Isotretinoin in retrospect.

Clin Dermatol. 2017 May - Jun;35(3):335-339

Authors: Karadag AS, Parish LC, Lambert WC

PMID: 28511833 [PubMed - indexed for MEDLINE]

Drug-Induced Sleep-Disordered Breathing and Ventilatory Impairment.

Sleep Med Clin. 2018 Jun;13(2):161-168

Authors: Grote L

Abstract
This article describes current knowledge about drug entities that have the potential to induce, aggravate, or modify sleep-disordered breathing. The drug effects on sleep-disordered breathing may vary by patient age, gender, and comorbidity. In general, the clinical relevance of drug-induced sleep-disordered breathing is increasing in sleep medicine and the evidence in the field is growing in parallel.

PMID: 29759267 [PubMed - indexed for MEDLINE]

Drug-Induced Insomnia and Excessive Sleepiness.

Sleep Med Clin. 2018 Jun;13(2):147-159

Authors: Van Gastel A

Abstract
Psychotropic and nonpsychotropic drugs, which may induce or aggravate insomnia and/or daytime sleepiness, are discussed. These central nervous system effects are possible from the interactions of a drug with any of the many neurotransmitters or receptors that are involved in sleep and wakefulness. Multiple interactions between disease, sleep, comorbid sleep disorders, and direct or indirect influences of pharmacologic agents are possible. Awareness of these effects is important to adapt treatment and reach optimal results for every patient. Besides the importance for health and quality of life, effects on sleep or waking function can be a potential source of noncompliance.

PMID: 29759266 [PubMed - indexed for MEDLINE]

Dose-Dependent Teratology in Humans: Clinical Implications for Prevention.

Paediatr Drugs. 2018 Aug;20(4):331-335

Authors: Koren G, Berkovitch M, Ornoy A

Abstract
Since the inception of clinical teratology, the vast majority of scientific work has focused on identification of drugs and environmental agents causing malformations in humans as a dichotomous variable (i.e. yes or no), as well as the relative and absolute risks of such occurrences. Generally, the dose dependency of such events has not been investigated. With the establishment of large pregnancy databases, dose-dependence relationships are being uncovered for increasing numbers of medications, including valproic acid, carbamazepine, phenobarbital, lamotrigine, topiramate, and lithium. In this review we discuss newly recognized dose-dependent human teratogens and the implications to counseling and clinical management of pregnant women. The option of limiting the dose below a teratogenic threshold for women who may need these drugs may be important in managing such pregnancies. Similarly, in women that were exposed before they realized they had conceived, this new knowledge may lead to significant improvement in risk assessment. A common denominator of all studies calculating dose-dependent teratogenicity in humans is their use of total daily drug dose. None of these studies have standardized their calculations for women's body weight. It is quite possible that the teratogenic dose threshold may be below the clinically effective dose levels for specific women, and hence such information needs to be considered and applied individually. With large administrative databases now reporting on drug safety in pregnancy, more accurate data will likely emerge on dose dependency of human teratogens, and these will likely increase the accuracy of risk assessment.

PMID: 29725877 [PubMed - indexed for MEDLINE]

Use and safety of antiepileptic drugs in psychiatric inpatients-data from the AMSP study.

Eur Arch Psychiatry Clin Neurosci. 2018 Mar;268(2):191-208

Authors: Druschky K, Bleich S, Grohmann R, Engel RR, Kleimann A, Stübner S, Greil W, Toto S

Abstract
The psychiatric utilization patterns and risks of antiepileptic drugs (AEDs) were assessed by using data from the drug safety programme Arzneimittelsicherheit in der Psychiatrie over the time period 1993-2013. In a total of 432,215 patients, the main indications for AED use were acute mania, schizoaffective disorder, and schizophrenic and organic psychoses. Valproic acid (VPA) was the most common substance across all of those groups, reaching administration rates of up to 50% since 2005, at which time carbamazepine (CBZ) administration consistently dropped below a rate of 10%. Lamotrigine (LTG) and pregabalin (PGB) increased in relevance after 2005 and 2010, respectively (with administration rates of up to 9%), whereas oxcarbazepine (OXC) was least prevalent (<3%). The mean rates of severe adverse drug reactions (ADRs) ranged from 6 cases per 1000 patients treated (VPA) to 19/1000 (OXC) and were significantly lower with treatment with VPA compared to OXC and CBZ. Hyponatremia was the leading ADR during treatment with OXC; severe allergic skin reactions were most often observed during treatment with CBZ and LTG, and severe oedema was most common during treatment with PGB. Severe hyponatremia induced by OXC was observed significantly more often in female patients than in male patients.

PMID: 28766129 [PubMed - indexed for MEDLINE]

Avoidable drug-gene conflicts and polypharmacy interactions in patients participating in a personalized medicine program.

Per Med. 2017 05;14(3):221-233

Authors: Reynolds KK, Pierce DL, Weitendorf F, Linder MW

Abstract
AIM: Determine the ability of a pharmacogenetic service, PRIMER, to identify drug-gene (DGI) and drug-drug interactions (DDI) in patients across multiple conditions. PRIMER consists of patient selection criteria, a gene panel and actionable guidance for DGIs and DDIs.
RESULTS: The average patient was prescribed 12 medications. PRIMER identified significant DGIs in 73% of patients tested, with 43% having more than one DGI. DDIs were found in 87% of patients. The most common actionable DGIs were for opioid, psychotropic and cardiovascular medications.
CONCLUSION: The pairing of patient selection criteria, a multigene panel with evidence-based interpretation and review of DDIs maximizes the patients tested who have actionable benefit and alerts physicians to potentially critical adjustments needed for the patient's medication regimen.

PMID: 29767587 [PubMed - indexed for MEDLINE]

Lethal hepatotoxicity following 5-fluorouracil/cisplatin chemotherapy: a relevant case report.

Per Med. 2017 05;14(3):197-201

Authors: Hajj A, Ghosn M, Mourad D, Hojaiban K, Mousallem P, Khabbaz LR

Abstract
Some articles have reported severe toxicities induced by cisplatin/5-fluorouracil regimens, nevertheless, severe and lethal liver toxicity has not been previously reported. In this article, we report the case of a 72-year-old woman, who developed fulminant hepatitis, hypoglycemia and hypotension with atrial fibrillation not responding to treatment. After ruling out all other possible causes of hepatitis, the toxicity was more likely attributed to 5-fluorouracil. Genotyping was performed and the patient was found to be a homozygote carrier of the T variant of the MTHFR gene. The patient died two days later. Several factors, including genetic factors, could explain this severe toxicity. The present case discusses the importance of personalized medicine in oncology based on pharmacogenetic analysis of polymorphisms.

PMID: 29767581 [PubMed - indexed for MEDLINE]

Pediatric pharmacovigilance in an institute of national importance: Journey has just begun.

Indian J Pharmacol. 2017 Sep-Oct;49(5):390-395

Authors: Sharma PK, Misra AK, Gupta N, Khera D, Gupta A, Khera P

Abstract
OBJECTIVE: The objective of this study is to determine the nature and severity of adverse drug reactions (ADRs) in pediatric patients.
MATERIALS AND METHODS: In this retrospective cohort study, we extracted the data from all the available pediatric ADR forms submitted to ADR monitoring center (AMC) from May 2014 to December 2016. The data including nature, frequency, causality (World Health Organization [WHO] causality scale), and the severity (Hartwig and Siegel scale for severity) of ADR were extracted. We also assessed the preventability of the event on modified Schumock and Thornton scale of ADR preventability.
RESULTS: There were a total of 20 pediatric ADRs reported during this period. Nearly two-thirds of the ADRs occurred in patients who were receiving multiple drugs (polytherapy). Antimicrobial agents were the most commonly implicated drugs. The most common ADRs were skin rash (maculopapular, erythematous, and urticaria, itching, etc.). The severity and preventability scales indicated that most reactions (18/20) were moderate in nature and all were preventable. Four reactions were "certainly" and ten ADRs were "probably" related to the suspected drug as determined by the WHO causality assessment.
CONCLUSION: Frequency of ADR increased with number of medications patient was receiving. Health-care providers (HCPs) involved in the care of children must be aware of this fact and should use additional drugs when absolutely necessary. They should be involved in pharmacovigilance program by exchanging and updating each other through sharing constructive information, communication, and education concerning the appropriate use of drugs in children. Pediatric pharmacovigilance is the need of the hour and should be given utmost importance for monitoring the safety of drugs in children. Motivating HCPs for voluntary reporting of ADRs for preventing the morbidity and mortality in this vulnerable population could be of immense importance.

PMID: 29515280 [PubMed - indexed for MEDLINE]

Comparison of online reporting systems and their compatibility check with respective adverse drug reaction reporting forms.

Indian J Pharmacol. 2017 Sep-Oct;49(5):374-382

Authors: Maharshi V, Nagar P

Abstract
AIM: Different forms and online tools are available in different countries for spontaneous reporting, one of the most widely used methods of pharmacovigilance. Capturing sufficient information and adequate compatibility of online systems with respective reporting form is highly desirable for appropriate reporting of adverse drug reactions (ADRs). This study was aimed to compare three major online reporting systems (US, UK, and WHO) of the world and also to check their compatibility with the respective ADR reporting form.
MATERIALS AND METHODS: A total of 89 data elements to provide relevant information were found out from above three online reporting systems. All three online systems were compared regarding magnitude of information captured by each of them and scoring was done by providing a score of "1" to each element. Compatibility of ADR reporting forms of India (Red form), US (Form 3500), and UK (Yellow card form) was assessed by comparing the information gathered by them with that can be entered into their respective online reporting systems, namely, "VigiFlow," "US online reporting," and "Yellow card online reporting." Each unmatching item was given a score of "-1".
RESULTS: VigiFlow scored "74" points, whereas online reporting systems of the US and UK scored "56" and "49," respectively, regarding magnitude of the information gathered by them. Compatibility score was found to be "0," "-9," and "-26" in case of ADR reporting systems of US, UK, and India, respectively.
CONCLUSION: Our study reveals that "VigiFlow" is capable of capturing the maximum amount of information but "Form 3500" and "Online reporting system of US" are maximally compatible to each other among ADR reporting systems of all three countries.

PMID: 29515278 [PubMed - indexed for MEDLINE]

Visits by pharmaceutical representatives in general practice as observed by fifth-year medical students.

Tidsskr Nor Laegeforen. 2018 01 09;138(1):

Authors: Straand J, Cooper J

Abstract
BACKGROUND: Many general practitioners receive visits at their surgery from pharmaceutical representatives. The purpose of this study was to describe these visits, their framework and content (especially discussions of safety information), and to compare the findings with a corresponding study conducted in 2001–02.
BACKGROUND: A total of 116 fifth-year medical students (2001–02: 144) at the University of Oslo in practical training at GP surgeries in the South-Eastern Norway Regional Health Authority in the period 2014–16 completed an electronic questionnaire after attending a visit by a pharmaceutical representative at the medical centre.
RESULTS: A total of 116 visits took place during lunch breaks, when the representative paid for the food. In 90 % (2001–02: 81 %) of the visits, both doctors and their colleagues attended. Free samples were given out in 28 % (2001–02: 41 %) of the meetings, and small gifts in 5 % (2001–02: 44 %). Although the representative often refrained from raising the topic of safety information about the medication, this nevertheless happened less often than in 2001–02: adverse effects (42 % vs 55 %; p=0.04), interactions (53 % vs 64 %; p=0.07), contraindications (37 % vs 61 %; p= 0.0002) and precautions (30 % vs 56 %; p<0.0001). The medical students gave a below average score for their own learning outcome from the presentations (4.8 on a scale from 0–10) (2001–02: 4.2).
INTERPRETATION: Although the study shows improvements since 2001–02, it is still common for information provided at visits by pharmaceutical representatives to be deficient with regard to discussion of adverse effects, interactions, contraindications and precautions. Doctors must base their judgement on independent sources of information in order to stay abreast of the latest safety data on the medications.

PMID: 29313642 [PubMed - indexed for MEDLINE]

Predicting neurological Adverse Drug Reactions based on biological, chemical and phenotypic properties of drugs using machine learning models.

Sci Rep. 2017 04 13;7(1):872

Authors: Jamal S, Goyal S, Shanker A, Grover A

Abstract
Adverse drug reactions (ADRs) have become one of the primary reasons for the failure of drugs and a leading cause of deaths. Owing to the severe effects of ADRs, there is an urgent need for the generation of effective models which can accurately predict ADRs during early stages of drug development based on integration of various features of drugs. In the current study, we have focused on neurological ADRs and have used various properties of drugs that include biological properties (targets, transporters and enzymes), chemical properties (substructure fingerprints), phenotypic properties (side effects (SE) and therapeutic indications) and a combinations of the two and three levels of features. We employed relief-based feature selection technique to identify relevant properties and used machine learning approach to generated learned model systems which would predict neurological ADRs prior to preclinical testing. Additionally, in order to explain the efficiency and applicability of the models, we tested them to predict the ADRs for already existing anti-Alzheimer drugs and uncharacterized drugs, respectively in side effect resource (SIDER) database. The generated models were highly accurate and our results showed that the models based on chemical (accuracy 93.20%), phenotypic (accuracy 92.41%) and combination of three properties (accuracy 94.18%) were highly accurate while the models based on biological properties (accuracy 82.11%) were highly informative.

PMID: 28408735 [PubMed - indexed for MEDLINE]

Highly personalized reports for personalized drug selection by expert systems as clinical decision support.

Per Med. 2017 03;14(2):93-97

Authors: Hizel HC

PMID: 29754552 [PubMed - indexed for MEDLINE]

Performance measures, perceptions of quality and safety, and experience of adverse events.

Int J Qual Health Care. 2016 Dec 01;28(6):639

Authors: Iqbal U, Li YJ

PMID: 27816928 [PubMed - indexed for MEDLINE]

Cyclosporine-A induces endoplasmic reticulum stress in human gingival fibroblasts - An in vitro study.

J Oral Biol Craniofac Res. 2018 Sep-Dec;8(3):165-167

Authors: Rao SR, Ajitkumar S, Subbarayan R, Girija DM

Abstract
Drug induced gingival overgrowth is one of the side effects affecting the gingiva due to administration of certain systemic drugs. Cyclosporine A is one such drug which is commonly used in organ transplant conditions. The resultant overgrowth is fibrotic and extensive in nature which could impair patient esthetics and masticatory function. Endoplasmic reticulum stress is a recently identified phenomenon implicated in other fibrotic pathologies such as lung and renal fibrosis. In fact, endoplasmic reticulum stress has been known to play an important role in cyclosporine A induced renal fibrosis. Thus in this study, we sought to identify it's role in drug induced gingival overgrowth.

PMID: 30191101 [PubMed]

Ecopipam, a D1 receptor antagonist, for treatment of tourette syndrome in children: A randomized, placebo-controlled crossover study.

Mov Disord. 2018 Sep 07;:

Authors: Gilbert DL, Murphy TK, Jankovic J, Budman CL, Black KJ, Kurlan RM, Coffman KA, McCracken JT, Juncos J, Grant JE, Chipkin RE

Abstract
BACKGROUND: Dopamine D2 receptor antagonists used to treat Tourette syndrome may have inadequate responses or intolerable side effects. We present results of a 4-week randomized, double-blind, placebo-controlled crossover study evaluating the safety, tolerability, and efficacy of the D1 receptor antagonist ecopipam in children and adolescents with Tourette syndrome.
METHODS: Forty youth aged 7 to 17 years with Tourette syndrome and a Yale Global Tic Severity Scale - total tic score of ≥20 were enrolled and randomized to either ecopipam (50 mg/day for weight of <34 kg, 100 mg/day for weight of >34 kg) or placebo for 30 days, followed by a 2-week washout and then crossed to the alternative treatment for 30 days. Stimulants and tic-suppressing medications were excluded. The primary outcome measure was the total tic score. Secondary outcomes included obsessive compulsive and attention deficit/hyperactivity disorder scales.
RESULTS: Relative to changes in placebo, reduction in total tic score was greater for ecopipam at 16 days (mean difference, -3.7; 95% CI, -6.5 to -0.9; P = 0.011) and 30 days (mean difference, -3.2; 95% CI, -6.1 to -0.3; P = 0.033). There were no weight gain, drug-induced dyskinesias, or changes in laboratory tests, electrocardiograms, vital signs, or comorbid symptoms. Dropout rate was 5% (2 of 40). Adverse events reported for both treatments were rated predominantly mild to moderate, with only 5 rated severe (2 for ecopipam and 3 for placebo).
CONCLUSIONS: Ecopipam reduced tics and was well tolerated. This placebo-controlled study of ecopipam supports further clinical trials in children and adolescents with Tourette syndrome. © 2018 International Parkinson and Movement Disorder Society.

PMID: 30192018 [PubMed - as supplied by publisher]

Regorafenib for Patients with Metastatic Colorectal Cancer Who Progressed After Standard Therapy: Results of the Large, Single-Arm, Open-Label Phase IIIb CONSIGN Study.

Oncologist. 2018 Sep 06;:

Authors: Van Cutsem E, Martinelli E, Cascinu S, Sobrero A, Banzi M, Seitz JF, Barone C, Ychou M, Peeters M, Brenner B, Hofheinz RD, Maiello E, André T, Spallanzani A, Garcia-Carbonero R, Arriaga YE, Verma U, Grothey A, Kappeler C, Miriyala A, Kalmus J, Falcone A, Zaniboni A

Abstract
BACKGROUND: In the phase III CORRECT trial, regorafenib significantly improved survival in treatment-refractory metastatic colorectal cancer (mCRC). The CONSIGN study was designed to further characterize regorafenib safety and allow patients access to regorafenib before market authorization.
METHODS: This prospective, single-arm study enrolled patients in 25 countries at 186 sites. Patients with treatment-refractory mCRC and an Eastern Cooperative Oncology Group performance status (ECOG PS) ≤1 received regorafenib 160 mg once daily for the first 3 weeks of each 4-week cycle. The primary endpoint was safety. Progression-free survival (PFS) per investigator assessment was the only efficacy evaluation.
RESULTS: In total, 2,872 patients were assigned to treatment and 2,864 were treated. Median age was 62 years, ECOG PS 0/1 was 47%/53%, and 74% had received at least three prior regimens for metastatic disease. Median treatment duration was three cycles. Treatment-emergent adverse events (TEAEs) led to dose reduction in 46% of patients. Regorafenib-related TEAEs led to treatment discontinuation in 9%. Grade 5 regorafenib-related TEAEs occurred in <1%. The most common grade ≥3 regorafenib-related TEAEs were hypertension (15%), hand-foot skin reaction (14%), fatigue (13%), diarrhea (5%), and hypophosphatemia (5%). Treatment-emergent grade 3-4 laboratory toxicities included alanine aminotransferase (6%), aspartate aminotransferase (7%), and bilirubin (13%). Ongoing monitoring identified one nonfatal case of regorafenib-related severe drug-induced liver injury per DILI Working Group criteria. Median PFS (95% confidence interval [CI]) was 2.7 months (2.6-2.7).
CONCLUSION: In CONSIGN, the frequency and severity of TEAEs were consistent with the known safety profile of regorafenib. PFS was similar to reports of phase III trials. ClinicalTrials.gov: NCT01538680.
IMPLICATIONS FOR PRACTICE: Patients with metastatic colorectal cancer (mCRC) who fail treatment with standard therapies, including chemotherapy and monoclonal antibodies targeting vascular endothelial growth factor or epidermal growth factor receptor, have few treatment options. The multikinase inhibitor regorafenib was shown to improve survival in patients with treatment-refractory mCRC in the phase III CORRECT (N = 760) and CONCUR (N = 204) trials. However, safety data on regorafenib for mCRC in a larger number of patients were not available. The CONSIGN trial, carried out prospectively in more than 2,800 patients across 25 countries, confirmed the safety profile of regorafenib from the phase III trials and reinforced the importance of using treatment modifications to manage adverse events.

PMID: 30190299 [PubMed - as supplied by publisher]

Targeted therapy of pulmonary arterial hypertension: Updated recommendations from the Cologne Consensus Conference 2018.

Int J Cardiol. 2018 Aug 25;:

Authors: Hoeper MM, Apitz C, Grünig E, Halank M, Ewert R, Kaemmerer H, Kabitz HJ, Kähler C, Klose H, Leuchte H, Ulrich S, Olsson KM, Distler O, Rosenkranz S, Ghofrani HA

Abstract
In the summer of 2016, delegates from the German Respiratory Society, the German Society of Cardiology and the German Society of Pediatric Cardiology met in Cologne, Germany, to define consensus-based practice recommendations for the management of patients with pulmonary arterial hypertension (PAH). These recommendations were built on the 2015 European Pulmonary Hypertension guidelines and included new evidence, where available. The treatment algorithm for PAH was modified based on the observation that there are now many patients diagnosed with IPAH who are at an advanced age and have significant cardiopulmonary comorbidities. For patients newly diagnosed with classic forms of PAH, i.e. younger patients without significant cardiopulmonary comorbidities, the consensus-based recommendation was to use initial combination therapy as the standard approach. The use of monotherapies was no longer considered appropriate in such patients. The choice of treatment strategies should be based on the risk assessment as proposed in the European guidelines. In patients presenting with a low or intermediate risk, oral combination therapy with endothelin receptor antagonists and phosphodiesterase-5 inhibitors or soluble guanylate cyclase stimulators, respectively, should be used. In high-risk patients, triple combination therapy including a subcutaneous or intravenous prostacyclin analogue should be considered. For patients who suffer from PAH and significant cardiopulmonary comorbidities, initial monotherapy is recommended and the use of combination therapies should be considered on an individual basis. The latter recommendations are based on the scarcity of evidence supporting the use of combination therapy and the higher risk of drug-related adverse events in such patients.

PMID: 30190158 [PubMed - as supplied by publisher]

Adverse drug reactions upon use of new anticoagulants.

Tidsskr Nor Laegeforen. 2018 08 21;138(12):

Authors: Ghanima W

PMID: 30132601 [PubMed - indexed for MEDLINE]

Non-menopausal endocrine and non-endocrine causes of flushing and sweating.

Post Reprod Health. 2017 Dec;23(4):177-182

Authors: Lal V, Mamoojee YH, Quinton R

Abstract
Hot flushes and generalised sweating are relatively common presenting complaints, with hypogonadism an important differential diagnosis in both sexes and menopause being the most typical cause in females of climacteric age. However, a variety of other conditions do need to be carefully considered in respect of eugonadal individuals and also for those hypogonadal ones where properly dosed sex steroid replacement has failed to control flushing and sweating, or where the presentation is atypical. Alternative aetiologies may be immediately obvious from the history and physical examination, but more unusual conditions may require deeper scrutiny. This clinical review elaborates on the non-menopausal endocrine and non-endocrine causes of flushing and sweating, including both common and rarer conditions.

PMID: 28649907 [PubMed - indexed for MEDLINE]

Drugs that Suppress Lactation, Part 1.

Breastfeed Med. 2017 04;12:128-130

Authors: Anderson PO

PMID: 28394656 [PubMed - indexed for MEDLINE]