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Deltamethrin (DLM) is a commonly used pesticide that helps to control crop destruction, disease, and nuisance insects. In rodents DLM can produce choreoathetosis, salivation, and decreased acoustic startle responses (ASR). Herein, adult Sprague Dawley rats were assessed for ASR 2 h after DLM delivered in 5 ml/kg corn oil, however no decrease was observed. Therefore, a test-retest protocol was used to reduce variability, and the effects on ASR on postnatal day 15 (P15) and adult rats were assessed 2, 4, 6, and 8 h after DLM administration (0, 1, 2, or 4 mg/kg for P15 rats and 0, 2, 8, or 25 mg/kg for adults). In a separate set of rats identically treated, DLM levels were determined in blood and brain. DLM (8 or 25 mg/kg) in adult rats decreased ASR up to 4 h, whereas in P15 rats decreases were observed between 2 and 8 h. The adult 25 mg/kg group showed consistent signs of salivation and tremor, whereas in P15 rats salivation was observed in the 2 and 4 mg/kg groups and tremor was observed at all doses over the 8-h period. Mortality was observed in all P15 dose groups but not in adults. Dose-dependent increases of DLM in blood and brain regardless of age were observed. At approximately equivalent whole brain concentrations, effects were more pronounced in P15 rats than in adult rats. Comparable brain levels of DLM do not explain differences in ASR and tremor between the P15 and adult rats. These data indicate age-dependent differences in sensitivity to DLM., (© The Author(s) 2018. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The major objective of this project was to characterize the systemic disposition of the pyrethroid, deltamethrin (DLT), in immature rats, with emphasis on the age dependence of target organ (brain) dosimetry. Postnatal day (PND) 10, 21, and 40 male Sprague-Dawley rats received 0.4, 2, or 10 mg DLT/kg by gavage in glycerol formal. Serial plasma, brain, fat, liver, and skeletal muscle samples were collected for up to 510 h and analyzed for DLT and/or 3-phenoxybenzoic acid (PBA) content by high-performance liquid chromatography. Toxicokinetic data from previous experiments of the same design with young adult (PND 90) rats (Kim, K.-B., Anand, S. S., Kim, H. J., White, C. A., and Bruckner, J. V. [2008]. Toxicokinetics and tissue distribution of deltamethrin in adult Sprague-Dawley rats. Toxicol. Sci. 101, 197-205) were used to compare to immature rat data. Plasma and tissue DLT levels were inversely related to age. Preweanlings and weanlings showed markedly elevated brain concentrations and pronounced salivation, tremors, choreoathetosis, and eventual fatalities. Plasma DLT levels did not reliably reflect brain levels over time. Plasma:brain ratios were time and dose dependent, but apparently not age dependent. Brain levels were better correlated with the magnitude of salivation and tremors than plasma levels. Hepatic intrinsic clearance of DLT progressively increased during maturation, as did the hepatic extraction ratio. Thus, limited capacity to metabolically inactivate DLT appeared primarily responsible for the inordinately high target organ doses and acute neurotoxicity in pups and weanling rats. Hepatic blood flow was not rate limiting in any age group. Limited DLT hydrolysis was manifest in vivo in the pups by relatively low plasma PBA levels. Elevated exposure of the immature brain to a pyrethroid may prove to be of consequence for long-term, as well as short-term neurotoxicity.

Fungi in the genus Penicillium, particularly P. crustosum, produce tremorgenic mycotoxins, as well as suspected tremorgenic compounds. The accidental intoxication of six dogs with such toxins are reported. The clinical signs included vomiting, convulsions, tremors, ataxia, and tachycardia, all of which are indicators of intoxications affecting the nervous system. This symptomatology caused us to think that the dog poisoning was the result of tremorgenic mycotoxins. One dog was euthanized in the acute phase, while three others recovered completely within a few days. However, neurological symptoms were still observed four months after the poisoning of two of the dogs. One of these recovered completely within the next 2-3 months, while the other still suffers from ataxia three years later. Available samples of feed, stomach content and/or tissues from the intoxications were subjected to mycological and chemical analysis. Penitrem A was found in all reported poisonings and roquefortine C in all cases when this toxin was included in the analysis. The producer of these toxins, Penicillium crustosum, was detected in all cases where material suitable for mycological examinations (feed or vomit) was available. To our knowledge, this is the first report documenting the presence of penitrems and roquefortine C in organs from poisoned dogs. Furthermore, the report indicates that the recovery period after severe poisonings with P. crustosum may be protracted.

Objective: To evaluate the long-term safety of tacrolimus 3 mg/day in patients with rheumatoid arthritis (RA)., Methods: Patients with active RA who had discontinued all DMARDs for at least 2 weeks and had at least five tender/painful joints and three swollen joints, and required DMARD treatment in the opinion of the investigator, were enrolled into this open-label long-term safety trial. In addition, patients who had completed at least 3 months of treatment with tacrolimus 2 mg/day, tacrolimus 3 mg/day or placebo in a Phase III double-blind efficacy trial were allowed to roll over into this study. This latter group of patients did not have to fulfil any joint count requirements prior to entry into the long-term safety study, provided that no more than 14 days had elapsed between the end of their participation in the double-blind study and screening for the long-term safety study. All patients enrolled received tacrolimus 3 mg/day in addition to their current regimen of NSAIDs and corticosteroids., Results: 896 patients received at least one dose of tacrolimus 3 mg. The median duration of treatment was 359 days. 145 patients (16.2%) withdrew from the study for adverse events possibly or probably related to tacrolimus, 33 patients (3.7%) withdrew from the study for adverse events unrelated to tacrolimus and 112 (12.5%) withdrew for lack of efficacy. No adverse event with an incidence >0.7% appeared for the first time after the first 3 months of treatment with 3 mg tacrolimus. 529 patients (59%) experienced an adverse event that was possibly or probably related to tacrolimus; the most common were diarrhoea (14.6%), nausea (10.3%), tremor (9.0%), headache (8.7%), abdominal pain (7.9%), dyspepsia (7.6%), increased creatinine (6.8%) and hypertension (5.4%). Twenty-four patients (2.7%) experienced serious adverse events possibly or probably related to study drug; the most common were pneumonia (0.6%), hyperglycaemia (0.3%), gastroenteritis (0.2%), pancreatitis (0.2%) and diabetes mellitus (0.2%). The mean creatinine level increased from 67+/-19 micromol/l (0.76+/-0.22 mg/dl) at baseline to 75+/-26 micromol/l (0.85+/-0.30 mg/dl) (P<0.0001) at end of treatment. 351 (40.3%) of the 872 patients for whom creatinine levels were available at both baseline and during treatment had > or =30% increase from baseline in serum creatinine during the study, either related or unrelated to tacrolimus, with 73 patients (8.4%) having creatinine levels exceeding the normal range. At end of treatment, 177 patients (20.3%) had a > or =30% increase from baseline in creatinine. Serum creatinine remained within the normal range throughout the trial in approximately 90% of patients. At the end of treatment, the ACR20, ACR50 and ACR70 response rates were 38.4%, 18.6% and 9.0% respectively. Over 26% of patients had at least a 70% improvement in both swollen and painful/tender joints., Conclusion: This study demonstrates that tacrolimus was safe and well-tolerated and provided clinical benefit over a period of at least 12 months.

Twelve healthy volunteers were enrolled in an open-label, randomized, crossover study. Subjects received single doses of theophylline (5 mg/kg) alone and after a 10 day course of dirithromycin (two 250 mg tablets od). The study phases were separated by a 3 week washout period. Serum samples were collected before and for 24 h after theophylline doses. Serum theophylline concentrations were measured via a validated immunoassay system and the data were modelled via non-compartmental analysis. When the control phase (i.e. no dirithromycin) was compared with the treatment phase (i.e. with dirithromycin), theophylline exposures as measured by AUC0-->infinity were not significantly different: 141.7+/-25.9 and 136.4+/-33.1 mg x h/L respectively (P = 0.16). No significant changes in other theophylline pharmacokinetic parameters were evident. These results indicate that theophylline can be safely co-administered with dirithromycin.

A tropane ester, three tropane ethers, atropine and mecamylamine were compared in mice for their anti-muscarinic and anti-nicotinic activity against arecoline-induced tremor and nicotine-induced convulsions, respectively. Their receptor-binding characteristics were studied in neuronal membranes prepared from rat cerebral cortex. The results showed that the tropane ester, 2 alpha R-tropanyl benzylate, was more potent than atropine in its anti-muscarinic activity, but the anti-muscarinic activity of the tropane ethers, 2 alpha-(2',2'-diphenyl-2'-hydroxy-ethoxy)tropane (alpha-DPT) and its two isomers (1R,2 alpha R- and 1S,2 alpha S-) were less potent than that of atropine. In contrast with their anti-muscarinic potency, 2 alpha R-tropanyl benzylate and the three tropane ethers were equipotent in their anti-nicotinic activities. The order of potencies of these compounds to displace the binding of [3H]quinuclidinyl benzylate to brain membranes was similar to that of their anti-muscarinic potencies. The binding of [3H]nicotine to nicotinic receptors from brain was not inhibited by these compounds. Analyses of structure-activity relationships of these compounds suggested that it is the ester groups that determine the anti-muscarinic potencies of 2 alpha R-tropanyl benzylate; their anti-nicotinic activities were independent of the structural changes and of the anti-muscarinic activities of these compounds.

Rats given a liquid diet containing 10% (v/v) alcohol consume high quantities of alcohol. Within 8 hr after cessation of the alcohol intake, the animals will show alcohol-withdrawal reactions including a supersensitivity to harmine-induced tremor and an inhibition of exploratory behaviour in a neutral environment. Several drugs can overcome one or more of these alcohol-withdrawal reactions. A reduction of the alcohol withdrawal-induced inhibition of exploration, in terms of both the number of transits into the open field and the time spent in the open field, was obtained with chlordiazepoxide, ritanserin, mianserin and propranolol. Of these four compounds, propranolol and mianserin were also active against the supersensitivity to both 5.00 and 10.00 mg/kg harmine-induced tremor. Chlordiazepoxide and ritanserin were only active against 5.00 mg/kg harmine. Other compounds that reversed the supersensitivity to harmine-induced tremor during alcohol withdrawal included buspirone, fluoxetine, haloperidol, clonidine, flunarizine and baclofen. Very limited effects on both alcohol-withdrawal reactions were observed with ondansetron, nimodipine and MK-801. Risperidone and SCH 23390 were inactive. These results demonstrate that some alcohol withdrawal reactions can be studied in a systematic way and that various pharmacological agents can differentially interact with these alcohol withdrawal reactions.

The concentration-time profiles of ethanol were determined for capillary blood, end-expired breath, and saliva after 21 healthy men ingested ethanol at 0.68 g/kg body weight. Near the time of obtaining body fluids, the volunteers estimated their feelings of intoxication, and body sway (with open and closed eyes), hand tremor, positional alcohol nystagmus (PAN), and roving ocular movements (ROM) were quantitatively recorded. The concentration-time profiles of ethanol in blood, breath, and saliva agreed well within individuals but there were large variations between subjects. The mean saliva-ethanol profiles ran slightly above those for blood and breath. Subjective ratings of intoxication and impairment of body function (standing steadiness and hand steadiness) were highest at the time of reaching the peak concentrations of ethanol in body fluids. PAN was evident in most subjects between 60 and 120 min after the start of drinking, whereas ROM appeared mainly during the postabsorptive phase of ethanol kinetics (120-420 min). The blood ethanol concentration thresholds were between 500 and 700 mg/L (50-70 mg/dL) when the diminished performance had recovered to baseline values.

One of the prominent symptoms in alcoholics during withdrawal is an intense feeling of anxiety. Recently new tests have become available which may index anxiety in rodents. We have evaluated two such tests in our model of withdrawal from ethanol (ET) in rats. Rats were given either ET in milk (7-13 g/kg/4 days) or equicaloric dextrin maltose in milk via implanted gastric cannuli. Rats were scored for classical withdrawal symptoms (tremors, convulsions, stereotyped behavior), for stimulus-elicited ultrasonic vocalizations (USVs), and in one study for exploration of novel objects placed in their home cage at various points after the last dose of ET. In Sprague-Dawley rats, classical withdrawal symptoms were highest between 8-12 hours, and disappeared by 36 hours. Latency to explore a novel object was unchanged, but duration was depressed between 10-30 hours, and was recovered by 70 hours. Following a less intense Day 1 treatment regimen in Long-Evans rats, the vocalizations were greatly increased in number, and peak response occurred sooner (6 hours post-infusion) and was of shorter overall duration (50 hours). Pretreatment with diazepam (1.25-5.0 mg/kg) depressed the number of vocalizations during ET withdrawal (ETW), which suggests that this measure could index anxiety in animal models of withdrawal from ET.

In a cross-sectional study of 4558 Australians, it was found that the proportion of subjects reporting indigestion, palpitations, tremor, headache and insomnia increased significantly with mean caffeine intake. A multiple logistic regression model was used to show that the association between the prevalence of these symptoms and usual daily caffeine consumption remained significant in both males and females for palpitations, tremor, headache and insomnia after controlling for the potential confounding factors of age, adiposity, smoking, alcohol intake and occupation. Adiposity was strongly correlated with the prevalence of indigestion and the apparent association between caffeine and indigestion disappeared when adiposity was controlled for. According to the logistic model, the relative risk of experiencing symptoms for people consuming 240 mg of caffeine (approximately 4-5 cups of coffee or tea) per day (the population average) compared with caffeine abstainers is 1.6 for palpitations, 1.3 for tremor, 1.3 for headache, and 1.4 for insomnia in males and 1.7, 1.5, 1.2 and 1.4 respectively for females. Further logistic regression analysis indicated that the associations found between caffeine intake and symptoms did not depend on the source of caffeine. In general, coffee consumption has no significant effect over and above that attributable to its caffeine content. If these associations are causal, then approximately one quarter of the reported prevalence of palpitations, tremor, headache and insomnia is attributable to caffeine consumption in this study population.

N-Carbamoyl-2-(2,6-dichlorophenyl)acetamidine HCl (LON 954), a tremorogenic drug, inhibited MAO activity in various tissue preparations in a reversible, competitive manner showing some degree of selectivity towards type-B MAO.

Six forms of reversible adverse reactions to adenine arabinoside (vidarabine) were observed in a two-year period among 42 patients (19 of whom had lymphomas, leukemias, or other malignancies) who were treated for complicated infections with varicella-zoster or herpes simplex virus. Six patients received placebo. Ten patients received 10 mg of adenine arabinoside/kg per day; three received 15 mg/kg; 22 received 20 mg/kg; and one received 30 mg/kg. Patients were treated (by continuous intravenous injection) for an average of seven days. Toxic effects were nausea and vomiting, weight loss, weakness (often with impaired ambulation), megaloblastosis in erythroid series in bone marrow, tremors five to seven days after the start of therapy (including tremors in one patient with abnormal electroencephalograms that were consistent with toxic-metabolic encephalopathy), and thrombophlebitis at the intravenous site. Side effects clearly predominated in patients who received 20 mg/kg per day. Therefore, treatment with 10 mg/kg per day appears preferable until the relation of toxicity to dosage level can be clarified.

The beta-adrenoceptor blockers propranolol, PhQA33 and LB-46 exhibited appreciable activity against tremorine-(TMN) and oxotremorine-(OTMN) induced tremor, whereas pronethalol, (+)-H56/28, (-)-H56/28, Kö-592 and L(+)-INPEA possessed weak action. The two beta-blockers, namely D,L(+/-)-INPEA and D(-)-INPEA acted as weak tremorgens. None of the above compounds suppressed the induced peripheral cholinergic phenomena; or possessed any central anticholinergic activity, as they were unable to afford protection against physostigmine-induced death. Propranolol, PhQA33 and LB-46 antagonized TMN-induced hypothermia and analgesia, but were inactive against OTMN-induced changes. A correlation of the beta-blocking and anti-tremor activity of these agents is unlikely.

Oxotremorine-induced tremor activity in mice was suppressed by pretreatment with either L-dopa or atropine. Additional pretreatment with the opiate receptor blocker naloxone significantly potentiated the antitremor effect of L-dopa but not that of atropine. These findings indicate a selectivity of drug interaction between naloxone and L-dopa.

The effects of inhaling an aerosol preparation containing fenoterol 200 micrograms and ipratropium bromide 80 micrograms were compared with those of inhaling 200 micrograms of salbutamol and a similar dose of fenoterol on 20 patients with chronic bronchitis and four patients with chronic stable asthma. The dose of each drug was contained in 2 puffs taken from a metered-dose inhaler. Changes in airways function were assessed by measuring peak expiratory flow rate. Pulse, blood pressure and presence of any tremor were monitored to detect drug-induced side effects. No significant difference was found in the onset of action and overall bronchodilator effects between the three drugs. The combined preparation was found to have a significantly greater bronchodilator action three and four hours after inhalation compared to the other two drugs. A significant effect lasting six hours was found with salbutamol and fenoterol, but the combined preparation had an effect which was significant up to seven hours. There was no significant difference in the side effects which were minimal for all three drugs.

Two oxotremorine antagonists have been examined using oxotremorine as the tremor salivation inducer and the ratios between the central and peripheral nervous systems determined. Under these conditions these compounds are still more effective antagonists centrally than peripherally. Differences in distribution to the various muscarinic receptors involved is believed to be the major factor in determining this separation of central and peripheral activities.

The stereoisomers of some analogues of oxotremorine containing two chiral centres, one in the 1-position of the butynyl chas are oxotremorine antagonists. They show a marked stereoselectivity, which depends mainly on the configuration of the chiral centre in the butynyl chain and to a lesser extent on the configuration of that in the pyrrolidine ring.

Five patients were treated with pindolol for various indications. The patients called attention to the appearance of fine tremors in their extremities 6-72 hr after starting treatment with the drug. The tremors disappeared 24-72 hr after stopping the drug. Beta-adrenoceptor-blockers are known to suppress different types of tremor and the paradoxical appearance of tremors during pindolol treatment is attributed to its powerful partial agonist activity. To the best of the authors' knowledge this side effect has not been previously described in the literature.

Despite the lack of virus-specified thymidine kinase activity, human cytomegalovirus may be sensitive to acyclovir in vitro at concentrations between 10 and 25 mg/l. The inhibitory effect of acyclovir can be further increased by the presence of small amounts of human alpha or beta interferon. Twenty-one allogeneic marrow graft recipients with biopsy-proven cytomegalovirus pneumonia were treated with either high doses of acyclovir (eight patients) or the combination of acyclovir and human alpha (leukocyte) interferon (13 patients). Acyclovir doses of 400 to 1200 mg/m2/dose and interferon doses of 2 to 40 X 10(4) units/kg/day were used. There was no consistent effect of treatment on the likelihood or duration of survival, titre of virus in paired lung specimens, or shedding of virus. However, four patients survived and four others had 2-log or greater decreases in the amount of virus in paired lung specimens, suggesting a possible effect on cytomegalovirus strains with increased sensitivity to these agents. Acyclovir treatment of cytomegalovirus infection may be more effective in patients with lesser degrees of immunosuppression, but was not effective in the treatment of marrow transplant patients with cytomegalovirus pneumonia.

Administration of thyroliberin (TRH) to reserpinized mice causes tremor and counteracts the hypothermia in a dose-dependent fashion. The thyroliberin response is inhibited by gamma-hydroxybutyric acid (GHB) and baclofen, but not by other, more specific GABA-ergic agents, such as THIP, gamma-acetylenic GABA, and sodium valproate. Picrotoxin neither potentiates nor inhibits the thyroliberin actions. Nor are the thyroliberin effects dependent on cholinergic, monoaminergic or histaminergic mechanisms. The results repudiate a current hypothesis, that the peptide actions may be mediated by GABA-ergic pathways in the brain.