scholarly journals Genetic Polymorphisms Associated With the Pharmacokinetics, Pharmacodynamics and Adverse Effects of Olanzapine, Aripiprazole and Risperidone

2021 ◽  
Vol 12 ◽  
Author(s):  
Paula Soria-Chacartegui ◽  
Gonzalo Villapalos-García ◽  
Pablo Zubiaur ◽  
Francisco Abad-Santos ◽  
Dora Koller
Keyword(s):  
Adverse Effects ◽  
Metabolic Effects ◽  
Individual Response ◽  
Cytochrome P450 Enzymes ◽  
Glucose And Lipid Metabolism ◽  
Starting Dose ◽  
Ultrarapid Metabolizers ◽  
Dopamine And Serotonin Receptors ◽  
Cyp3a4 Inhibitors ◽  
Extrapyramidal Effects

Olanzapine, aripiprazole and risperidone are atypical antipsychotics or neuroleptics widely used for schizophrenia treatment. They induce various adverse drug reactions depending on their mechanisms of action: metabolic effects, such as weight gain and alterations of glucose and lipid metabolism; hyperprolactinemia and extrapyramidal effects, such as tremor, akathisia, dystonia, anxiety and distress. In this review, we listed polymorphisms associated with individual response variability to olanzapine, aripiprazole and risperidone. Olanzapine is mainly metabolized by cytochrome P450 enzymes, CYP1A2 and CYP2D6, whereas aripiprazole and risperidone metabolism is mainly mediated by CYP2D6 and CYP3A4. Polymorphisms in these genes and other enzymes and transporters, such as enzymes from the uridine 5'-diphospho-glucuronosyltransferase (UGT) family and ATP-binding cassette sub-family B member 1 (ABCB1), are associated to differences in pharmacokinetics. The three antipsychotics act on dopamine and serotonin receptors, among others, and several studies found associations between polymorphisms in these genes and variations in the incidence of adverse effects and in the response to the drug. Since olanzapine is metabolized by CYP1A2, a lower starting dose should be considered in patients treated with fluvoxamine or other CYP1A2 inhibitors. Regarding aripiprazole, a reduced dose should be administered in CYP2D6 poor metabolizers (PMs). Additionally, a reduction to a quarter of the normal dose is recommended if the patient is treated with concomitant CYP3A4 inhibitors. Risperidone dosage should be reduced for CYP2D6 PMs and titrated for CYPD6 ultrarapid metabolizers (UMs). Moreover, risperidone dose should be evaluated when a CYP2D6, CYP3A4 or ABCB1 inhibitor is administered concomitantly.

scholarly journals Restarting antidepressant and antipsychotic medication after intentional overdoses: need for evidence-based guidance

2019 ◽  
Vol 9 ◽  
pp. 204512531983688
Author(s):  
Emma Tay ◽  
Andreas Sotiriou ◽  
Garry G. Graham ◽  
Kay Wilhelm ◽  
Leone Snowden ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Adverse Effects ◽  
Antipsychotic Drugs ◽  
Plasma Concentrations ◽  
Pharmacokinetic Data ◽  
Psychoactive Drugs ◽  
Cytochrome P450 Enzymes ◽  
Psychoactive Medication ◽  
Drug Overdoses ◽  
P450 Inhibitors

Intentional drug overdoses with antidepressant and antipsychotic medications are an increasingly common problem. Currently, there is little guidance with regard to reintroduction of these medications after intentional overdoses. We have used published toxicological and pharmacokinetic data to obtain factors which control the recovery from overdoses. From such data, we have proposed guidance regarding their reintroduction, provided there are no adverse effects or contraindications. Tentatively, we suggest that when adverse effects from the overdose are lost, treatment could recommence after a further mean half-life of elimination. Most antidepressant and antipsychotic drugs are metabolized by cytochrome P450 enzymes and, where cytochrome P450 inhibitors are co-ingested, serial plasma concentrations should optimally be obtained in order to assess a suitable time for reintroduction of the psychoactive drugs. We hope the proposals presented will stimulate research and discussion that lead to better guidance for clinicians concerning reintroduction of psychoactive medication after intentional overdose.

Patterns Of Non-Hematological Adverse Effects In Patients With Chronic Myeloid Leukemia In Chronic Phase (CML-CP) Treated With Ponatinib – Experience At a Single Institution

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4019-4019 ◽  
Author(s):  
Preetesh Jain ◽  
Hagop M. Kantarjian ◽  
Carlos Guillermo Romo ◽  
Alfonso Quintas-Cardama ◽  
Elias Jabbour ◽  
...  
Keyword(s):  
Risk Factors ◽  
Adverse Effects ◽  
Dose Reduction ◽  
Research Funding ◽  
Skin Toxicity ◽  
Qtc Prolongation ◽  
Single Institution ◽  
Dry Skin ◽  
Starting Dose ◽  
Grade 3

Abstract Introduction Ponatinib is a multi-targeted tyrosine kinase inhibitor (TKI) efficacious in pts with refractory CML. Ponatinib inhibits other tyrosine kinases (e.g. RET, FGFR, FLT3) that may lead to off target adverse effects (AE). We report a single-institution experience of frequencies of non-hematological AE among pts on therapy with ponatinib. Methods A total of 90 pts with CML-CP[49 relapsed refractory (RR), 41 frontline] treated at our institution on clinical trials with ponatinib were analyzed. AE were recorded on each pt visit and charts were reviewed for AE and risk factors. Results For RR pts (n=49)the starting dose of ponatinib was 45 mg in 42 (86%) pts. 39 (80%) had dose interruptions, due in 17 (44%) to grade 3 thrombocytopenia and in 22 (56%) to non-hematological AE (elevated pancreatic enzymes 7 pts of whom 5 had pancreatitis; body aches and headache 7; hypertension 7; skin toxicity 5; fatigue 5). 35 pts (71%) had dose reduction to 30 or 15 mg. Hypertension (H.T.) stage 2 (≥160/100 mm Hg) occurred in 15 (31%) pts; only 2 of new onset. Blood pressure was controlled in all with antihypertensives. Other cardiovascular AE included QTc prolongation in 1 pt, atrial fibrillation in 1 pt, acute myocardial infarction in 3, venous thrombosis in 3, arterial thrombosis in 4, transient ischemic attack (TIA) in 1 and Raynaud’s in 1. No pt discontinued ponatinib due to cardiovascular AE’s. Symptomatic pancreatitis developed in 8 pts (16%). Grade 3/4 elevations in serum lipase and amylase occurred in 12 (24%) pts and 2 (4%) pts respectively. Median days to onset of pancreatitis was 24 (range 7-456). 27 pts (55%) developed cutaneous toxicity including xerosis/dry skin in 10 (37%) and grade 3 erythroderma and exfoliation of the skin in 5. Four pts died, none related to ponatinib. 13 pts went off the study: 5 went to SCT, 3 progressed, 1 pt died in CCyR of multiple co-morbidities, 1 pt had progressive melanoma, 1 pt was transferred to another hospital, and 2 for ponatinib-related AE (headache in 1 and headache, fatigue, depression, and abdominal pain in 1). For pts in frontline setting (n=41) the starting dose was 45 mg in all. 29 pts (71%) had dose interruptions due to one or more of the following: grade 3/4 pancreatic enzyme elevation in 16, myelosuppression in 4, and various non-hematological AE in 15 (skin toxicity in 4, fatigue in 2, headache in 1, chest pain in 2, elevated liver enzymes in 2, suspected seizure vs. TIA in 1, grade 3 diarrhea in 1, memory disturbances in 1, and grade 3 hypertension in 1, erectile dysfunction in 1). 24 pts (59%) had dose reduction, from 45 mg to 30 mg in 20 pts and then to 15 mg in 4 pts. H.T. stage 2 occurred in 3 (7%) pts usually among patients with pre-existing H.T. Other cardiovascular AE included grade 2 QTc prolongation in 1 pt, possible TIA vs. possible seizure in 1, and Raynaud’s in 2. Pancreatitis was seen in 12 pts (29%) with grade 1-2 and 6 pts (15%) with grade 3/4. Grade 3/4 lipase/amylase elevations occurred in 16 (39%) and 3 (7%) pts. Median days to the onset of pancreatitis were 6 (4-22). 34 pts (83%) developed skin toxicity with rash (any grade) in 25 pts (61%), xerosis/dry skin in 18 pts (44%) and grade 3 erythroderma and skin exfoliation in 2 (pts may have had ≥1 type of skin AE). 2 pts discontinued therapy, due to severe xerosis in 1 and recurrent gra 4 neutropenia in another. 1 pt developed grade 2 pericarditis possibly related to ponatinib. For all the 90 pts, risk factors for cardiovascular and pancreatic toxicities included 20 (22%) smokers, 2 heavy alcohol consumers, 27 (30%) obese (BMI ≥30 Kg/m2), 30 (33%) with hypertriglyceridemia, 17 (19%) had hypercholesterolemia and 10 pts were receiving lipid lowering therapies. Conclusions Ponatinib is generally well tolerated and AEs can usually be properly managed. AE are more common in RR pts with greater frequency of hypertension, cardiovascular complications, headache, dry mouth and dose interruptions. Most pts are able to continue therapy after dose adjustments. Disclosures: Kantarjian: ARIAD: Research Funding. Cortes:Ariad, Pfizer, Teva: Consultancy; Ariad, BMS, Novartis, Pfizer, Teva: Research Funding.

scholarly journals Urine Metabolomics by 1H-NMR Spectroscopy Indicates Associations between Serum 3,5-T2 Concentrations and Intermediary Metabolism in Euthyroid Humans

2015 ◽  
Vol 4 (Suppl. 1) ◽  
pp. 92-100 ◽  
Author(s):  
Maik Pietzner ◽  
Georg Homuth ◽  
Kathrin Budde ◽  
Ina Lehmphul ◽  
Uwe Völker ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Nmr Spectroscopy ◽  
1H Nmr ◽  
1H Nmr Spectroscopy ◽  
Population Based ◽  
Metabolic Effects ◽  
Linear Regression Models ◽  
Urine Metabolites ◽  
Glucose And Lipid Metabolism ◽  
Design And Methods

Context: 3,5-Diiodo-L-thyronine (3,5-T2) is a thyroid hormone metabolite which exhibited versatile effects in rodent models, including the prevention of insulin resistance or hepatic steatosis typically forced by a high-fat diet. With respect to euthyroid humans, we recently observed a putative link between serum 3,5-T2 and glucose but not lipid metabolism. Objective: The aim of the present study was to widely screen the urine metabolome for associations with serum 3,5-T2 concentrations in healthy individuals. Study Design and Methods: Urine metabolites of 715 euthyroid participants of the population-based Study of Health in Pomerania (SHIP-TREND) were analyzed by 1H-NMR spectroscopy. Multinomial logistic and multivariate linear regression models were used to detect associations between urine metabolites and serum 3,5-T2 concentrations. Results: Serum 3,5-T2 concentrations were positively associated with urinary levels of trigonelline, pyroglutamate, acetone and hippurate. In detail, the odds for intermediate or suppressed serum 3,5-T2 concentrations doubled owing to a 1-standard deviation (SD) decrease in urine trigonelline levels, or increased by 29-50% in relation to a 1-SD decrease in urine pyroglutamate, acetone and hippurate levels. Conclusion: Our findings in humans confirmed the metabolic effects of circulating 3,5-T2 on glucose and lipid metabolism, oxidative stress and enhanced drug metabolism as postulated before based on interventional pharmacological studies in rodents. Of note, 3,5-T2 exhibited a unique urinary metabolic profile distinct from previously published results for the classical thyroid hormones.

scholarly journals Assessing Steroid Toxicity in the Elderly with Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5557-5557
Author(s):  
Vidhya Nair ◽  
Hadi Mohammed ◽  
Sharmeen Mahmood ◽  
Pushpinderdeep Singh Kahlon ◽  
Philip Kuriakose
Keyword(s):  
Central Nervous System ◽  
Multiple Myeloma ◽  
Nervous System ◽  
Adverse Effects ◽  
Elderly Patients ◽  
Dose Reduction ◽  
The Elderly ◽  
High Dose ◽  
Full Dose ◽  
Starting Dose

Background The mainstay of treatment for Multiple Myeloma (MM) includes various combinations of chemotherapy, which generally includes high dose steroids. The median age at diagnosis for MM is above 60 years. Patients above the age of 70 may not be considered for an auto peripheral blood transplant, resulting in being treated with chemotherapy alone. This often leads to a relatively long period of steroid exposure. Increasing age is a risk factor for decreased tolerance to steroids, and increased drug toxicity. As such, the steroid dose (usually Dexamethasone) is often considered for reduction in patients above a certain age. However, there are no clear guidelines regarding a standard dose to use in the elderly, nor is there uniformity among clinicians in the way doses are chosen. Purpose To assess a) the starting dose of Dexamethasone (dex) in the elderly, b) frequency of dose reduction of dexamethasone, c) adverse effects of dex treatment in the elderly with MM, and d) average time after dose reduction. Methods We performed a 10 year retrospective chart review on patients, age 70 or greater treated at Henry Ford Health System with a diagnosis of MM from 2000-2015. Patients were grouped by age 70-75 years, 76-80 years, and greater than 80 years based on when treatment was initiated. We investigated the starting treatment dose of dex, ranging from 1-20 mg weekly and 21-40 mg weekly. Secondly, we assessed for the occurrence of dose reduction; and, if present, the length of time to reducing the dose. Lastly, the types of adverse effects to dex leading to dose reduction were grouped by system, such as, central nervous system, musculoskeletal, endocrine, gastrointestinal and psychiatric. Data collected was categorical, thus, no statistical tests were performed as this was a descriptive study. Results A total of 150 patients were reviewed and 91 patients met the inclusion criteria. Of these patients, 8 (8.8%) were started at doses between 1-20 mg and majority (62.5%) were ages 70-75, thus, there was no relation between lower starting dose and age. Of the 91 patients, 24 (26.4%) had a dose reduction and 11 (12.1%) had both chemotherapy and dex discontinued prior to therapy completion. Majority (87.5%) of patients that had a dose reduction were initially started at 40 mg. The reasons for dose reduction included adverse effects grouped by musculoskeletal (29.17%), psychiatric (16.67%), endocrine (12.3%), central nervous system (4.17%), and gastrointestinal (4.17%). Of note, 8 patients (33.3%) had dose reductions as result of their clinical trial requirement. The average length of dex therapy before dose reduction was 17.2 months. Conclusion The majority of elderly patients (age 70 or above) with MM tolerated full doses of dex without adverse effects. Secondly, there was no relation between lower starting dose for dex and advanced age. However, since there were limited patients (n=8) who started at a low dose, other than those on clinical trials, we were not able to do a comparison of starting doses. But we were able to show that the majority of patients tolerated full dose, despite their age. The most frequent cause of steroid toxicity was musculoskeletal, such as leg swelling. On average, elderly patients were able to tolerate full dose of dex for over 1 year prior to requiring a dose reduction. Summary Our data demonstrates no correlation between advanced age in MM and lack of tolerability of high dose steroids. In conclusion, current findings do not justify reduced doses solely based on age alone. Future studies could include investigating statistical analysis on steroid exposure and survivorship. Disclosures Kuriakose: Alexion: Consultancy, Honoraria, Speakers Bureau; Bayer: Consultancy.

scholarly journals The Role of Fructose, Sucrose, and High-fructose Corn Syrup in Diabetes

2013 ◽  
Vol 09 (02) ◽  
pp. 128 ◽  
Author(s):  
Adrian I Cozma ◽  
John L Sievenpiper ◽  
◽  
◽  
◽  
...  
Keyword(s):  
Adverse Effects ◽  
Excess Energy ◽  
Metabolic Effects ◽  
High Fructose Corn Syrup ◽  
Corn Syrup ◽  
Obesity And Diabetes ◽  
High Fructose ◽  
Show Evidence ◽  
Meta Analyses

Concerns are growing regarding the role of dietary sugars in the development of obesity and cardiometabolic diseases, including diabetes. High-fructose corn syrup (HFCS) and sucrose are the most important dietary sweeteners. Both HFCS and sucrose have overlapping metabolic actions with adverse effects attributed to their fructose moiety. Ecologic studies have linked the rise in fructose availability with the increases in obesity and diabetes worldwide. This link has been largely underpinned by animal models and select human trials of fructose overfeeding at high levels of exposure. Although prospective cohort studies have shown significant associations comparing the highest with the lowest levels of intake sugar-sweetened beverages, these associations are small, do not hold at moderate levels of intake, and are subject to collinearity effects from related dietary and lifestyle factors. Most systematic reviews and meta-analyses from controlled feeding trials have shown that fructosecontaining sugars in isocaloric exchange for other carbohydrates do not show evidence of harm and, in the case of fructose, may even have advantages for glycemic control, especially at small doses. Nevertheless, trials in which fructose-containing sugars supplement diets with excess energy have shown adverse effects, effects that appear more attributable to the excess energy than the sugar. There is no unequivocal evidence that fructose intake at moderate doses is directly related with adverse metabolic effects, although there is potentially cause for concern where fructose is provided at high doses or contributes excess energy to diets. Further investigation is warranted due to the significant knowledge gaps and weaknesses in existing research.

scholarly journals Cannabis Therapy in the Management of Fibromyalgia: A Systematic Review

2021 ◽  
Author(s):  
Yuri Borges Bitu de Freitas ◽  
Caio de Almeida Lellis ◽  
Jhenefr Ribeiro Brito ◽  
Rodrigo Souza Ramos ◽  
Maria Luiza Gonzaga de Oliveira
Keyword(s):  
Systematic Review ◽  
Clinical Trials ◽  
Adverse Effects ◽  
Therapeutic Option ◽  
Life Quality ◽  
Pain Reduction ◽  
Catholic University ◽  
Randomized Studies ◽  
Starting Dose ◽  
Painful Syndrome

Introduction: Fibromyalgia is a painful syndrome of little known etiology, characterized by generalized pain with difficult management. Thus, cannabis therapy, a therapeutic option for other painful conditions, becomes an alternative. Objective: To review the literature on cannabis therapy in the treatment of fibromyalgia. Design and Setting: A systematic review conducted at the Pontifical Catholic University of Goiás. Methods: Systematic review. Randomized studies and clinical trials published between 01/2011 and 01/2021 were selected. Incomplete studies and those that did not fit the objectives were excluded. Results: When analyzing the combination of inhaled CBD and THC, it was concluded that, regardless of the dosage, neither showed significantly greater response than placebo. Studies pointed out that THC-rich cannabis oil, at starting dose of one drop a day, reduced pain, fatigue, and depression scores; moreover, the therapy proved tolerated and without serious adverse effects. Third-level evidence indicated better effects of nabilone on sleep than amitriptyline, without significant differences for pain, mood, and life quality. Conclusion: Different approaches to cannabis therapy for patients with fibromyalgia lead to diverse effects, with some not proving effective and others promoting pain reduction, sleep and life qualities improvements and satisfactory effects on depression and fatigue scores. Hence, scientifically relevant studies should be done on this subject.

scholarly journals Effects of various types of anesthesia on hemodynamics, cardiac function, and glucose and lipid metabolism in rats

2016 ◽  
Vol 311 (6) ◽  
pp. H1360-H1366 ◽  
Author(s):  
Yusuke Sano ◽  
Shogo Ito ◽  
Mamoru Yoneda ◽  
Kai Nagasawa ◽  
Natsumi Matsuura ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Cardiac Function ◽  
Insulin Level ◽  
Left Ventricular Diastolic Function ◽  
Aortic Pressure ◽  
Left Ventricular ◽  
Metabolic Effects ◽  
High Dose ◽  
Sprague Dawley ◽  
Glucose And Lipid Metabolism

Anesthesia can affect respiratory, circulatory, and endocrine systems but is necessary for certain experimental procedures such as echocardiography and blood sampling in small animals. We have now investigated the effects of four types of anesthesia [pentobarbital sodium (PENT), ketamine-xylazine (K/X), and low- or high-dose isoflurane (ISO)] on hemodynamics, cardiac function, and glucose and lipid metabolism in Sprague-Dawley rats. Aortic pressure, heart rate, and echocardiographic parameters were measured at various time points up to 45 min after the induction of anesthesia, and blood was then collected for measurement of parameters of glucose and lipid metabolism. Systolic aortic pressure remained constant in the PENT group, whereas it showed a biphasic pattern in the K/X group and a gradual decline in the ISO groups. Marked bradycardia was observed in the K/X group. The serum glucose concentration was increased and the plasma insulin level was reduced in the K/X and ISO groups compared with the PENT group. The concentrations of free fatty acids and norepinephrine in plasma were increased in the K/X group. Despite the metabolic effects of K/X and ISO, our results suggest that the marked bradycardic effect of K-X renders this combination appropriate for measurement of Doppler-derived indexes of left ventricular diastolic function, whereas the relative ease with which the depth of anesthesia can be controlled with ISO makes it suitable for manipulations or data collection over long time periods. On the other hand, PENT may be best suited for experiments that focus on measurement of cardiac function by M-mode echocardiography and metabolic parameters.

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