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[Oral single-dose toxicity study of a new antineoplastic agent S-1, and its components, CDHP, and Oxo].

S-1, an antineoplastic formulation of a fluorinated pyrimidine derivative containing tegafur (FT), CDHP, and potassium oxonate (Oxo) in a molar ratio of 1:0.4:1, was recently developed by Taiho Pharmaceutical Co., Ltd., with the aim of prolonging the effective plasma concentration of 5-fluorouracil (5-FU) over that produced by FT alone and reducing its dose-limiting gastrointestinal toxicity. As a part of the S-1 toxicity study, the single-dose toxicity of S-1 as well as that of its components, CDHP and Oxo, was investigated in mice, rats, and dogs. The following results were obtained. 1. In mice and rats, excretion of diarrheal stools, salivation, and alopecia were observed after S-1 administration. In severe cases, the animals subsequently showed emaciation due to weight loss or suppressed weight gain, decreased spontaneous motor activity, an anemic appearance, bradypnea, prone position, and death. In the CDHP and Oxo treatment groups of rats, the only toxic signs were soft or diarrheal stools on the dosing day. 2. In dogs, vomiting and excretion of diarrheal, mucous, or soft stools was observed after S-1 administration. In the CDHP and Oxo treatment groups, excretion of soft and diarrheal stools and vomiting were observed relatively frequently from the dosing day until day 1. 3. In the pathological examination of the animals given S-1, mice and rats showed pulmonary congestion/edema, dark red discoloration of the mesenteric lymph nodes, atrophy of lymphatic tissues such as the thymus and lymph nodes, decreases of lymphocytes in the splenic white pulp and mesenteric lymph nodes, a decrease in bone marrow cells, congestion of the glandular stomach, and aggregates of bacteria in the lung, liver, or spleen. In dogs, abnormal changes were observed mainly in the lymphatic organs such as the thymus and lymph nodes. 4. The LD50 values of S-1 in terms of the amount FT they contained were estimated to be 549 mg/kg for mice(male), 441-551 mg/kg for rats (both sexes) and about 53 mg/kg for dogs (male). The LD50 values of CDHP and Oxo were 2000 mg/kg or higher for both rats (both sexes) and dogs (male). 5. Hematopoietic and lymphatic impairments, immunosuppression associated with respiratory were considered to be the cause of death from S-1. The toxicity of S-1 reflects the toxicity of 5-FU and was not found the different toxicity by the addition of CDHP and Oxo.

Administration, Oral↗

[Acute toxicity studies of taltirelin tetrahydrate in mice, rats, and dogs].

The acute toxicity studies of taltirelin tetrahydrate (TA-0910), a new thyrotropin-releasing hormone (TRH) analogue, were performed in Slc:ddY mice, Slc:Wistar rats and beagle dogs of both sexes. The drug was administered to mice and rats by oral (p.o.), intravenous (i.v.) and subcutaneous (s.c.) routes, and to dogs by the p.o. and i.v. routes. LD50 values were more than 5,000 mg/kg in mice and rats of both sexes by the p.o. and s.c. routes. Some mice and rats died immediately after i.v. injection, the LD50 values were more than 2,000 mg/kg in mice of both sexes and calculated as 799 and 946 mg/kg in male and female rats, respectively. The minimum lethal doses were more than 2000 mg/kg in dogs of both sexes by the p.o. route. Though all dogs treated intravenously with 1000 mg/kg could survive during the observation period, a female dog with 500 mg/kg died on the day after administration. In general condition, hyperactivity, tremor and straub tail, that reflected central stimulatory effects of TA-0910, were observed in mice and rats, and also wet dog shaking in only rats. Vomiting and hyperactivity were seen in dogs by the p.o. route, and exaltation (during the dosing) and sedation by the i.v. route. In addition, salivation and transient tachycardia were observed in the both routes. In blood chemical examination, the transient changes of glucose, protein, lipid and/or serum enzyme were shown. In autopsy, no notable changes were seen in mice, rats and dogs.

Administration, Oral↗

[Repeated dose toxicity studies of taltirelin tetrahydrate (TA-0910) with oral administration to dogs].

Taltirelin tetrahydrate (TA-0910), novel thyrotropin-releasing hormone (TRH) analogue, was orally administered to dogs as dose levels 0.5, 5, and 50 mg/kg for 13 weeks and 0.15, 1.5 and 15 mg/kg for 52 weeks. Blood concentrations of test substance measured in 52-week study revealed that absorption of TA-0910 was with dose-dependent manner and not changed through the treatment period. These toxicokinetics suggested that there were no alterations on metabolism of TA-0910 with repeated treatment. The animals receiving 5 or 50 mg/kg showed decrease in body weight or suppression of body weight gain, and decrease in food intake (13-week study). As an abnormality in general conditions, vomiting and salivation (5 mg/kg or more, both in 13- and 52-week studies), increase in behavior as water intake (5 mg/kg or more, 13-week study), and hyperlocomotion (50 mg/kg) were observed. Elevating GPT values were noted temporally in the animals treated with 5 mg/kg or more (both in 13- and 52-week studies) without abnormal findings in histopathology. The thyroid weights were increased in treated animals receiving 5 or 50 mg/kg in 13-week study, but no histopathological changes were noted. Electron microscopy revealed dilatation of granular endoplasmic reticulums in follicular cells of thyroid from 50 mg/kg group in 13-week study. It was concluded that no-effect levels of 13- and 52-week studies were 0.5 mg/kg and 1.5 mg/kg, respectively.

Administration, Oral↗

Thirteen-week repeated oral dose toxicity study of ecabapide, a gastroprokinetic drug, in dogs and rats.

Thirteen-week oral repeated dose toxicity of ecabapide, a gastroprokinetic drug, was investigated in dogs at dosage levels of 50, 175 or 600 mg/kg, and in rats at dosage levels of 25, 100, 400 or 1600 mg/kg. In dogs, vomiting, aqueous salivation, body weight gain inhibition, and hemolytic anemia, together with an increase in Heinz body formation, were observed at 175 and/or 600 mg/kg. Histological examination revealed enhanced hemosiderin deposition in the liver and spleen, retention of erythrocytes in the splenic sinus and enhanced erythropoiesis in bone marrow at 175 and/or 600 mg/kg. In the rat study, although increases in serum total protein, albumin and calcium, as well as increased liver and kidney weights, were observed at 400 and/or 1600 mg/kg, no obvious morphological changes were seen. The hemolytic anemia and an increased Heinz body formation were not observed in rats, indicating a species difference. On the basis of these results, the non-toxic dose of ecabapide was considered to be 50 mg/kg in dogs and 100 mg/kg in rats.

Administration, Oral↗

Toxicological response of rats to a novel monoamine oxidase type-A inhibitor, (5R)-3-[2-((1S)-3-cyano-1-hydroxypropyl)benzothiazol-6-yl]-5- methoxymethyl-2-oxazolidinone (E2011), orally administered for 13 weeks.

(5R)-3-[2-((1S)-3-cyano-1-hydroxypropyl)benzothiazol-6-yl]-5- methoxymethyl-2-oxazolidinone (E2011) is a novel monoamine oxidase type-A (MAO-A) inhibitor. In order to assess toxicological profiles of E2011, doses of 0 (as controls), 30, 100 mg/kg of E2011 were administered to male and female Sprague-Dawley rats once a day for 13 weeks orally by gavage. No mortality or any toxic signs except salivation occurred due to E2011 treatment. Decreased body weight gain and food consumption, increases of alkaline phosphatase and increases of liver weight were the major treatment-related findings observed predominantly in the 100 mg/kg group. Histological examination revealed nuclear enlargement of hepatocytes with appearance of altered cell foci in some cases, and acinar atrophy in Harderian glands in the 100 mg/kg group. Since the histopathological findings in the liver were indicative of an ongoing carcinogenic process, glutathione S-transferase placental form (GST-P) positive hepatic foci were identified immunohistochemically and examined morphometrically. Although GST-P positive hepatic foci were detected in all groups including controls, the number and area of GST-P positive hepatic foci were significantly higher in female rats treated with 100 mg/kg than those in controls. In this paper, possible mechanisms of specific lesions in the liver and Harderian glands will be discussed.

Administration, Oral↗

[On the subacute toxicity of labetalol (AH5158): a combined alpha-and beta-adrenoceptor blocking agent (author's transl)].

Subacute toxicity and recovery tests of labetalol hydrochloride, alpha- and beta-adrenoceptor blocking agent, were carried out using male and female Wistar strain rats. The drug was orally administered at 50, 150, 450 or 1000 mg/kg/day for 1 month. In all the drug-treated groups, increase in salivation was observed from immediately to 15 minutes after dosing through the treatment period. Eight of the 10 males and 9 of the 10 females in the group treated with 1000 mg/kg/day died of intoxication. Suppression of body weight gain was observed in male rats in the 450 and 1000 mg/kg/day groups and in female rats in the 1000 mg/kg/day group. In the 150 mg/kg/day and higher dose groups, water consumption showed a tendency to increase as compared with that of control group. Increase in urine volume was observed in female rats in the 450 mg/kg/day group. In the serum biochemical examination, slight elevation in potassium levels was noted in the 150 and 450 mg/kg/day groups. In histopathological findings, some abnormalities were found in the groups treated at 150 mg/kg/day and higher. Major abnormalities found in organs were; congestion and hypremia of various organs due to vasodilation, swelling of parenchymatous cells in liver and kidneys, and loose arrangement and change in the thickness of muscle fibers in cardiac and skeletal muscles. None of these abnormal findings was found in any examination in recovery tests.

Animals↗

[Fertility study on ranitidine hydrochloride in rats].

A fertility study was carried out in Crj: CD (SD) rats orally administered ranitidine hydrochloride, a histamine H2-receptor antagonist, at dose levels of 50, 200 and 800 mg/kg/day in base weight. Male rats were treated from 60 days before mating until the completion of mating. Female rats were administered ranitidine hydrochloride from 14 days prior to mating up to day 7 of gestation. All pregnant females were sacrificed on day 20 of gestation and all fetuses were examined for abnormalities. Temporary salivation was noted in rats of both sexes given 800 mg/kg/day of ranitidine and in the male rat group given 200 mg/kg/day. No abnormal signs were seen in mating or fertility in the rats treated with ranitidine. No external, internal and skeletal anomalies attributable to ranitidine hydrochloride were observed in the fetuses. It was concluded that ranitidine hydrochloride has no harmful effect on mating, fertilization, implantation, or embryonic development.

Administration, Oral↗

The involvement of slaframine and swainsonine in slobbers syndrome: a review.

The history of "slobbers syndrome," a mycotoxicosis associated with Rhizoctonia leguminicola infestation of pastures and stored forages, is discussed. The chemistry and physiological effects of the two known biologically active alkaloids of R. leguminicola, slaframine and swainsonine, are described. Slaframine administration is generally associated with increased exocrine function, especially salivation. Ingestion of swainsonine may be linked to serious and potentially lethal central nervous system defects similar to that described for locoism. However, the singular effects of these alkaloids do not completely account for the total clinical picture noted in the field during the occurrence of slobbers syndrome. It is possible that this phenomenon is the result of an interaction between both known and unidentified biologically active metabolites of R. leguminicola.

Alkaloids↗

Effects of a salivary stimulant, slaframine, on ruminal fermentation, bacterial protein synthesis and digestion in frequently fed steers.

Slaframine (SF), a parasympathomimetic salivary stimulant, was administered i.m. (10, 15 or 20 micrograms SF/kg BW) to ruminally and abomasally fistulated steers at 12-h intervals for 18-d periods in a latin square-designed experiment. Steers were fed semicontinuously (12 times daily) a 40:60 roughage:concentrate diet at twice their net energy requirement for maintenance. Ruminal digestion coefficients for DM, ADF and starch were 10 to 16% lower and linearly related in an inverse manner to the level of SF administered (P less than .05). Postruminal digestion of DM, ADF and starch increased as much as 46.7, 9.5 and 44.0%, respectively, in a fashion linearly related (P less than .05) to the level of SF administered. Total tract digestion of DM and ADF were not affected by SF; however, total tract starch digestion was increased as much as 5% and was related linearly (P less than .05) to SF treatment. With SF administration, as much as 13% more bacterial protein exited the rumen, resulting in a 16.5% linear improvement (P less than .1) in the efficiency of ruminal bacterial protein production per 100 g of OM fermented. Ruminal concentrations of VFA, ammonia and pH were not affected by SF. These results demonstrate a positive relationship between salivation and ruminal bacterial protein synthesis and suggest that feed utilization by ruminants may be improved by pharmacological stimulation of salivary secretions.

Abomasum↗

Premedication in upper gastrointestinal endoscopy. A comparison of glucagon and atropine given in combination with diazepam and pethidine.

The effects of four premedication regimes on clinical variables regarded as important in upper gastrointestinal endoscopy were evaluated in a double-blind randomized study. The drug combinations were diazepam/glucagon, diazepam/atropine, pethidine/glucagon, and pethidine/atropine. No significant difference was observed among the combinations of regimes or between diazepam and pethidine or between glucagon and atropine with regard to the variables duration of examination, vomiting, secretion and maximal pyloric opening. Pethidine was more effective than diazepam in reducing salivation and pyloric reflux. Glucagon was more effective than atropine in reducing motility and reflux and was also superior to atropine with regard to diagnostic accuracy. Glucagon caused less subjective discomfort than atropine 2 h and 1 day after the investigation.

Adult↗

A subchronic toxicity study of two inhaled aerosolized atropine sulfate formulations in rats and dogs.

The potential subchronic (21 days) toxicity of inhaled metered aerosol formulations (solution and suspension) of atropine sulfate was investigated in rats and dogs. The doses administered to rats were 0.78 and 2.5 mg/kg/day (solution) or 1.4 and 3.2 mg/kg/day (suspension). In the dog, the daily doses achieved were 0.5 and 1.3 mg/kg/day, regardless of formulation. In both species, sham control animals inhaled air only and vehicle control animals inhaled either placebo solution or placebo suspension. There was no mortality or other evidence of a toxic effect of atropine sulfate. The expected mydriatic effect of atropine sulfate was seen in both species and, similarly, the pupillary light reflex was impaired in rats and dogs receiving either formulation of atropine sulfate at both dose levels. Reduced salivation was also noted and ophthalmologic examinations in both species were unremarkable. In dogs, atropine sulfate (high-dose) caused tachycardia but there was no evidence of an adverse effect on the electrocardiogram or on systolic blood pressure. In both species, atropine sulfate did not alter body weight, food consumption or clinical pathology parameters. Necropsy observations and histopathological findings revealed no effect of atropine sulfate in either species although, in the rat, adrenal gland hypertrophy in both sexes followed inhalation of the suspension at both dose levels. With this possible exception, nothing but the expected pharmacological effects of atropine sulfate were seen in either rats or dogs.

Administration, Inhalation↗

Kallikrein, nitric oxide and the vascular responses of the submaxillary glands in rats exposed to heat.

During exposure of normal rats to an ambient temperature of 36 degrees C or 40 degrees C, body temperature increases; thermolytic processes are set up and saliva is spread on the skin. In Wistar rats, thermolytic salivation started when body temperature was above 39 degrees C. This water loss was associated with a loss of body weight. A 10% reduction of plasma volume was observed in animals exposed to 40 degrees C but no change was observed in those exposed to 36 degrees C. Body weight loss was reduced by hexamethonium, atropine, prazosin, HOE 140, a bradykinin-antagonist, and NG-nitro-L-arginine (NOARG), a NO synthase inhibitor. The weight and blood content of the submaxillary glands, which are the main effectors of the thermolytic processes, increased as a function of the ambient temperature. The increase of blood content was enhanced by hexamethonium but reduced by atropine and NOARG. The weight increase was inhibited by hexamethonium, prazosin, HOE 140 and NOARG. At an ambient temperature of 40 degrees C, a large swelling developed around the submaxillary glands, resulting in a distention of the surrounding soft tissues. This local oedema fluid contained low levels of endogenous proteins but accumulated exogenous labelled albumin. This swelling was enhanced by atropine but decreased by hexamethonium, trasylol, HOE 140, NOARG, ketoprofen, a cyclooxygenase inhibitor, and prazosin. In kininogen deficient rats, the blood content of submaxillary glands increased as a function of ambient temperature. No increase in glandular weight and no swelling of the of the soft tissues were observed. After atropine, the weight of the glands increased and a swelling of the soft tissues appeared.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Oxidoreductases↗

Effect of concentrate level and feeding management on chewing activities, saliva production, and ruminal pH of lactating dairy cows.

Eight ruminally cannulated lactating Holstein cows were used in a double 4 x 4 Latin square to determine the effects of 1) proportion of barley silage [40, 50, and 60% of dry matter (DM)] in the diet, and 2) feeding a total mixed ration (TMR) compared with separate ingredients (SI) on chewing activities, saliva production, and ruminal pH. Although cows fed SI were offered a diet containing 50% silage, they actually consumed a diet containing 43% silage (DM basis). Dry matter intake and milk yield were similar for all diets (18.2 kg of DM/d and 27.2 kg/d, respectively). Cows fed the 40% silage TMR spent more time eating than cows fed SI (243 vs. 198 min/d), but rumination time was similar (546 min/d). Eating time was similar among the TMR diets, but rumination time increased from 498 to 516 and 584 min/d as silage in the TMR increased from 40 to 50, and then to 60%, respectively. The secretion of saliva per gram of feed was 4.43, 3.18, and 1.19 ml/g of DM with consumption of silage, TMR, and concentrate, respectively. Resting salivation rate was similar for all diets (101 ml/min). Regardless of the diet, cows secreted 239 +/- 17 L/d of saliva, and ruminal pH was below 5.8 for 10 h/d. Results indicated increased chewing time did not increase total daily saliva secretion because increased eating and ruminating saliva was associated with decreased resting saliva. Feeding SI increased the risk of acidosis, because cows ate a higher proportion of concentrate than intended.

Animal Feed↗

The use of ketamine hydrochloride as an anesthetic for raccoons.

Ketamine hydrochloride was observed to be an effective anesthetic for recently captured raccoons (Procyon lotor) when they were injected intramuscularly with 20-29 mg/kg body weight. Excellent anesthesia occurred from 5 to 15 min after injection. No respiratory difficulties were encountered. The only undesirable clinical sign was excessive salivation.

Anesthesia, General↗

Effect of timed hygienic measures on oral mucosa in a group of elderly subjects.

A study was conducted to identify and compare the effect produced on oral mucosa by the application of oral hygiene by the use of either a toothette or a toothbrush at two-, three-, or four-hour intervals during an eight-hour period for ten days. The sample consisted of 48 geriatric patients randomly selected from an extended care facility. Two investigators were responsible for scoring nine dependent variables--salivation, tongue moisture, tongue color, moisture of palates, color of gingiva, condition of membranes, lip texture, lip moisture, and soft tooth debris-- twice daily. Data were analyzed using multiple regression analysis. Results of the study indicated significant improvement in six dependent variables in the four-hour interval groups. In the two-hour interval groups, two dependent variables were improved significantly. The toothbrush was more effective in stimulating gingival tissue and removing soft tooth debris; the toothette was found to be more effective in producing improvement in other oral tissues.

Aged↗

The preclinical pharmacological profile of WAY-132983, a potent M1 preferring agonist.

Muscarinic M1 preferring agonists may improve cognitive deficits associated with Alzheimer's disease. Side effect assessment of the M1 preferring agonist WAY-132983 showed significant salivation (10 mg/kg i.p. or p.o.) and produced dose-dependent hypothermia after i. p. or p.o. administration. WAY-132983 significantly reduced scopolamine (0.3 mg/kg i.p.)-induced hyperswimming in mice. Cognitive assessment in rats used pretrained animals in a forced choice, 1-h delayed nonmatch-to-sample radial arm maze task. WAY-132983 (0.3 mg/kg i.p) significantly reduced scopolamine (0.3 mg/kg s.c.)-induced errors. Oral WAY-132983 attenuated scopolamine-induced errors; that is, errors produced after combining scopolamine and WAY-132983 (to 3 mg/kg p.o.) were not significantly increased compared with those of vehicle-treated control animals, whereas errors after scopolamine were significantly higher than those of control animals. With the use of miniosmotic pumps, 0.03 mg/kg/day (s.c.) WAY-132983 significantly reduced AF64A (3 nmol/3 microliter/lateral ventricle)-induced errors. Verification of AF64A cholinotoxicity showed significantly lower choline acetyltransferase activity in the hippocampi of AF64A-treated animals, with no significant changes in the striatal or frontal cortex. Cognitive assessment in primates involved the use of pretrained aged animals in a visual delayed match-to-sample procedure. Oral WAY-132983 significantly increased the number of correct responses during short and long delay interval testing. These effects were also apparent 24 h after administration. WAY-132983 exhibited cognitive benefit at doses lower than those producing undesirable effects; therefore, WAY-132983 is a potential candidate for improving the cognitive status of patients with Alzheimer's disease.

Animals↗

Patient preference between visible light-cured and heat-cured acrylic splints.

PURPOSE: To compare the advantages/disadvantages concerning patient subjective preferences of splints made with heat-cured acrylic (Splint Resin Polymer) or visible light-cured material. MATERIAL AND METHODS: A questionnaire was developed assessing: comfort, stability, fit, taste, occlusal contacts, lip seal, smoothness, hygiene, color stability, stain resistance, salivation level, gingival irritation, bulkiness and odor. 10 patients already treatment planned to receive splints, were chosen at random from the dental school. Splints made from the two types of materials were delivered to each patient to be used for 3 wks. The material to initially be used was chosen at random and the questionnaire was answered after each 3-wk period. RESULTS: The MacNemar's Chi-square test revealed that there was no statistical difference in patient preference between the two splint materials.

Acrylic Resins↗

[Radiation of parotid glands for salivary flow reduction in amyotrophic lateral sclerosis].

Radiation of the parotid and submandibular glands was performed in 18 patients with pronounced hypersalivation at a late stage of amyotrophic lateral sclerosis (ALS). Single bilateral radiation of the parotid and posterior submandibular glands was made in the dosage of 7.0-7.5 Gy. Salivation volume was measured before and after the radiation therapy. Sixteen patients exhibited satisfactory and marked salivary flow reduction during 4-6 months. Xerostomia developed in 1 patient who needed assignment of artificial salivary substitute and 1 patient did not respond to the therapy. The patient's caregivers reported a positive effect in all the cases. Tolerance of the therapy was good except rare side effects. Radiation of the parotid glands significantly reduced salivary flow in ALS, especially in patients receiving an adequate amount of water.

Amyotrophic Lateral Sclerosis↗