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American Journal of Health-system... Jul 2022We report a unique case of transiently elevated liver function test (LFT) values associated with concurrent use of dabigatran and primidone, which has not previously...
PURPOSE
We report a unique case of transiently elevated liver function test (LFT) values associated with concurrent use of dabigatran and primidone, which has not previously been described in the scientific literature.
SUMMARY
Management of drug-drug interactions requires a fundamental understanding of pharmacodynamic and pharmacokinetic parameters. Despite the use of available best predictive models, idiosyncratic drug reactions may still occur when a newly approved medication begins to be used in the general population. We report a case of a possible interaction (Naranjo adverse drug reaction probability score of 3, Roussel Uclaf causality assessment method score of 3) between dabigatran and primidone in a 70-year-old Caucasian male resulting in a transient elevation of LFT values. The patient was transitioned from warfarin to dabigatran in the setting of persistently subtherapeutic international normalized ratio values. During a routine outpatient follow-up appointment approximately 1 month after dabigatran initiation, the patient was discovered to have LFT values greater than 5 times the upper limit of normal. Dabigatran was thus discontinued; the patient was returned to warfarin therapy and their LFT values returned to baseline.
CONCLUSION
Studies have indicated a potential for reduced dabigatran efficacy with concurrent use of primidone due to P-glycoprotein induction, thereby potentiating the risk for thrombosis. To date, reports of this interaction resulting in hepatic injury are lacking. The present case suggests that this interaction may be clinically significant with regard to selection of antithrombotic medication therapy in patients on primidone therapy.
Topics: Aged; Anticoagulants; Atrial Fibrillation; Dabigatran; Humans; International Normalized Ratio; Liver Function Tests; Male; Primidone; Warfarin
PubMed: 35212353
DOI: 10.1093/ajhp/zxac054 -
Biomedical Chromatography : BMC Dec 2022Oral antiseizure medications are the preferred option for the clinical treatment of epilepsy. Therapeutic drug monitoring has become an important means of achieving...
Oral antiseizure medications are the preferred option for the clinical treatment of epilepsy. Therapeutic drug monitoring has become an important means of achieving individualized treatment of epilepsy. A sensitive, accurate and rapid LC-ESI-MS/MS method was developed and validated for the simultaneous determination of 15 antiseizure medications in human plasma (carbamazepine, gabapentin, pregabalin, phenytoin, zonisamide, oxcarbazepine, tiagabine, lamotrigine, topiramate, phenobarbital, lacosamide, primidone, 10,11-Dihydro-10-hydroxy carbamazepine, ethosuximide, and levetiracetam). The sample preparation procedure was an one-step protein precipitation with methanol. Mass detection was performed in ionization polarity switching mode (positive-negative-positive) using multiple reaction monitoring mode. A "boot-shaped" gradient elution program was applied to separate and concentrate those target analytes, resulting in symmetrical peak shapes within 10 min, without endogenous interference. The method showed great linearity over the concentration ranges with acceptable correlation coefficients (0.9966-0.9996). The precision and accuracy values for intra- and inter-assays were within ±15%. Consequently, the method was successfully implemented on pediatric patients undergoing mono- or polytherapy for epilepsy and provided timely concentration results to ordering clinicians.
Topics: Humans; Child; Drug Monitoring; Tandem Mass Spectrometry; Epilepsy; Anticonvulsants; Carbamazepine
PubMed: 35997075
DOI: 10.1002/bmc.5484 -
Epilepsy Research Feb 2021This study aimed at providing valid estimates for the risk of clinically relevant seizure aggravation by recommended anti-seizure medications in patients with Genetic...
This study aimed at providing valid estimates for the risk of clinically relevant seizure aggravation by recommended anti-seizure medications in patients with Genetic Generalized Epilepsy (GGE). To this aim, treatment response, side effects and paradoxical reactions to anti-seizure treatment were retrospectively assessed in a near-population based cohort comprising 471 adult GGE patients. A total of 1046 treatment attempts were analyzed (lamotrigine: 351, valproic acid: 295, levetiracetam: 249, primidone/phenobarbital: 94, zonisamide: 57). Under lamotrigine, seizure aggravation was observed in 15 patients (two patients during levetiracetam, one patient during zonisamide, none during phenobarbital and valproic acid). All but two patients with paradoxical reactions to lamotrigine were diagnosed with juvenile myoclonic epilepsy (JME), otherwise, the clinical and electroencephalographic characteristics of patients with paradoxical reactions did not differ. At treatment start, the estimated risk of a paradoxical reaction to lamotrigine was 7.9 % in JME patients (n = 190). For all GGE patients (incl. JME), the estimated risk of clinically relevant seizure aggravation under treatment with lamotrigine was 3.7 % (1.8 % for zonisamide and 0.8 % for levetiracetam). In conclusion, clinical significant aggravation of seizure frequency is common in lamotrigine-treated JME patients but rare in patients with other GGE subsyndromes or under treatment with other recommended anti-seizure medication.
Topics: Adult; Anticonvulsants; Epilepsy, Generalized; Humans; Lamotrigine; Levetiracetam; Myoclonic Epilepsy, Juvenile; Phenobarbital; Retrospective Studies; Risk Factors; Seizures; Valproic Acid; Zonisamide
PubMed: 33421702
DOI: 10.1016/j.eplepsyres.2020.106547 -
Environmental Science and Pollution... Aug 2021From 2001 to 2014, 13 surveys were conducted in the Baltic Sea, to determine its pollution of 50 micropollutants. The investigations focused mostly on the German western...
From 2001 to 2014, 13 surveys were conducted in the Baltic Sea, to determine its pollution of 50 micropollutants. The investigations focused mostly on the German western Baltic Sea; in 2008, one survey covered the entire Baltic Sea. Various groups of herbicides (such as triazines, phenoxyacetic acid, phenylurea), perfluoroalkyl substances, pharmaceuticals, and industrial products were analyzed during these surveys. The highest concentrations (median 1 to 4 ng/L) were observed for atrazine, simazine, chloridazone, 2,4-dichlorophenoxyacetic acid, benzotriazole, primidone, and carbamazepine. Most micropollutants exhibited a relatively homogenous spatial distribution, though some herbicides show elevated concentrations in certain regions (e.g., Odra estuary), indicating a riverine input. The data set was analyzed, both for seasonal influences and long-time trends. Some herbicides exhibited higher concentrations during summertime. Both upward- and downward-directed time trends could be identified for some herbicides and perfluorinated compounds. For most of the detected compounds, a low-risk quotient was calculated. Only the occurrence of carbendazim could potentially pose a higher risk to the Baltic Sea.
Topics: Baltic States; Environmental Monitoring; Estuaries; Risk Assessment; Seasons; Water Pollutants, Chemical
PubMed: 33755886
DOI: 10.1007/s11356-021-13254-5 -
ELife Apr 2020Transient Receptor Potential Melastatin 3 (TRPM3) is a Ca permeable non-selective cation channel activated by heat and chemical agonists such as pregnenolone sulfate and...
Transient Receptor Potential Melastatin 3 (TRPM3) is a Ca permeable non-selective cation channel activated by heat and chemical agonists such as pregnenolone sulfate and CIM0216. TRPM3 mutations in humans were recently reported to be associated with intellectual disability and epilepsy; the functional effects of those mutations, however, were not reported. Here, we show that both disease-associated mutations in the human TRPM3 render the channel overactive, but likely via different mechanisms. The Val to Met substitution in the S4-S5 loop induced a larger increase in basal activity and agonist sensitivity at room temperature than the Pro to Gln substitution in the extracellular segment of S6. In contrast, heat activation was increased more by the S6 mutant than by the S4-S5 segment mutant. Both mutants were inhibited by the TRPM3 antagonist primidone, suggesting a potential therapeutic intervention to treat this disease.
Topics: Calcium; Cells, Cultured; Ganglia, Spinal; HEK293 Cells; Humans; Mutation; Pregnenolone; TRPM Cation Channels
PubMed: 32343227
DOI: 10.7554/eLife.55634 -
Journal of Veterinary Internal Medicine Jan 2022Orthostatic tremor (OT) is a rare movement disorder characterized by high-frequency (>12 Hz) involuntary, rhythmic, sinusoidal movements affecting predominantly the...
BACKGROUND
Orthostatic tremor (OT) is a rare movement disorder characterized by high-frequency (>12 Hz) involuntary, rhythmic, sinusoidal movements affecting predominantly the limbs while standing.
OBJECTIVE
To describe the signalment, presenting complaints, phenotype, diagnostic findings, treatment, and outcome of a large sample of dogs with OT.
ANIMALS
Sixty dogs diagnosed with OT based on conscious electromyography.
METHODS
Multicenter retrospective case series study. Dogs were included if they had a conscious electromyography consistent with muscle discharge frequency >12 Hz while standing.
RESULTS
Fifty-three cases were diagnosed with primary OT (POT). Giant breed dogs represented most cases (83%; 44/53). Most dogs (79%; 42/53) were younger than 2 years of age at onset of signs, except for Retrievers which were all older than 3.5 years of age. The most common presenting complaints were pelvic limb tremors while standing (85%; 45/53) and difficulty when rising or sitting down (45%; 24/53). Improvement of clinical signs occurred in most dogs (85%; 45/53) treated medically with phenobarbital, primidone, gabapentin, pregabalin or clonazepam, but it was mostly partial rather than complete. Orthostatic tremor-plus was seen in 7 dogs that had concurrent neurological diseases.
CONCLUSIONS AND CLINICAL IMPORTANCE
Primary OT is a progressive disease of young, purebred, giant/large-breed dogs, which appears to begin later in life in Retrievers. Primary OT apparently responds partially to medications. Orthostatic tremor-plus exists in dogs and can be concomitant or associated with other neurological diseases.
Topics: Animals; Dizziness; Dog Diseases; Dogs; Electromyography; Retrospective Studies; Tremor
PubMed: 34897811
DOI: 10.1111/jvim.16328 -
Environmental Geochemistry and Health Oct 2020Active pharmaceutical ingredients (APIs) are typical endocrine disruptors found in common pharmaceuticals and personal care products, which are frequently detected in...
Active pharmaceutical ingredients (APIs) are typical endocrine disruptors found in common pharmaceuticals and personal care products, which are frequently detected in aquatic environments, especially surface water treated for drinking. However, current treatment technologies are inefficient for removing emerging endocrine disruptors, leading to the potential contamination of tap water. This study employed an optimized analytical method comprising solid-phase extraction and liquid chromatography-tandem mass spectrometry (SPE-LC-MS/MS) to detect APIs in tap water in Putrajaya, Malaysia. Several therapeutic classes of pharmaceuticals and personal care products, including anti-inflammatory drugs (dexamethasone and diclofenac), antibiotics (sulfamethoxazole and triclosan), antiepileptics (primidone), antibacterial agents (ciprofloxacin), beta-blockers (propranolol), psychoactive stimulants (caffeine), and antiparasitic drugs (diazinon), were detected in the range of < 0.03 to 21.39 ng/L, whereas chloramphenicol (an antibiotic) was below the detection limit (< 0.23 ng/L). A comparison with global data revealed the spatial variability of emerging tap water pollutants. Diclofenac accounted for the highest concentration (21.39 ng/L), followed by triclosan and ciprofloxacin (9.74 ng/L and 8.69 ng/L, respectively). Caffeine was observed in all field samples with the highest distribution at 35.32%. Caffeine and triclosan exhibited significantly different distributions in household tap water (p < 0.05). Humans are exposed to these APIs by drinking the tap water; however, the estimated risk was negligible (risk quotient < 1). APIs are useful water quality monitoring indicators for water resource conservation and water supply safety related to emerging organic contaminants; thus, API detection is important for safeguarding the environment and human health.
Topics: Drinking; Drinking Water; Endocrine Disruptors; Environmental Exposure; Environmental Monitoring; Humans; Malaysia; Risk Assessment; Water Pollutants, Chemical
PubMed: 32328897
DOI: 10.1007/s10653-020-00565-8 -
Clinical Epidemiology 2021To determine the risk of hip fracture in persons with Alzheimer´s disease (AD) who initiated antiepileptic drugs (AEDs).
OBJECTIVE
To determine the risk of hip fracture in persons with Alzheimer´s disease (AD) who initiated antiepileptic drugs (AEDs).
METHODS
In the Medication use and AD (MEDALZ) cohort of 70,719 Finnish community dwellers with clinically verified incident AD diagnosis in 2005-2011, we identified all incident users of AEDs using national Prescription register. AEDs were classified as older (valproate, carbamazepine, clonazepam, phenytoin, levetiracetam, primidone) or newer (pregabalin, gabapentin, oxcarbazepine, lamotrigine, topiramate). We matched each user to 2 non-users. Incident hip fractures until 2015 were identified from the Care register for health care. We calculated inverse probability of treatment weighted hazard ratios (HR), with 95% confidence intervals, using Cox regression.
RESULTS
Altogether 5522 incident users were identified and matched to 11,044 non-users (in both groups, women: 65%; median age: 81 years). Altogether 53.3% of users initiated with newer AEDs (pregabalin 79.8%, gabapentin 10.2%) while 46.7% initiated with older AEDs (valproate 67.6%, carbamazepine 13.0%). Age- and sex-adjusted IR of hip fracture per 100 person-years was 1.8 (95% CI 1.6-1.9) in non-users and 2.0 (95% CI 1.8-2.2) in users. Increased risk of hip fracture was observed in users (HR 1.17, 95% CI 1.05-1.30) compared with non-users. The risk was higher for short duration of use (<14 weeks, HR 3.64, 95% CI 2.90-4.58) than for medium duration (14 to <64 weeks, HR 1.74, 95% CI 1.48-2.05) or ≥64 weeks' use (HR 1.23, 95% CI 1.08-1.40), compared to non-users with same follow-up time. Older AEDs had HR of 1.46 (1.03-2.08) compared with newer AEDs.
CONCLUSION
Our results imply that AED use is associated with an increased risk of hip fracture in people with AD. These findings prompt careful consideration before prescribing AEDs to persons with AD. Persons with AD treated with antiepileptics should be carefully monitored due to their increased risk of falling and fractures.
PubMed: 33911901
DOI: 10.2147/CLEP.S278306 -
Brain and Nerve = Shinkei Kenkyu No... May 2022For essential tremors that are refractory to standard medical treatment, surgical treatment is considered when there is obstruction in activities of daily living....
For essential tremors that are refractory to standard medical treatment, surgical treatment is considered when there is obstruction in activities of daily living. However, there are patients who do not wish to undergo or are contraindicated for surgical treatment. In this paper, we explored what is considered to be the standard medical treatment and when surgery cannot be performed. In Japan, medical treatment is based on the use of arotinolol and primidone, and combination therapy and second-line drugs are extensively discussed. Furthermore, an algorithm of the treatment for essential tremors in Japan has been provided.
Topics: Activities of Daily Living; Essential Tremor; Humans; Japan; Primidone
PubMed: 35589658
DOI: 10.11477/mf.1416202091 -
Environmental Pollution (Barking, Essex... Oct 2022The presence of contaminants of emerging concern in the aquatic environment directly impacts water-living organisms and can alter their living functions. These compounds...
Prioritization based on risk assessment to study the bioconcentration and biotransformation of pharmaceuticals in glass eels (Anguilla anguilla) from the Adour estuary (Basque Country, France).
The presence of contaminants of emerging concern in the aquatic environment directly impacts water-living organisms and can alter their living functions. These compounds are often metabolized and excreted, but they can also be accumulated and spread through the food chain. The metabolized contaminants can also lead to the formation of new compounds with unknown toxicity and bioaccumulation potential. In this work, we have studied the occurrence, bioconcentration, and biotransformation of CECs in glass eels (Anguilla anguilla) using UHPLC-HRMS. To select the target CECs, we first carried out an environmental risk assessment of the WWTP effluent that releases directly into the Adour estuary (Bayonne, Basque Country, France). The risk quotients of every detected contaminant were calculated and three ecotoxicologically relevant contaminants were chosen to perform the exposure experiment: propranolol, diazepam, and irbesartan. An experiment of 14 days consisting of 7 days of exposure and 7 days of depuration was carried out to measure the bioconcentration of the chosen compounds. The quantitative results of the concentrations in glass eel showed that diazepam and irbesartan reached BCF ≈10 on day 7, but both compounds were eliminated after 7 days of depuration. On the other hand, propranolol's concentration remains constant all along with the experiment, and its presence can be detected even in the non-exposed control group, which might suggest environmental contamination. Two additional suspect screening strategies were used to identify metabolization products of the target compounds and other xenobiotics already present in wild glass eels. Only one metabolite was identified, nordiazepam, a well-known diazepam metabolite, probably due to the low metabolic rate of glass eels at this stage. The xenobiotic screening confirmed the presence of more xenobiotics in wild glass eels, prominent among them, the pharmaceuticals exemestane, primidone, iloprost, and norethandrolone.
Topics: Anguilla; Animals; Bioaccumulation; Biotransformation; Diazepam; Eels; Estuaries; Irbesartan; Pharmaceutical Preparations; Propranolol; Risk Assessment; Spain; Water Pollutants, Chemical
PubMed: 36007789
DOI: 10.1016/j.envpol.2022.120016