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PubMedDate not supplied

The contrasting actions of two pyrethroids (deltamethrin and cismethrin) in the rat.

Deltamethrin and cismethrin are representative members of the two classes of pyrethroid insecticide which can be distinguished on the basis of the symptoms which they produce in mammals. This paper reviews the relevant literature together with some new findings. The motor symptoms produced by the deltamethrin class are a complex but distinctive sequence of co-ordinated movements which are accompanied by EEG spiking, increased brain blood flow, increased brain glucose utilization in some regions, salivation, hyperglycaemia and, in vitro, increased cardiac contractility. The cismethrin class produces a different pattern of uncoordinated tremor accompanied by increased brain blood flow and regional glucose utilization, but without EEG spiking, salivation, hyperglycaemia or cardiac actions. Both compounds produce regional dissociations between brain blood flow and glucose utilization. It is concluded that most of these actions are attributable to prolongation of membrane sodium currents, and that the more widespread actions of deltamethrin are due to the much greater sodium current prolongation which it produces.

Animals↗
PubMed1980

Some pharmacological properties of a novel series of 2-substituted 2-phenylcyclohexyl N,N-diethylaminoethyl ethers I.

Two 2-phenylcyclohexyl N,N-diethylaminoethyl ethers were studied for their pharmacological actions in vitro-the cis- and trans- isomers; and in vivo,-the cis- isomer. These compounds (5 mg/ml) significantly depressed acetylcholine-induced contractions in the isolated guineapig ileum. The trans- isomer produced a greater depression of contraction. The cis- isomer shortened the duration of methacholine-induced salivation in mice when administered intraperitoneally in increasing doses. The duration was found to be inversely proportional to the dose of the compound. In anesthetized rats, pretreatment with either a dose of 5 mg/Kg of the cis- compound or 0.25 mg/Kg of atropine changed the methacholine depressor response to a pressor response. Heart rate was increased in both groups of pretreated rats. Respiratory rate was further augmented by methacholine in the presence of either atropine or the cis- compound, while rectal temperature was slightly decreased. Effects of the cis- isomer when administered alone, on heart rate and blood pressure responses usggest cholinergic activity. However, its ability to decrease the duration of methacholine-induced salivation in mice and its reversal of methacholine-evoked cardiovascular effects are indicative of anticholinergic activity. These experiments suggest that the cis- isomer has a mixed cholinergic and anticholinergic action and thus may be classed as a partial antagonist of the parasympathetic system.

Animals↗
PubMed1994

Evaluation and management of sialorrhea of pregnancy with concomitant hyperemesis.

This article describes two gravid patients who presented with first-trimester sialorrhea and hyperemesis. Although excessive salivation, especially when accompanied by protracted nausea and vomiting, is an unusual occurrence, it can have serious consequences for both the mother and fetus when left untreated. Initially, phenothiazine was prescribed and later belladonna alkaloid was added separately to the two treatment regimens. In order to successfully treat the excessive salivation, it was necessary to control the nausea and vomiting. Eradication of sialorrhea and hyperemesis were effected 10 days posttreatment. For both patients, pregnancy, delivery, and postpartum intervals proceeded uneventfully. Mothers and infants remain in good health 2 years posttreatment.

Adult↗
PubMed1993

Action of nerve agents to cholinesterases.

Changes of acetylcholinesterase activity in the blood and different organs of the rat following intoxication with sarin, soman, VX and 2-dimethylamino-ethyl-(dimethylamido)phosphonofluoridate (GV) in doses of approximately 2 x LD50 (i.m.) were obtained from literature data and by experiment. The time course of acetylcholinesterase inhibition in the blood, regions of brain and diaphragm and the occurrence of signs and symptoms of poisoning (none, salivation, disturbed ventilation and fasciculations, convulsions or death) were summarized and compared. When blood enzyme activities were 70-100% normal, no signs were seen; at 60-70%, salivation occurred; at less than 30-55%, disturbed ventilation and fasciculations were seen while at 15-30%, convulsions occurred. Less than 10% was fatal. In experiments with narcotized dogs, the blood acetylcholinesterase activity and its reactivatability with trimedoxime were determined following intoxication (i.m.) with the above mentioned four compounds. It can be concluded that acetylcholinesterase activity in the blood corresponds to that in the target organs and can be considered as an appropriate parameter for biological monitoring of nerve gas exposure. Moreover, determination of reactivatability of blood acetylcholinesterase indicates more information than simple enzyme activity determination.

Acetylcholinesterase↗
PubMed1997

Pharmacology of butylthio[2.2.2] (LY297802/NNC11-1053): a novel analgesic with mixed muscarinic receptor agonist and antagonist activity.

Butylthio[2.2.2], ((+)-(S)-3-(4-butylthio-1,2,5-thiadiazol-3-yl)-1-azabicyclo[2.2.2] octane; LY297802/NNC11-1053) is a muscarinic receptor ligand which is equiefficacious to morphine in producing antinociception. In vitro, butylthio[2.2.2] had high affinity for muscarinic receptors in brain homogenates, but had substantially less or no affinity for several other neurotransmiter receptors and uptake sites. In isolated tissues, butylthio[2.2.2] was an agonist with high affinity for M1 receptors in the rabbit vas deferens (IC50 = 0.33 nM), but it was an antagonist at M2 receptors in guinea pig atria (pA2 = 6.9) and at M3 receptors in guinea pig urinary bladder (pA2 = 7.4) and a weak partial agonist in guinea pig ileum, which contains a heterogeneous population of muscarinic receptors. In vivo, butylthio[2.2.2] was without effect on acetylcholine, dopamine and serotonin levels in rat brain. Moreover, butylthio[2.2.2] did not decrease charcoal meal transit in mice, nor did it significantly alter heart rate in rats. Further, butylthio[2.2.2] did not produce parasympathomimetic effects such as salivation or tremor in mice, but it antagonized salivation and tremor produced by the nonselective muscarinic agonist oxotremorine. The present data demonstrate that butylthio[2.2.2] is a novel muscarinic receptor mixed agonist/antagonist and its pharmacological profile suggests that it may have clinical utility in the management of pain as an alternative to opioids.

Analgesics↗
PubMed1997

Pharmacokinetics and pharmacodynamics of tolterodine in man: a new drug for the treatment of urinary bladder overactivity.

The aim of this study was to determine the pharmacokinetics, pharmacodynamics, and safety of tolterodine following single oral and intravenous doses in healthy volunteers. A secondary aim was to identify major urinary metabolites and determine mass balance. Single oral doses of 0.2, 0.4, 0.8, 1.6, 3.2, 6.4, and 12.8 mg of tolterodine (as the tartrate salt) were given to 17 healthy male volunteers. Two intravenous doses (0.64 and 1.28 mg) were administered to 8 of the volunteers and mass balance was studied after a single oral dose of 5 mg (14C)-tolterodine in 6 subjects. Tolterodine was rapidly absorbed following oral administration (time to peak serum concentration 0.9 +/- 0.4 h). The absolute bioavailability was highly variable, ranging from 10 to 70%. The volume of distribution at steady-state ranged from 0.9 to 1.6 l/kg and systemic clearance ranged from 0.23 to 0.52 l/h/kg, which resulted in a terminal half-life of 2-3 h. Tolterodine exhibited high first-pass metabolism and 2 hepatic metabolic pathways were identified: oxidation and dealkylation. Independent of route of administration, < 1% of the parent compound was excreted unchanged in urine. Five metabolites were structurally identified in urine. Following oral administration of (14C)-tolterodine, the excretion of radioactivity into urine and feces was 77 +/- 4.0% and 17 +/- 3.5%, respectively. Tolterodine decreased stimulated salivation after 3.2 mg, increased heart rate after 6.4 mg, and nearpoint of vision after 12.8 mg. Six of 8 subjects reported micturition difficulties after a dose of 12.8 mg. The lack of a direct relationship between tolterodine serum concentrations and effects on stimulated salivation suggested the presence of pharmacologically active metabolite(s).

Adult↗
PubMed1997

Recognizing and Managing the Oral Clues That Point to Sjögren's Syndrome.

Sjögren's syndrome (SS), a chronic autoimmune exocrinopathy, occurs mainly after age 40. Most SS patients--80% to 90%--are women. SS is characterized by dry eyes and mouth due to lacrimal and salivary gland lymphocytic infiltration. It may be primary or secondary in association with a connective tissue disease, usually rheumatoid arthritis. Lymphoproliferation may produce extraglandular manifestations in pulmonary, cardiac, genitourinary, vascular, and/or nervous systems. The risk of lymphoma is increased 40-fold among SS patients. Dry mouth, or xerostomia, hinders eating, speaking, and swallowing. A thorough patient history, serum analysis, and salivary function tests are essential to determine the genesis of the xerostomia. Insufficient salivary protection can cause rampant dental destruction and soft-tissue mycosis in the mouth. A biopsy of the minor salivary gland from the lower lip is used to detect hallmark inflammatory changes that confirm the diagnosis of SS. Therapy is symptomatic. Regardless of the cause of xerostomia, therapy has 3 fundamental aspects: preventive dental care, dietary counseling (reduction of sugar intake to avoid caries), and moisture replacement (including artificial salivas, frequent sips of water, and room humidifiers). Women taking xerostomic medications may need to lower the dose or substitute them with less xerogenic drugs if possible. Salivation can be stimulated by chewing gum, mints, or paraffin. Cracked lips are treated with petroleum. Dental flossing, supplemental fluoride, and dental appointments every 3 to 4 months are essential to control caries. Pilocarpine, a parasympathomimetic drug that increases salivation, has been found to reduce the severity of xerostomia from radiotherapy; multicenter trials in SS patients are ongoing.

Journal Article↗
PubMed1996

Autosomal recessive disorder with muscle contractions resembling neonatal tetanus, characteristic face, camptodactyly, hyperthermia, and sudden death: a new syndrome?

This work describes an autosomal recessive syndrome observed over the past 25 years in 17 newborn babies (8 males, 9 females), from 12 different families in Southern Sardinia. This disorder is evident at birth and is characterized by marked muscular contraction of the facial muscles in response to tactile stimuli or during crying, with trismus and abundant salivation simulating a tetanic spasm. The contractions slowly disappear as the infant calms. There is also neck muscle hypertonia with a tendency to opisthotonus. All patients present facial anomalies such as large face, chubby cheeks, broad nose with anteverted nostrils, and long philtrum. The hands show bilateral camptodactyly. The clinical course in all patients was characterized by marked feeding difficulties and appearance of variable fever at about 38 degrees C, with peaks of irregular hyperthermia of over 42 degrees C, with onset ranging from birth to a few weeks. In some patients these symptoms were accompanied by generalized seizures. Death occurred after a period of a few weeks to some months and coincided with fever above 42 degrees C. Laboratory investigations performed in all of these cases did not give any useful pathogenetic indications. Only patients 10 and 16 are still alive today. Patient 10 is now 14 years old. She presents slow regression of the dystonic symptomatology, while dysthermia and mild psychomotor delay persist.

Chromosome Aberrations↗
PubMedDate not supplied

Relative neurotoxicological properties of five unsaturated aliphatic nitriles in rats.

Motor and sensory conduction velocities (MCV and SCV) and amplitudes of the sensory and motor action potentials (ASAP and AMAP) of the tail nerve were studied in male Sprague-Dawley rats during chronic oral treatment with five unsaturated aliphatic nitriles. Rats were given doses of 12.5, 25 and 50 mg kg(-1) of acrylonitrile, 50, 70 and 90 mg kg(-1) of methacrylonitrile, 25, 50 and 100 mg kg(-1) of trans-3-pentenenitrile and 50, 100 and 200 mg kg(-1) of either 3-methyl-2-butenenitrile or 4-pentenenitrile once a day, 5 days per week for 12 weeks. Moreover, due the the early results obtained after oral treatment, neurophysiological examinations were also carried out in rats exposed by inhalation to 25, 50 and 100 ppm of acrylonitrile for 6 h a day, 5 days per week for 24 weeks. Rats given acrylonitrile orally developed behavioural sensitization characterized by salivation, locomotor hyperactivity and moderately intense stereotypies. Moreover, rats in the high dose group developed weakness in hindlimbs associated with decreases in SCV and ASAP. Rats exposed to acrylonitrile vapours exhibited time- and concentration-dependent decreases in MCV, SCV and ASAP, which were partially reversible after 8 weeks of recovery. None of the other four nitriles caused any abnormal behaviour or any changes in the electrophysiological parameters in spite of an obvious general toxicity. Based upon these results, it can be concluded that the nervous system of the rat appears to be a target following either oral or inhalation exposures of acrylonitrile.

Acrylonitrile↗
PubMedDate not supplied

Disability and rehabilitation in head and neck cancer patients after treatment.

In an effort to obtain quantitative and qualitative information regarding the extent of disability sustained following definitive treatment for head and neck cancer, 51 patients--28 who had had laryngectomy and 23 who had had other major surgery--were interviewed. Also examined were the types of rehabilitation measures taken. In all cases, the following areas in which disability could occur were identified and explored: physical appearance, speech, deglutition, mastication, salivation, sensory deficits, cranial motor-nerve deficits, pain, nutrition, activities of daily living, psychosocial functioning, vocational status, environmental parameters, and delayed complications. Where appropriate, ratings and delineations of severity were compiled. Nine methods of rehabilitation were assessed with regard to frequency of utilization: surgical reconstruction, dental-maxillofacial prosthetics, speech therapy, physical therapy, rehabilitation nursing, occupational therapy, vocational rehabilitation, rehabilitation counseling, and social service. Our conclusions were that half of the patients studied had sustained significant disability in three to four areas, while 43% had moderate or severe disability in five to nine areas. Additionally, the head and neck surgeon was found to have used surgical reconstruction and dental-maxillofacial prosthetic measures, as well as the services of seven categories of allied health professionals, to provide rehabilitation.

Deglutition↗
PubMedDate not supplied

Pharmacology and clinical efficacy of terfenadine, a new H1-receptor antagonist.

Terfenadine is the first of a new class of non-sedating H1 antihistamines. It differs from chlorpheniramine in its lower anticholinergic activity in rabbit salivation tests. In animal model distribution studies, the drug is not found in the brain. In most clinical studies sedation attributed to terfenadine was on the order of that observed with placebo. Clinical trials of efficacy show that at best terfenadine is slightly less effective than or as effective as chlorpheniramine.

Animals↗
PubMed2003

Botulinum toxin B reduces sialorrhea in parkinsonism.

We report on our open-label experience with botulinum toxin B for the treatment of severe sialorrhea associated with parkinsonism. Nine adult patients with parkinsonism and medically intractable sialorrhea were treated with botulinum toxin B (1,000 units into each parotid gland using superficial landmarks). After treatment, patients experienced a 61% mean subjective improvement and a 42% mean reduction of quantitative saliva production. There were no adverse effects seen in any subjects. Mean peak benefit from injections lasted 14 weeks. We conclude that denervation of salivary glands with botulinum toxin B produces excellent reduction of excessive salivation associated with parkinsonism.

Aged↗
PubMed2000

Responsivity to food cues in bulimic women and controls.

The current study investigated responsivity to individualized food cues consisting of binge/favourite foods in 17 women with bulimic nervosa (BN) and 17 women with no history or current symptoms of eating disorders (C). The hypothesis that increasing cue salience would be associated with an increase in responsivity was tested by comparison of self reported urges, affective responses and salivation to the sight and smell (SS) and the sight, smell and taste (SST) of a binge/favourite food compared to a neutral stimulus (lettuce leaf). As predicted, the BN group reported a greater urge to binge and higher levels of stress/arousal to selected binge/favourite food cues compared to the C group. The BN group also reported lower confidence to resist the urge to binge and control over food intake compared to the C group. Further, a series of planned comparisons in the BN group found that the urge to binge, stress, and loss of control were greater when participants were exposed to the SST cue than to the SS cue. There was no difference between the groups in salivary responsivity to food cues. These results are discussed in terms of a conditioning model of cue reactivity.

Adult↗
PubMed2000

Cephalic phase responses, craving and food intake in normal subjects.

Cephalic phase responses (CPRs) are elicited during exposure to food cues. They gear up the body to optimize digestion or they compensate for unwanted changes during a meal. The cue reactivity model of binge eating predicts that CPRs are experienced as craving for food, thereby increasing food intake and playing a role in abnormal eating behaviour. The present experiment was designed to measure CPRs in normal women and to examine its relationship with craving, food intake and restraint. Results show that normal subjects do react to food exposure with changes in heart rate, heart rate variability (HRV), salivation, blood pressure, skin conductance and gastric activity. These CPRs presumably gear up the body and presumably do not reflect compensatory responses. Significant correlations between restraint and blood pressure, between blood pressure and craving, and between craving and food intake were also found. These results are in line with the cue reactivity model and suggest that research into physiological CPRs and craving in the field of eating disorders is valuable.

Adult↗
PubMed1993

Subacute toxicity of a novel inhibitor of acyl-CoA: cholesterol acyltransferase in beagle dogs.

PD 132301-2 is a substituted urea hypolipidemic and antiatherosclerotic agent that is a potent inhibitor of acyl-CoA:cholesterol acyltransferase (ACAT). To determine its subacute toxicity, PD 132301-2 was administered orally to beagle dogs at 0, 6, 12, 25, 50, 200, 400, or 800 mg/kg/day for 2 weeks. Clinico-pathologic evaluations were completed on all dogs. Liver and adrenal total and esterified cholesterol concentrations, adrenocorticotrophic hormone (ACTH) responsiveness, and adrenal ultrastructure were determined at 0, 6, 12, and 25 mg/kg. At 12 mg/kg or greater, salivation, epiphora, conjunctivitis, emesis, anorexia or decreased food consumption, and soft to mucoid feces and/or diarrhea were noted. Suppression of ACTH response occurred by Day 6 at all doses. Adrenocortical degeneration and/or necrosis in zona fasciculata and reticularis was seen at all doses; adrenal free and esterified cholesterol were normal at 6 mg/kg and decreased at 12 and 25 mg/kg. Increases in serum alanine aminotransferase (2- to 15-fold), aspartate aminotransferase (2- to 12-fold), and alkaline phosphatase (2- to 7-fold) were noted at 50 mg/kg or greater. Periportal hepatocellular hypertrophy and hypereosinophilia occurred at 50 mg/kg or greater; hepatic cholesterol values were not significantly affected by treatment. Dose-dependent ultrastructural alterations in adrenocortical cells included decreased numbers of mitochondria and smooth endoplasmic reticulum profiles, qualitative and quantitative changes in lipid globules, and increased numbers of autolysosomes. PD 132301-2 or one of its metabolites has potent adrenocorticolytic properties and limited hepatotoxic properties by mechanism(s) that are likely independent of systemic ACAT inhibition.

Adrenal Glands↗
PubMed1987

Central action of cesium chloride in streptozotocin-diabetic mice.

The changes in the pharmacological responses to cesium were examined in streptozotocin(STZ)-induced diabetic mice. An acute administration of cesium chloride (10 mEqCs+/kg IP) to non-diabetic control mice elicited increased salivation and inhibition of respiration followed by death in about half of the animals examined. These effects of cesium were diminished in STZ-diabetic mice. LD50 for acute cesium was higher in STZ-diabetic mice (14.3 mEq/kg) than non-diabetic buffer controls (11.7 mEq/kg): however, subchronic administration of cesium did not decrease the LD50 in STZ-diabetic mice. The sleeping time induced by pentobarbital was reduced in STZ-diabetic mice and the reduction of the pentobarbital-induced hypnosis was reversed by subchronic cesium pretreatment but not by acute cesium administration. Methamphetamine-induced mortality was increased in STZ-diabetic mice and acute administration of cesium decreased the toxicity in both control and diabetic mice. Inhibition of locomotor activity elicited by acute single injection of cesium chloride was observed in both STZ-diabetic and non-diabetic mice. These results indicate that responses to cesium as well as centrally-acting drugs are affected differentially in STZ-diabetic mice.

Animals↗
PubMed1990

Analgesic, central, cardiovascular and endocrine effects of the enkephalin analogue Tyr-D.Arg-Gly-Phe(4NO2)-Pro-NH2 (443C81) in healthy volunteers.

443C81 is a synthetic enkephalin thought to act on peripheral opiate receptors. The analgesic, central, cardiovascular and endocrine effects of two i.v. doses of 443C81 were investigated in 12 healthy male volunteers. Its effects were compared with those of placebo and the classical opiate dipipanone given orally using a double dummy design. 443C81 produced dose-related analgesia; dipipanone 10 mg had a greater effect than the high dose 443C81. In contrast to dipipanone, 443C81 did not cause significant miosis or reduce minute volume on rebreathing CO2 and there was no evidence of sedation. Dry mouth was reported frequently and associated with reduced salivation after all active treatments. Both 443C81 and dipipanone increased circulating prolactin and growth hormone and reduced cortisol levels. This novel enkephalin appears to possess analgesic activity and some other properties of opiates but is devoid of clinically relevant narcotic effects.

Adult↗
PubMed1993

A comparison of the effects of single doses of amoxapine and amitriptyline on autonomic functions in healthy volunteers.

We have studied the effects of single oral doses of amoxapine (100 mg and 200 mg), amitriptyline (50 mg and 100 mg), and placebo on some autonomic functions in ten healthy volunteers, using a balanced double-blind crossover design. Amitriptyline significantly reduced salivation and it significantly attenuated both miosis evoked by locally applied pilocarpine and sweat secretion evoked by locally applied carbachol. Amoxapine did not significantly alter any of these measures. Neither treatment significantly altered the pupillary light reflex (latency, amplitude, or 75% recovery time). Resting pupil diameter was significantly reduced by the higher dose of amoxapine but was not affected by the other treatments. The higher dose of amoxapine significantly increased supine systolic blood pressure, but did not affect heart rate or diastolic blood pressure; amitriptyline had no effect on any of these cardiovascular measures. These results confirm the antimuscarinic effects of amitriptyline in man, but provide no evidence for antimuscarinic effects of amoxapine.

Adolescent↗