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- Investigation of Developmental Toxicity and Teratogenicity of Antiemetics on Rat Embryos Cultured In Vitro. [JOURNAL ARTICLE]
- Anat Histol Embryol 2012 Sep 25.
In this study, we aimed to investigate and compare the direct toxic and teratogenic effects of dimenhydrinate, metoclopramide and trimethobenzamide HCl, antiemetic drugs on embryonic growth and development in cultured rat embryos. Embryos were explanted on day 9.5 of gestation and cultured. Whole rat serum was used as a culture medium for the control group while different concentrations of dimenhydrinate (2.5-20 μg/ml), metoclopramide (10-50 μg/ml) and trimethobenzamide HCl (25-100 μg/ml) were added to serum for the experimental groups. Effects of antiemetics on embryonic developmental parameters were compared, and embryos were evaluated for the presence of any malformations. Also, the total DNA was extracted from the cells to determine the fragmentation of nuclear DNA of embryonic cells. Compared with the control embryos, the antiemetics significantly decreased all growth and developmental parameters dose dependently. There was no difference regarding the fragmentation of nuclear DNA of the all used agents and controls. Amongst the agents, trimethobenzamide HCl was found to have more toxic and teratogenic potential, and metoclopramide appears to be the least toxic antiemetic and therefore could be more safely used and might be preferred for the treatment of nausea and vomiting in pregnancy.
- Apomorphine injections: predictors of initial common adverse events and long term tolerability. [Journal Article]
- Parkinsonism Relat Disord 2012 Jun; 18(5):619-22.
Apomorphine injections effectively abort "off" episodes in Parkinson's disease (PD). However, their use is limited by actual and perceived adverse events (AE). To our knowledge, no study has evaluated for predictors of these problems.To assess predictors of initial common AE and long-term tolerability of apomorphine injections in PD.We prospectively monitored for AE in 28 consecutive PD patients receiving initial apomorphine injections. Sequential visual analogue scale scores for nausea and in standing systolic blood pressure drops at baseline (mean of 2 assessments), 10, 20, and 40 min post-injection were acquired. Assessed historic variables included patient demographics and clinical data, treatment histories, previous AE to other dopaminergic treatments and whether patients received the recommended three day pre-treatment dose of trimethobenzamide. We also correlated the L-dopa equivalent doses with apomorphine dose needed to turn "on".No patient demographic or previous history of dopaminergic AE predicted nausea, except for baseline pre-injection nausea that day at baseline. Three days of trimethobenzamide, as recommended, was actually associated with more nausea than a single dose or no dose, even though a lack of association after matched analysis was found. A younger patient age was associated with hypotension. L-dopa equivalent dose modestly correlated with final apomorphine dose to turn "on".A previous history of nausea and hypotension, and older age should not dissuade a trial of apomorphine if clinically justified. A three day pre-treatment dose of trimethobenzamide, as recommended in the United States, does not reduce nausea.
- Subcutaneous delivery of sumatriptan in the treatment of migraine and primary headache. [Journal Article]
- Patient Prefer Adherence 2012.:27-37.
Subcutaneous sumatriptan is an effective treatment for pain from acute migraine headache, and can be used in patients with known migraine syndrome and in patients with primary headaches when secondary causes have been excluded. In limited comparative trials, subcutaneous sumatriptan performed in a manner comparable with oral eletriptan and intravenous metoclopramide, was superior to intravenous aspirin and intramuscular trimethobenzamide-diphenhydramine, and was inferior to intravenous prochlorperazine for pain relief. The most common side effects seen with subcutaneous sumatriptan are injection site reactions and triptan sensations. As with all triptans, there is a risk of rare cardiovascular events with subcutaneous sumatriptan and its use should be limited to those without known cerebrovascular disease and limited in those with known cardiovascular risk factors and unknown disease status. In studies of patient preference and tolerability, the subcutaneous formulation has a faster time of onset and high rate of efficacy when compared with the oral formulation, but the oral formulation appears to be better tolerated. It is important to consider the needs of the patient, their past medical history, and what aspects of migraine treatment are most important to the patient when considering treatment of acute migraine or primary headache. Subcutaneous sumatriptan is a good first-line agent for the treatment of pain from acute migraine headaches and primary headaches.
- Growth failure, tardive dyskinesia, megacolon development, and hepatic damage in neonatal rats following exposure to trimethobenzamide in utero. [Evaluation Studies, Journal Article]
- J Matern Fetal Neonatal Med 2011 Sep; 24(9):1176-80.
Trimethobenzamide (TMB) has a pregnancy category C labeling. Tardive dyskinesia and gastrointestinal involvement in neonates were not described earlier. We aimed to investigate neurological, developmental, and hepatic effects of TMB.Ten 10 pregnant rats were divided into two groups. During pregnancy, Group I (control) were injected with saline; Group II with TMB (5 mg/kg/day). After delivery, two experiments were planned: experiment 1 (neuro) and Experiment 2 (hepatic). Control groups contained offsprings delivered from Group I mothers: Group I-offsp-neuro (n = 15) and Group I-offsp-hepatic (n = 15). Thirty offsprings delivered from Group II mothers formed Group II-offsp-neuro (n = 15) and Group II-offsp-hepatic (n = 15). Neuro group offsprings were followed-up to observe neurological symptoms and assessed for normal growth. Hepatic group livers were excised for histological evaluation.The body weight between neuro groups showed significant differences (p < 0.05). In Group II-offsp-neuro low body weight, poor hair growth, tardive dyskinesia and megacolon were observed. Some alterations of liver histology were noticed in Group II-offsp-hepatic (p < 0.001).In utero TMB exposure may cause growth retardation, neurological damage in the developing brain and intestine, and hepatic damage. Despite recent publications reporting safety of TMB, we suggest that obstetricians and pediatricians should make a good risk-benefit assessment before prescribing TMB.
- Standardizing emergency department-based migraine research: an analysis of commonly used clinical trial outcome measures. [Journal Article, Research Support, N.I.H., Extramural]
- Acad Emerg Med 2010 Jan; 17(1):72-9.
Although many high-quality migraine clinical trials have been performed in the emergency department (ED) setting, almost as many different primary outcome measures have been used, making data aggregation and meta-analysis difficult. The authors assessed commonly used migraine trial outcomes in two ways. First, the authors examined the association of each commonly used outcome versus the following patient-centered variable: the research subject's wish, when asked 24 hours after investigational medication administration, to receive the same medication the next time they presented to an ED with migraine ("would take again"). This variable was chosen as the criterion standard because it provides a simple, dichotomous, clinically sensible outcome, which allows migraineurs to factor important intangibles of efficacy and adverse effects of treatment into an overall assessment of care. The second part of the analysis assessed how sensitive to true efficacy each outcome measure was by calculating sample size requirements based on results observed in previously conducted clinical trials.This was a secondary analysis of data previously collected in four ED-based migraine randomized trials performed between 2003 and 2007. In each of these trials, subjects were asked 24 hours after administration of an investigational medication whether or not they would want to receive the same medication the next time they came to the ED with a migraine. Odds ratios (ORs) with 95% confidence intervals (CIs), adjusted for sex and medication received, were calculated as measures of association between the most commonly used outcome measures and "would take again." The sensitivity of each outcome measure to treatment efficacy was determined by calculating the sample size that would be required to detect a statistically significant result using estimates of that outcome obtained in two clinical trials.Data from 378 subjects were used for this analysis. Adjusted ORs for association of "would take again" and other commonly used primary headache outcomes are as follows: achieving a pain-free state by 2 hours, OR = 3.1 (95% CI = 1.8 to 5.4); sustained pain-free status, OR = 4.5 (95% CI = 1.9 to 11.0); and no need for rescue medication, OR = 3.7 (95% CI = 2.1 to 6.6). An improvement on a standardized 11-point pain scale of > or =33% had an adjusted OR = 5.2 (95% CI = 2.2 to 12.4). The best performing alternate outcome, > or =33% improvement, correctly classified 288 subjects and misclassified 77 subjects when compared to "would take again." At least 33% improvement and pain-free by 2 hours required the smallest sample sizes, while sustained pain-free and "would take again" required many more subjects."Would take again" was associated with all migraine outcome measures we examined. No individual outcome was more closely associated with "would take again" than any other. Even the best-performing alternate outcome misclassified more than 20% of subjects. However, sample sizes based on "would take again" tended to be larger than other outcome measures. On the basis of these findings and this outcome measure's inherent patient-centered focus, "would take again," included as a secondary outcome in all ED migraine trials, is proposed.
- Clinical and economic outcomes associated with potentially inappropriate prescribing in the elderly. [Journal Article]
- Am J Manag Care 2010 Jan; 16(1):e1-10.
To evaluate the risk of adverse events (AEs) and the healthcare costs for elderly patients receiving specific potentially inappropriate medications (PIMs).Retrospective cohort study.Patients 65 years and older who started 1 of 23 PIMs were matched with control subjects who were not receiving PIMs. The following 4 AEs and PIMs were evaluated: delirium or hallucinations with Beers high-severity (BHS) anticholinergics, delirium or hallucinations with BHS narcotics (meperidine hydrochloride or pentazocine lactate or pentazocine hydrochloride), extrapyramidal effects with trimethobenzamide hydrochloride, and falls or fractures with BHS sedative hypnotics. The risk of having the AE of interest within 360 days and the annual healthcare costs were examined.Patients receiving BHS sedative hypnotics were significantly more likely to have a fall or fracture than controls (hazard ratio, 1.22; 95% confidence interval [CI], 1.10-1.35). Patients receiving BHS anticholinergics did not have higher risk of delirium or hallucinations than controls (hazard ratio, 1.03; 95% CI, 0.91-1.16). Delirium or hallucinations occurred at a higher rate among patients receiving BHS narcotics, and extrapyramidal effects occurred at a higher rate among patients receiving trimethobenzamide; however, too few events occurred to assess statistical significance. For all PIMs evaluated, annual adjusted medical and total healthcare costs were significantly higher for patients exposed to PIMs than for controls.The use of certain BHS PIMs in the elderly may increase AEs or healthcare costs.
- Apomorphine in the treatment of Parkinson disease and other movement disorders. [Journal Article, Review]
- Expert Opin Pharmacother 2009 Apr; 10(6):1027-38.
Apomorphine, a medication that has been studied intensively over the years, is available in the US as intermittent subcutaneous injections for treatment of 'off' motor states in Parkinson disease.The clinical literature is summarized with particular focus on randomized controlled studies of apomorphine in the treatment of Parkinson disease.After reviewing the pharmacologic properties of apomorphine, the English language literature is summarized with particular attention on articles resulting from a Medline search of apomorphine and Parkinson disease limited to randomized controlled studies. Other formulations and indications for treatment of movement disorders are also discussed.Subcutaneous apomorphine is well tolerated when co-administered with trimethobenzamide or domperidone premedication. It has a unique efficacy as a 'rescue' medication owing to its rapid onset of action. Subcutaneous infusion, although not an approved route of administration in the US, provides more continuous dopaminergic stimulation and, therefore, ameliorates dyskinesia and motor fluctuations.
- Use of antiemetic agents in acute gastroenteritis: a systematic review and meta-analysis. [Journal Article, Meta-Analysis, Review]
- Arch Pediatr Adolesc Med 2008 Sep; 162(9):858-65.
To perform a systematic review and meta-analysis to determine whether taking antiemetic drugs reduces vomiting and decreases the need for further intervention in children with gastroenteritis without causing significant adverse effects.Computerized databases, reference lists, and expert recommendations.Prospective controlled trials evaluating medication use in children with vomiting from gastroenteritis.Antiemetic drug therapy.Emesis cessation, use of intravenous fluid for rehydration, hospital admission, return to care, and medication adverse effects.The 11 articles that met the inclusion criteria evaluated various antiemetic agents: ondansetron (n = 6), domperidone (n = 2), trimethobenzamide (n = 2), pyrilamine-pentobarbital (n = 2), metoclopramide (n = 2), dexamethasone (n = 1), and promethazine (n = 1). Meta-analysis of 6 randomized, double-masked, placebo-controlled trials of ondansetron demonstrated decreased risk of further vomiting (5 studies; relative risk [RR], 0.45; 95% confidence interval [CI], 0.33-0.62; number needed to treat [NNT] = 5), reduced need for intravenous fluid (4 studies; RR, 0.41; 95% CI, 0.28-0.62; NNT = 5), and decreased risk of immediate hospital admission (5 studies; RR, 0.52; 95% CI, 0.27-0.95; NNT = 14). Diarrheal episodes increased in ondansetron-treated patients in 3 studies. Ondansetron use did not significantly affect return to care (5 studies; RR, 1.34; 95% CI, 0.77-2.35).Ondansetron therapy decreases the risk of persistent vomiting, the use of intravenous fluid, and hospital admissions in children with vomiting due to gastroenteritis. Future treatment guidelines should incorporate ondansetron therapy for select children with gastroenteritis.
- [Apomorphine in off state--clinical experience]. [English Abstract, Journal Article, Review]
- Neurol Neurochir Pol 2007 Mar-Apr; 41(2 Suppl 1):S40-8.
Apomorphine, a non-ergot derivative, is a potent, directly acting dopamine receptor agonist with high affinity to D4, lower to D2, D3, D5, the lowest to D1-like dopamine receptors as well as to serotonin and adrenoreceptors. Subcutaneous apomorphine is currently used in Parkinson's disease as an add-on to levodopa therapy or monotherapy for management of sudden, unexpected and refractory to levodopa-induced off state and fluctuation in advanced stage of illness. Many clinical trials have shown markedly (about 50-72%) reduced time of off phases. Other indications include the challenge test for determining the dopaminergic responsiveness. Apomorphine is used subcutaneously either as intermittent rescue injections or continuous infusions. Several other routes - transdermal, sublingual, intranasal, rectal and intravenous infusion - have been tried. Oral administration is not recommended. Apomorphine has rapid onset of antiparkinsonian action, qualitatively comparable to that of levodopa, short duration of action and stable efficacy with usually mild adverse events similar to other dopamine agonists. Domperidone or trimethobenzamide should be introduced before starting apomorphine treatment to reduce occurrence of peripheral adverse events (nausea, vomiting, orthostatic hypotension). Dyskinesias, sleep disturbances, hallucinations, delusion, oedema and yawning can occur, but some side effects are connected only with a specific route (for example skin nodules appearing during subcutaneous administration). Despite its long history, apomorphine is registered and used in only a few countries. Apomorphine warrants wider application in treatment of advanced Parkinson disease but the high cost of the drug, the necessity of concomitant treatment for prevention of side effects and subcutaneous administration restrict its use.
- FDA halts sales of some anti-vomiting suppositories...and are cough medications effective in children? [Journal Article]
- Child Health Alert 2007 May.:1-2.