMed for papers published from 1 January 1995 to 30 November 2020. The key search phrases for identifying potentially relevant articles were "topical AND pain", "topical AND neuropathic", "topical AND treatment", "topical AND mechanism", "peripheral neuropathic", and "mechanism". The result of our search was 23 randomized controlled trials (RCT), 9 open-label studies, 16 retrospective studies, 20 case (series) reports, 8 systematic reviews, 66 narrative reviews, and 140 experimental studies. The data from preclinical studies revealed that active compounds of topical treatments exert multiple mechanisms of action, directly or indirectly modulating ion channels, receptors, proteins, and enzymes expressed by neuronal and non-neuronal cells, and thus contributing to antinociception. However, which mechanisms and the extent to which the mechanisms contribute to pain relief observed in humans remain unclear. The evidence from RCTs and reviews supports 5% lidocaine patches, 8% capsaicin patches, and botulinum toxin A injections as effective treatments in patients with peripheral neuropathic pain. In turn, single RCTs support evidence of doxepin, funapide, diclofenac, baclofen, clonidine, loperamide, and cannabidiol in neuropathic pain states. Topical administration of phenytoin, ambroxol, and prazosin is supported by observational clinical studies. For topical amitriptyline, menthol, and gabapentin, evidence comes from case reports and case series. For topical ketamine and baclofen, data supporting their effectiveness are provided by both single RCTs and case series. The discussed data from clinical studies and observations support the usefulness of topical treatments in neuropathic pain management. This review may help clinicians in making decisions regarding whether and which topical treatment may be a beneficial option, particularly in frail patients not tolerating systemic pharmacotherapy.
PubMed: 33810493
DOI: 10.3390/pharmaceutics13040450 -
Pharmacopsychiatry Mar 2024CYP2D6 and CYP2C19 functional status as defined by genotype is modulated by phenoconversion (PC) due to pharmacokinetic interactions. As of today, there is no data on...
INTRODUCTION
CYP2D6 and CYP2C19 functional status as defined by genotype is modulated by phenoconversion (PC) due to pharmacokinetic interactions. As of today, there is no data on the effect size of PC for CYP2C19 functional status. The primary aim of this study was to investigate the impact of PC on CYP2C19 functional status.
METHODS
Two patient cohorts (total n=316; 44.2±15.4 years) were investigated for the functional enzyme status of CYP2C19 applying two different correction methods (PC, PC) as well as serum concentration and metabolite-to-parent ratio of venlafaxine, amitriptyline, mirtazapine, sertraline, escitalopram, risperidone, and quetiapine.
RESULTS
There was a decrease in the number of normal metabolizers of CYP2C19 and an increase in the number of poor metabolizers. When controlled for age, sex, and, in the case of amitriptyline, venlafaxine, and risperidone, CYP2D6 functional enzyme status, an association was observed between the CYP2C19 phenotype/functional enzyme status and serum concentration of amitriptyline, sertraline, and escitalopram.
DISCUSSION
PC of CYP2C19 changes phenotypes but does not improve correlations with serum concentrations. However, only a limited number of patients received perturbators of CYP2C19. Studies with large numbers of patients are still lacking, and thus, it cannot be decided if there are minor differences and which method of correction to use. For the time being, PC is relevant in individual patients treated with CYP2C19-affecting drugs, for example, esomeprazole. To ensure adequate serum concentrations in these patients, this study suggests the use of therapeutic drug monitoring.
Topics: Humans; Cytochrome P-450 CYP2D6; Venlafaxine Hydrochloride; Amitriptyline; Pharmacogenetics; Sertraline; Risperidone; Escitalopram; Cytochrome P-450 CYP2C19; Genotype
PubMed: 38354747
DOI: 10.1055/a-2248-6924 -
Cureus Aug 2023Introduction A common dental problem is the fear of pain during needle prick for giving local anesthesia (LA). The needle prick pain during dental procedures...
Introduction A common dental problem is the fear of pain during needle prick for giving local anesthesia (LA). The needle prick pain during dental procedures often varies with sex and age. Perception of pain depends on various factors, which can be psychological and biological. This perception of pain may change the behavior of patients toward dental treatments. Traditionally, lidocaine gel formulation was utilized before the parenteral dosage form. The lidocaine gel formulation is considered the drug of choice for LA in dental surgery. Currently, amitriptyline has been utilized in dental practice because of its beneficial pharmacology. Hence, the present study has been undertaken to compare the anesthetic ability of amitriptyline as an intraoral topical anesthetic agent with lidocaine gel. Methods This study was a comparative clinical study between two medications' anesthetic properties. This study included 120 patients indicated for bilateral orthodontics (the subdivision of dentistry that emphasizes identifying necessary interventions for the malocclusion of teeth) procedures. All the subjects were divided into amitriptyline and lidocaine groups. Both anesthetic gels were applied at separate sites before the injection of LA. The time of the onset of anesthesia was noted and analyzed. Patients were selected on the basis of inclusion and exclusion criteria. Individuals aged 18 to 30 years who were systemically healthy and orthodontically indicated for bilateral premolar extraction were included in this study. Again, patients with a history of neurological disorders and allergies to amitriptyline and lidocaine were excluded from the current study. Results Significant differences emerged between groups at five and 10 minutes, with amitriptyline-induced partial numbness (36.7% and 6.7%). At 40 and 45 minutes, both groups showed varied partial and complete numbness, with amitriptyline leading to partial recovery (23.3% and 73.3% complete numbness, 23.3% partial recovery) and lidocaine resulting in partial recovery (81.7%). When comparing the visual analog scale (VAS) scores, both groups exhibited a similar simultaneous effect at 15 minutes. Nonetheless, amitriptyline displayed significantly lower scores at 25 and 35 minutes (p < 0.001) in comparison to lidocaine. Similar observations were made when controlling for pain intensity. Conclusion It was concluded that amitriptyline holds both anesthetic and analgesic properties. Nevertheless, this study was unable to generalize the study findings because of the small sample size and being a single-center study. However, the VAS scores of anesthetic and analgesic pharmacodynamics properties of amitriptyline were statistically significantly lower than lidocaine, particularly at 25 and 35 minutes. Additionally, amitriptyline-induced anesthetic and analgesic pharmacology, especially pharmacokinetics properties, depends on the location and pattern of pain.
PubMed: 37581201
DOI: 10.7759/cureus.43405 -
Journal of Personalized Medicine Apr 2023Motorist's vestibular disorientation syndrome (MVDS) is a disorder in which patients experience dizziness while driving. MVDS is under-reported in the literature, and in...
Motorist's vestibular disorientation syndrome (MVDS) is a disorder in which patients experience dizziness while driving. MVDS is under-reported in the literature, and in clinical practice, it often goes unrecognized. We identified clinical characteristics of patients with MVDS using data from 24 patients who faced difficulties while driving and were diagnosed with MVDS. Their symptoms, duration of illness, precipitating factors, co-morbidities, history of other neuro-otological disorders, severity of symptoms, and associated anxiety and depression were reviewed. Ocular motor movements were recorded using video-nystagmography. Patients with vestibular disorders that can cause similar symptoms while driving were excluded. The mean age of the patients was 45.7 ± 8.7 years, and most were professional drivers (90.5%). The duration of the illness ranged from eight days to ten years. Most patients presented with disorientation (79.2%) exclusively while driving. The most common triggers for symptoms were higher speeds, i.e., >80 km/h (66.7%), multi-lane roads (58.3%), bends and turns (50%), and looking at other vehicles or signals while driving (41.7%). A history of migraines was reported in 62.5% of the patients, and motion sickness was reported in 50% of the patients. Anxiety was reported in 34.3% of patients, and 15.7% had depression. The video-nystagmography did not show any specific abnormalities. Patients responded to drugs used in prophylactic treatments for migraines such as Amitriptyline, Venlafaxine, Bisoprolol, and Magnesium, and to Pregabalin and Gabapentin. Based on these findings, a classification system and a diagnostic criterion for MVDS were proposed.
PubMed: 37240902
DOI: 10.3390/jpm13050732