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PubMed1980

Shy-Drager syndrome: diagnosis and treatment of cholinergic dysfunction.

Two patients with Shy-Drager syndrome demonstrated unusually widespread and unequivocal cholinergic dysfunction as well as the usual evidence of adrenergic insufficiency. Progressive constipation preceded impotence, nocturia, hesitancy in micturition, anhidrosis, orthostatic hypotension, and xerostomia. Nonautonomic neurologic signs appeared several years later. Cholinergic dysfunction involved eyes, lacrimal glands, salivary glands, heart, gastrointestinal tract, urinary bladder, and sweat glands. Subcutaneous administration of bethanechol chloride--a muscarinic receptor agonist--improved tearing, salivation, sweating, and gastrointestinal and bladder functions. Daily administration of this drug resulted in symptomatic improvement of the autonomic functions, and relapse followed discontinuation of treatment.

Aged↗
PubMed1990

Dexmedetomidine premedication for minor gynecologic surgery.

The effects of four different doses (0.167, 0.33, 0.67, and 1.0 microgram/kg) of dexmedetomidine, a novel alpha 2-adrenoceptor agonist, on anesthetic requirements, hemodynamics, and plasma catecholamine levels were investigated in a single-blind fashion in 20 healthy (ASA physical status I) women scheduled for uterine dilatation and curettage. The drug was administered intravenously 15 min before anesthesia induction with thiopental. Nitrous oxide/oxygen (70%/30%) was used for maintenance. Dexmedetomidine was well tolerated, and no serious drug-related subjective side effects or adverse events were observed. The most prominent subjective effects were tiredness and decreased salivation. The total amount of thiopental needed to perform uterine dilatation and curettage was decreased dose-dependently from 400 +/- 166 mg (mean +/- SD) after 0.167 microgram/kg of dexmedetomidine to 180 +/- 65 mg after 1.0 micrograms/kg of dexmedetomidine (P = 0.028). Blood pressure, heart rate, and plasma norepinephrine levels were reduced after dexmedetomidine. The optimal dose of dexmedetomidine for single-dose intravenous premedication studies in minor surgery appears to be in the range of 0.33-0.67 micrograms/kg.

Adrenergic alpha-Agonists↗
PubMed1988

Excitability and secretory activity in the salivary gland cells of jawed leeches (Hirudinea: Gnathobdellida).

Thousands of salivary cells fill the interstices throughout the anterior ends of jawed leeches. The somata are large (30-200 micron in diameter). They project single processes (ductules) into the three jaws, and were found to fire overshooting action potentials of 50-85 mV amplitude and 100-200 ms duration at low spontaneous rates. The action potentials were not detected in the presence of cobalt (10 mmol l-1), but could be recorded when sodium was absent from the Ringer, so they appear to be calcium-dependent. Salivary material is transported by the long processes of these unicellular glands and secreted into ducts which alternate with paired teeth on the jaws. Secretion is activated reliably by 10(-6) mol l-1 serotonin, but not by other neurotransmitters found in the leech nervous system. Each jaw secretes at an average rate of 230 nl min-1 in the presence of serotonin, and secretion is completely abolished by cobalt. Perfusion with serotonin excites the salivary gland cells into impulse activity, and often evokes bursting. Impulse activity of the peripherally projecting, serotonergic Retzius cells evokes both depolarizations and action potentials in the salivary gland cells. In jawed leeches, central neurones appear to control salivation by a peripheral release of serotonin. This neurotransmitter evokes calcium-dependent action potentials and calcium, in turn, stimulates secretion.

Action Potentials↗
PubMed1994

Inter-organ relation between salivary gland and kidney in lithium excretion. IV. Saturation of inhibitory effect of NaCl on ductal reabsorption of Li+ in beagle dogs.

The inhibitory effect of NaCl coadministration on the reabsorption of Li+ in the salivary ducts and the renal tubules was investigated in beagle dogs. Following the bolus intravenous administration of LiCl (0.145 meq/kg), 50 ml of NaCl solution (100, 200 meq/l) was administered orally each hour, and parotid saliva (Pr) and mandibular-sublingual saliva (MS) were collected under the continuous stimulation of salivation with citric acid. The renal clearance of Li+ increased with the increased concentration of administered NaCl solution. This could be a result of the competitive inhibition of the tubular reabsorption of Li+ by Na+. The salivary clearance of Li+ also tended to increase by the administration of NaCl. These results suggest the existence of a reabsorption process of Li+ in the salivary glands similar to that in the renal tubule. However, when the administered NaCl was increased from 100 to 200 meq/l, the renal clearance was further increased, but the salivary clearance was not. This suggests that the transport capacity of Li+ reabsorption is relatively small in the salivary glands, compared with that in the renal tubule, and that the inhibitory effect of NaCl on Li+ reabsorption had already reached a maximum level when 100 meq/l NaCl was administered.

Absorption↗
PubMed1988

Salivary excretion of 5-fluorouracil. II. Fluctuation of saliva/plasma concentration ratio and salivary clearance during a constant rate intravenous infusion in beagle dogs.

Salivary excretion of 5-fluorouracil (5-FU) was investigated during constant rate intravenous infusion (0.306 mg/kg/min) in three male beagle dogs. Parotid (Pr) and mandibular-sublingual (MS) saliva were collected separately by stimulating salivation with 10% citric acid. After the start of 5-FU infusion, plasma and salivary 5-FU concentration increased rapidly to approach their steady state levels. There was a significant correlation between each saliva and plasma 5-FU concentration (p less than 0.01). The saliva/plasma drug concentration ratio (S/P ratio) and salivary pH were significantly higher in Pr than in MS saliva (p less than 0.001), similar to the results following bolus intravenous administration of 5-FU in beagle dogs. Both S/P ratio and salivary clearance increased with time before steady state. Thereafter, these values approached almost constant levels and their fluctuations became smaller than those following the bolus intravenous administration. These results showing S/P ratio and salivary clearance of 5-FU were affected by the plasma drug concentration, suggested the possibility that non-linear pharmacokinetics may be involved in the salivary excretion of 5-FU.

Animals↗
PubMed1989

Salivary excretion of 5-fluorouracil (5-FU). IV. Dependency of saliva/plasma concentration ratio and salivary clearance on plasma concentration of 5-FU during constant-rate intravenous infusion in rats.

Salivary excretion profiles of 5-fluorouracil (5-FU) were investigated following simultaneous bolus intravenous injection of a loading dose and constant-rate intravenous infusion of a maintenance dose of at one of three dose levels in rats. By stimulating salivation with pilocarpine infused intravenously, mandibular (M) and parotid (Pr) saliva samples were periodically collected separately via cannulas inserted into the ducts. Simultaneously, salivary pH and salivary flow rate were determined. (1) There was a good correlation between plasma concentration and each of the saliva concentrations of 5-FU with regard to the pooled data of the three doses (p less than 0.01). (2) A gland type difference between M and Pr in the saliva/plasma concentration ratio (S/P ratio) of 5-FU was observed. This difference seemed to result from that in salivary pH. These findings were similar to the results following bolus intravenous administration of 5-FU in rats. (3) The fluctuations of the S/P ratio and salivary clearance of 5-FU were smaller than those following the bolus intravenous administration. (4) The S/P ratio and salivary clearance were larger at higher dose and higher plasma concentration of 5-FU. It was confirmed that non-linear kinetics might be involved in the salivary excretion of 5-FU in rats, and it was speculated that 5-FU excreted into primary saliva might be reabsorbed partly through some saturable process.

Animals↗
PubMed2006

[Roles of protease-activated receptor-2 (PAR-2), a G protein-coupled receptor, in modulation of exocrine gland functions].

Protease-activated receptor-2 (PAR-2), a G protein-coupled receptor, is activated by proteolytic unmasking of the N-terminal extracellular tethered ligand that presumably binds to the extracellular loop 2 of the receptor itself. PAR-2 is widely distributed in the mammalian body and plays various roles in biological events in the cardiovascular, respiratory, alimentary, and central neurons systems. PAR-2-activating peptides administered systemically to mice and rats trigger prompt salivation in vivo. In an in vitro study, PAR-2 agonists including the endogenous PAR-2 activator trypsin induce secretion of amylase and mucin from isolated rat parotid glands and sublingual glands, respectively. PAR-2-activating peptides administered systemically also modulate pancreatic exocrine secretion in vivo as well as in vitro. In the gastric mucosa, PAR-2 stimulation enhances secretion of mucus and pepsinogen and suppresses acid secretion. Tear secretion can also be caused by PAR-2-related peptides in PAR-2-dependent and -independent manners. PAR-2 thus plays a general or key role in the regulation of exocrine secretion. This review focuses on the physiologic and/or pathophysiologic roles of PAR-2 in glandular exocrine secretion. The possibility of PAR-2 as a target for drug development is also discussed.

Animals↗
PubMed1976

[Protective effect of tocopheryl esters on pulmonary edema induced by epinephrine].

The present study was performed in order to determine protective effect of dl-alpha-tocopheryl nictonate (EN) and dl-alpha-tocopheryl acetate (EA) on pulmonary edema induced by epinephrine (Epi) in mice. The tocopheryl esters were orally administered once a day for 10 days. Epi was then infused to induce pulmonary edema 3 hr after the final dosing. One or three min infusion of 0.01% Epi at a rate of 0.1 ml/min provoked toxic syndromes as pilorection, exophthalmos and salivation. Some animals died of respiratory failure. The lung weight either wet or dry increased after the EPi infusion and diffuse hemorrhage into alveoles was microscopically recognized in untreated animals. However, these findings were of lesser degree in animals receiving NE (20, 50 and 100 mg/kg/day) and Ea (corresponding doses with EN in molecular weight basis). When comparing the effect of EN with that of EA on the increase of lung weight and death from the Epi infusion, EN was more protective than EA. Although the mechanism of protecting action of these tocopheryl esters remains obscure, the interpretation is that these compounds did not affect the pressor response to Epi.

Animals↗
PubMed1978

[The study of developmental pharmacology (I). Effect of pentazocine HCl on the physiology of rats given the drug during perinatal and postnatal periods (author's transl)].

The effects of drug administration on the dams (F0) and their offspring (F1), particularly on the central nervous and reproductive functions of F1, were studied by oral administration of pentazocine HCl to rats during the perinatal and postnatal periods. No significant differences were observed between administered and control rats regarding body weight changes and food intake during perinatal and postnatal periods in F0 at all dosages, but temporary salivation was observed in the 200 and 100 mg/kg groups, and decline of spontaneous activity and respiratory rate, disappearance of righting reflex, clonic convulsion were observed in some of the 200 mg/kg group. No significant differences were observed regarding litter size, birth rate, state and timing of differentiation as postnatal development, sex maturity, reproductive function in F1, although some groups were slightly inferior in body weight at birth and during the nursing period. Furthermore, no differences were observed in respect to the nervous functions of balance, exercise and psychotic related activity in the open-field test.

Administration, Oral↗
PubMed1989

[Behavioral effects of NC-1100, 1-(3,4-dimethoxyphenyl)-2-(4-diphenylmethylpiperazinyl) ethanol dihydrochloride--on ambulatory activity, discrete lever-press response and shuttle avoidance response in mice].

Single administration of NC-1100 (3, 10 or 30 mg/kg, p.o.) produced no marked change in the ambulatory activity and discrete lever-press avoidance response. However, 100 mg/kg of this drug produced a toxic effect which was characterized by salivation, tremor, clonic convulsion, etc., but none of the mice died. NC-1100 enhanced the ambulation-increasing effect of methamphetamine (2 mg/kg, s.c.) at 3 and 10 mg/kg, while it failed to modify that of scopolamine (0.5 mg/kg, s.c.). NC-1100, at 100 mg/kg, suppressed both the established discrete lever-press and shuttle avoidance responses, probably due to non-specific and toxic effects. When NC-1100 at 10 mg/kg was administered, the response rate increased only in the shuttle avoidance situation in which the avoidance established mice were used. Furthermore, when NC-1100 at 30 mg/kg was administered immediately before the start of the training session, the avoidance rate increased. However, there was no marked change in the avoidance rate in the 2nd training session which was conducted 24 hr after the 1st training session without the drug administration. Additionally, the response rate increased in the 1st and 2nd training sessions after 10 and 30 mg/kg of NC-1100. The present results suggest that NC-1100 may show a behavior-facilitating effect, although its effect is mild and different from that of typical central stimulants such as methamphetamine.

Animals↗
PubMed1984

Induction of physical dependence on codeine in the rat by drug-admixed food ingestion.

The developmental process of physical dependence on codeine has been explored in rats treated with codeine-admixed food (0.5 mg/g food) during 1 to 7 days. In rats treated with codeine for more than 2 days, body weight loss was markedly observed after the abrupt codeine withdrawal. The intensity and time course of body weight loss increased according to the duration of codeine treatment. After the codeine withdrawal, behavioral signs such as diarrhea, ptosis and vocalization were observed. In the naloxone-precipitated withdrawal test, rats treated with codeine for 1 day manifested a loss of body weight after naloxone challenge, and the intensity of body weight loss increased according to the duration of codeine treatment. After naloxone injection, the codeine-treated rats showed abnormal behaviors such as diarrhea, ptosis, teeth chattering , salivation, body shakes, vocalization, nose bleed, irritability, lacrimation and writhing. The total score, evaluated by the ranking system for precipitated withdrawal behaviors, was correlated with the duration of codeine treatment. These results suggest that naloxone-precipitated withdrawal signs are powerful in comparison with that after codeine withdrawal, and the weight loss is a common index for quantitative assessment of physical dependence on narcotics in the natural and naloxone-precipitated withdrawal tests. It is concluded that the drug-admixed food ingestion method has the advantage of rapidly inducing a high degree of physical dependence on codeine.

Animals↗
PubMed1988

A comparative study of the effects of four choline esters on the secretion of fluid and glycoprotein from rat submandibular glands.

The actions of four choline esters, acetylcholine (ACH), methacholine (MET), carbachol (CAR) and bethanechol (BET), on the secretion of saliva and the specific glycoprotein (GP) contained in the secretory cells of the submandibular gland (SMG) of the rat were compared under conditions with and without physostigmine (PHY). The ED50 values with respect to salivation were 17 mg/kg for ACH, 1060 micrograms/kg for BET, 810 micrograms/kg for MET and 75 micrograms/kg for CAR, whereas after pretreatment with PHY, ED50 values were lowered to 7.5 mg/kg for ACH and 212 micrograms/kg for MET, but remained unchanged for CAR and BET. SDS-polyacrylamide gel electrophoresis demonstrated that the saliva from the SMG elicited by the four choline esters contained GP I (130 KDa) and GP IV (21.5 KDa), characteristic of the acinus, and a band of GP III (31 KDa), which originates from the granular tubules. The order of intensity of these bands was band I much greater than band III = band IV. Among these bands, band I increased in intensity in a dose-dependent manner. These results suggest that the four choline esters act mainly on the acinar cells, but exert some effects on the granular tubules of the rat SMG.

Acetylcholine↗
PubMed1990

Physical dependence potential of an enkephalin analog, EK-399, in rats.

The physical dependence potential of Tyr-D-Met(O)-Gly-EtPhe-NHNHCOCH3.AcOH (EK-399), a novel enkephalin analog with a potent analgesic effect, was assessed in rats. The animals were given EK-399 (0.008, 0.032, 0.125, or 0.5 mg/kg), morphine (0.125, 0.5, or 2 mg/kg), pethidine (2 or 8 mg/kg), or pentazocine (2 or 8 mg/kg) every hour through an implanted intravenous cannula. After 3 days of treatment, precipitated withdrawal tests were conducted: naloxone (5 mg/kg) was administered subcutaneously. Rats treated with morphine showed withdrawal signs such as hyperirritability, salivation, diarrhea, and weight loss. Rats treated with pethidine, pentazocine, or EK-399 showed similar signs, but they were less evident than those in morphine-treated rats. In abrupt withdrawal tests after 7 days of treatment, rats treated with morphine, pethidine, or pentazocine showed weight loss, whereas rats treated with EK-399 showed little or no weight loss. In substitution tests, EK-399 suppressed the withdrawal signs in morphine-dependent rats, and vice versa. These results show that EK-399 has a morphine-like physical dependence potential that is weaker than that of morphine, pethidine, or pentazocine in rats.

Animals↗
PubMed1998

(+/-)-cis-2-methylspiro[1,3-oxathiolane-5,3'-quinuclidine] hydrochloride, hemihydrate (SNI-2011, cevimeline hydrochloride) induces saliva and tear secretions in rats and mice: the role of muscarinic acetylcholine receptors.

We investigated effects of (+/-)-cis-2-methylspiro[1,3-oxathiolane-5,3'-quinuclidine] hydrochloride, hemihydrate (SNI-2011, cevimeline hydrochloride), a rigid analogue of acetylcholine, on saliva and tear secretions in rats and mice to evaluate its therapeutical efficacy for xerostomia and xerophthalmia in patients with Sjogren's syndrome and X-ray exposure in the head and neck. Intraduodenal administrations of SNI-2011 increased saliva secretion in a dose-dependent manner at doses ranging from 3 to 30 mg/kg in normal rats and mice, two strains of autoimmune disease mice and X-irradiated saliva secretion defective rats. The salivation elicited by SNI-2011 was completely inhibited by atropine. A similar atropine-sensitive response was observed in tear secretion. In rat submandibular/sublingual gland membranes, [3H]quinuclidinyl benzilate (QNB) binding was saturable, and Scatchard plot analysis revealed a single population of binding sites with a Kd of 22 pM and a maximal binding capacity of 60 fmol/mg protein. The competitive inhibition curve of the [3H]QNB binding by SNI-2011 was obtained, and its dissociation constant value calculated from IC50 was 1-2 microM. These results suggest that SNI-2011 increases saliva and tear secretions through a direct stimulation to muscarinic receptors in salivary and lacrimal glands, and they suggest that SNI-2011 should be beneficial to patients with Sjögren's syndrome and X-ray exposure in the head and neck.

Animals↗
PubMed2001

Mandibular advancement prosthesis: first-line alternative to surgery in snoring.

Mandibular advancement prosthesis (MAP) is infrequently used in the UK at present for snoring. First-line measures include dietary and weight modification for those that require it. Where such measures are unlikely to be useful or have already failed, surgery is sometimes utilized as a second-line treatment modality. We evaluate the use of MAP as an adjunct to first-line measures, with emphasis on efficacy, side-effects and patient compliance. Case notes of 30 snorers were reviewed and followed up with a questionnaire. Despite being useful in alleviating snoring, the prosthesis was poorly tolerated. Side-effects include increased salivation, temporomandibular joint pain, intra-oral and myofacial discomfort. Patients who persevered with the prosthesis found the early side-effects resolved after a few weeks and snoring reduced. MAP can be used in the initial management of snorers but patients need to be educated and encouraged, especially in the first few weeks.

Humans↗
PubMed1996

Acid-base status and cardiovascular function in mink (Mustela vison) anaesthetized with ketamine/midazolam.

Heart rate, arterial blood pressure and blood acid-base status were determined in 18 adult female mink (mean (+/- SEM) body weight 1052 +/- 34 g) during long-term anaesthesia with either controlled ventilation (n=12) or spontaneous respiration (n=6). Surgical anaesthesia was induced by intramuscular injection of ketamine hydrochloride (Ketaminol Vet, 40.0 +/- 1.7 mg/kg) and midazolam hydrochloride (Dormicum 2.8 +/- 0.1 mg/kg) and maintained for at least 5 h by continuous intravenous infusion of this drug combination in 0.9% saline. For all animals, the mean rates of infusion of ketamine and midazolam were 48.4 +/- 1.6 and 1.61 +/- 0.12 mg/h, respectively. Following continuous infusion of the anaesthetics in isotonic saline, at a rate of 20 ml/h, a moderate 'dilution acidosis' developed, which could be corrected by replacement of part of the saline with sodium bicarbonate to a final concentration of approximately 25 mmol NaHCO3 per litre. However, when the animals were allowed to breathe spontaneously, an increase in heart rate and a combined respiratory and metabolic acidosis occurred, due to severe respiratory depression. Apart from these effects and a few cases of increased salivation, no adverse effects over time were observed on the arterial blood acid-base status and cardiovascular function of the animals during ketamine/midazolam anaesthesia. It is concluded that the procedure described for long-term anaesthesia in mink is convenient and safe for acute physiological experiments in this species, provided normal body temperature and pulmonary gas exchange is sufficiently maintained. Thus, the need for an adequately controlled artificial ventilation is strongly emphasized. Finally, a proposal for the composition of an intravenous solution, containing ketamine and midazolam hydrochloride, and sodium bicarbonate in saline, suitable for long-term anaesthesia in adult mink is presented.

Acid-Base Equilibrium↗
PubMed1976

Natural history of bell's palsy: the salivary flow test and other prognostic indicators.

Fifty-one patients with Bell's palsy were evaluated within two days of onset and followed for six months without surgical intervention or effective medical treatment in order to observe the natural history of the disease. Sixty-three percent had a complete return while 37 percent had incomplete return. Age, the presence of pain, and taste alterations had no prognostic value. The progression of the palsy, response to maximal stimulation and salivary flow testing were approximately 80 percent accurate in predicting outcome. The salivary flow test was the most useful prognostic indicator since salivary flow became reduced within two days of onset in the patients likely to develop denervation while the other tests did not become altered until 3 to 14 days after onset. In patients with Bell's palsy, the salivation test seems to be the only method capable of predicting denervation before it begins; therefore, it should be ideal for selecting patients for appropriate treatment.

Adult↗
PubMed1978

Effects of PBBs on cattle. I. Clinical evaluations and clinical chemistry.

Toxicosis was induced in pregnant heifers by feeding 25,000 mg/head/day of FireMaster BP-6, a commercial blend of polybrominated biphenyls (PBB). The PBB feeding decreased dry matter intake approximately 50% by 4 days exposure. Emaciated animals became anorexic a few days prior to death at 33 to 66 days. Weight losses of heifers average 80 kg. Other clinical signs observed were dehydration, diarrhea, excessive salivation and lacrimation, fetal death, abortion, and general depression as evidenced by depressed heart and respiratory rates. Clinical signs were apparent after 10 days exposure and progressively intensified along with loss of condition until death. Clinicopathologic changes included significantly increased serum glutamic-oxaloacetic transaminase and decreased serum calcium by 30 days exposure. Lactate dehydrogenase, urea nitrogen, and bilirubin were elevated, and serum albumin decreased by 36 to 40 days. Principal urine changes were decreased specific gravity and moderate proteinuria. Pregnant heifers fed 0.25 or 250 mg/head/day for 60 days and nonpregnant heifers fed 250 mg/head/day for 180 days displayed neither clinical signs nor clinicopathologic changes indicating adverse effects from PBB exposure. Post-exposure, all heifers exposed to PBB for 60 days calved normally with zero calf mortality and were successfully rebred. Milk production was not different from control animals. Birth weights of calves from dams exposed to 250 mg PBB/head/day were significantly greater than calves of dams exposed to 0 mg or 0.25 mg/head/day. PBB exposure of dams produced no detrimental effects on calves as indicated by clinical signs, clinicopathologic changes, or performance.

Animal Diseases↗