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In vivo muscarinic cholinergic mediated effects of Lu 25-109, a M1 agonist and M2/M3 antagonist in vitro.

Lu 25-109 [5-(2-ethyl-2H-tetrazol-5-yl)-1,2,3,6-tetrahydro-1-methylpyridine] , has M agonistic and M2/M3 antagonistic effects at muscarinic receptors in vitro; a pharmacological profile that may be beneficial in treatment of Alzheimer's disease. In the present study, we compare functional in vivo effects of Lu 25-109 and reference compounds in animal models of muscarinic cholinergic function. Lu 25-109 substituted completely for the discriminative stimulus effects of (-)-7-methyl-3-(2-propynyloxy)-4,5,6,7-tetrahydroisothiazolo -[4, 5-c]pyridine (Lu 26-046), a partial M1/M2 agonist, but only weakly for the effects of the non-selective M1/M2/M3 agonist 3-methoxy-4,5,6,7-tetrahydro-isoxazolo[4, 5-c] pyridine (O-Me-THPO). Lu 25-109 did not reverse O-Me-THPO-induced discriminative stimulus. Tacrine did not substitute for any of the training drugs. Lu 25-109 did not substitute in (-)-nicotine trained rats. Lu 25-109 did not antagonize oxotremorine-induced hypothermia, tremor and salivation in mice and antagonized physostigmine-induced lethality with low potency. Unlike non-selective muscarinic agonists and acetylcholinesterase inhibitors, Lu 25-109 did not induce hypothermia, tremor or salivation in mice. Spontaneous locomotor activity and motor co-ordination were inhibited only at high doses. Lu 25-109 had no effect on mean blood pressure in anaesthetized rats. Lu 25-109 and O-Me-THPO produced a significant increase in heart rate. The maximum increase was 37%. In anaesthetized cats, increasing i.v. doses of Lu 25-109 were without effect on the mean blood pressure, except for a short lasting (<2 min) depressor effect following the IV injection. Furthermore, Lu 25-109 did not attenuate the reflex mechanisms restoring blood pressure following orthostasis in cats. In conclusion, the drug discrimination studies suggest a unique activity profile of Lu 25-109, and the in vivo profile suggests none or a very low frequency of unwanted cholinergic mediated effects.

Animals↗

Congenital absence of the lacrimal puncta associated with alacrima and aptyalism.

A 9-year-old girl had no lacrimal puncta, tearing (alacrima), or salivation (aptyalism). The lack of salivation caused florid dental caries. The same condition was found in the proband's father and paternal grandfather. Inheritance of this previously unreported trait appears to be autosomal dominant with variable expressivity.

Abnormalities, Multiple↗

Participation of different brain regions in the anti-narcotic withdrawal action of clonidine in the dependent rat.

The naloxone-precipitated withdrawal response in morphine dependent rats was quantitated by measuring the post-withdrawal increase in mean arterial pressure (MAP), heart rate and several characteristic behavioral changes. Pretreatment with intrathecal injection of clonidine produced a significant reduction in most of the autonomic symptoms of withdrawal, including the increase in MAP, salivation, and chromodacryorrhea, but did not effect the behavioral signs, body shakes, escape attempts or teeth chattering. Central i.c.v. injection of clonidine also reduced the autonomic symptoms of withdrawal. Two differences between the two routes of clonidine administration were with respect to (1) the degree of hind limb kicking where i.t., but not i.c.v. administration was effective at reducing this symptom; and (2) i.c.v., but not i.t. clonidine was effective in significantly reducing the incidence of diarrhea. In contrast, intracisternal (medullary level) injection of clonidine was without effect on the post-withdrawal increase in MAP, and inhibitory effects on the other symptoms included only salivation and diarrhea. Thus the effect of clonidine following intrathecal injection was not due to redistribution of drug to higher centers. Direct intrathecal injection of naloxone also precipitated withdrawal in morphine dependent rats. In this case, intrathecal pretreatment with clonidine did not inhibit the post-withdrawal increase in MAP. These results are consistent with a spinal component for the autonomic and behavioral symptoms of morphine withdrawal in the rat. Clonidine's antiwithdrawal response in mediated at least in part through a spinal action. However, this spinal antiwithdrawal action of clonidine is selective for withdrawal responses which originate from supraspinal centers.

Animals↗

Visual evoked response and behavioral correlates of plasma methadone concentrations in cats.

Twelve cats were implanted with cortical and depth electrodes. After they recovered from the operation, visual evoked responses (VERs) were recorded at 20 min following saline and methadone (0.5, 1, 2, 3, 4 mg/kg) administered IP in a semi-random order to each cat. Four other cats were similarly drugged and plasma was obtained for radioimmunoassay of methadone content. At the three lowest dose levels behavioral excitation and salivation were evident in some cats, while their VER configuration remained essentially unaltered and plasma methadone was barely measurable. Following the 3 and 4 mg/kg doses plasma methadone concentration increased dramatically, behavioral excitation and salivation were evident in most cats and VERs were reliably altered. The VER alterations, consisting of amplitude attenuation and a decrease in some latencies, were restricted to secondary VER components occurring between 50 and 100 msec despite the animals' extreme behavioral excitation. These results suggest that the reticular formation is not a principal site of the drug's effect.

Animals↗

Toxicity of methylenedioxymethamphetamine (MDMA) in the dog and the rat.

Methylenedioxymethamphetamine (MDMA) was administered to dogs and rats orally once a day for a 28-day period to evaluate the morphological and neuropathological effects. Major clinical signs associated with the administration of MDMA in the dog included circling, depression, dilated pupils, hyperactivity, rapid breathing, and salivation. Major clinical signs in the rat included hyperactivity, excitability, piloerection, exophthalmos, and salivation. Gross observations at necropsy in the dog possibly related to administration of the test article included reduced testicular size (one high and one medium dose) and prostatic enlargement in two high-dose animals. No gross lesions were seen in the rats at necropsy. The medium- and the high-dose groups in both sexes in both the rats and the dogs gained significantly less weight than the control and low-dose groups. Food consumption decreased the first week for the high- and medium-dose groups, but a significant reversal toward more normal consumption was noted in the following weeks in both the rats and the dogs. Hematologic, clinical chemistry, and urinalysis values did not appear to be affected by the administration of the test article in the dog. In the rat clinical pathology variables showing a trend to decrease with dose included urinary pH, blood urea nitrogen, glucose, creatinine (females), lactate dehydrogenase (LDH) (females), and chloride. Clinical pathology variables showing a trend to increase with dose included total white blood cell count and phosphorus. Microscopically, testicular atrophy was present in one medium-dose and two high-dose male dogs. Prostatic hyperplasia was present in two high-dose male dogs. No test article-related lesions were seen in the brains of either species.

3,4-Methylenedioxyamphetamine↗

Alpha-chloralose poisoning in dogs and cats: a retrospective study of 33 canine and 13 feline confirmed cases.

Alpha-chloralose (AC) is an anaesthetic compound also used as a rodenticide, and has dose-dependent central nervous system mixed effects of excitation and depression. The objectives of this study were to detail the clinical and clinicopathological characteristics, as well as the treatment and prognosis, of AC toxicosis in dogs and cats. Medical records were retrospectively reviewed for AC poisoning between the years 1989 and 2004, and 33 dogs and 13 cats were included in the study. The most common clinical signs were seizures, muscle tremor, hyperaesthesia, hypothermia, salivation, myosis, stupor, coma and ataxia. Coma was more common, while salivation and ataxia were less common in cats compared to dogs. Although hypothermia was very common, especially in cats (90.9%), hyperthermia was frequently observed in dogs (21%). Treatment in all patients was supportive and symptomatic, and the most commonly used anticonvulsants were diazepam and barbiturates; however, severe unresponsive seizures in three dogs had to be controlled with inhalant gas anaesthesia. The hospitalisation period was 1-3 days, and the overall mortality rate was 6.5%. Alpha-chloralose poisoning seems to have a favourable prognosis in dogs and cats.

Age Factors↗

Central moxonidine on salivary gland blood flow and cardiovascular responses to pilocarpine.

Peripheral treatment with the cholinergic agonist pilocarpine induces intense salivation that is inhibited by central injections of the alpha2-adrenergic/imidazoline receptor agonist moxonidine. Salivary gland blood flow controlled by sympathetic and parasympathetic systems may affect salivation. We investigated the changes in mean arterial pressure (MAP) and in the vascular resistance in the submandibular/sublingual gland (SSG) artery, superior mesenteric (SM) artery and low abdominal aorta (hindlimb) in rats treated with intraperitoneal (i.p.) pilocarpine alone or combined with intracerebroventricular (i.c.v.) moxonidine. Male Holtzman rats with stainless steel cannula implanted into lateral ventricle (LV) and anesthetized with urethane were used. Pilocarpine (4 micromol/kg of body weight) i.p. reduced SSG vascular resistance (-50+/-13% vs. vehicle: 5+/-3%). Pilocarpine i.p. also increased mesenteric vascular resistance (15+/-5% vs. vehicle: 2+/-3%) and MAP (16+/-3 mmHg, vs. vehicle: 2+/-3 mmHg). Moxonidine (20 nmol) i.c.v. increased SSG vascular resistance (88+/-12% vs. vehicle: 7+/-4%). When injected 15 min following i.c.v. moxonidine, pilocarpine i.p. produced no change on SSG vascular resistance. Pilocarpine-induced pressor responses and increase in mesenteric vascular resistance were not modified by i.c.v. moxonidine. The treatments produced no change in heart rate (HR) and hindlimb vascular resistance. The results show that (1) i.p. pilocarpine increases mesenteric vascular resistance and MAP and reduces salivary gland vascular resistance and (2) central moxonidine increases salivary gland vascular resistance and impairs pilocarpine-induced salivary gland vasodilatation. Therefore, the increase in salivary gland vascular resistance may play a role in the anti-salivatory response to central moxonidine.

Animals↗

10-Hydroxylation of nortriptyline in white persons with 0, 1, 2, 3, and 13 functional CYP2D6 genes.

OBJECTIVE: To investigate the disposition and effects of nortriptyline and its major metabolite 10-hydroxy-nortriptyline line in panels of white subjects with different CYP2D6 genotypes, including those with duplicated and multiduplicated CYP2D6*2 genes and to evaluate the contribution of the number of functional C gamma P2D6 alleles to the metabolism of nortriptyline, used here as a model drug for CYP2D6 substrates. METHODS: Oral single doses of 25 to 50 mg nortriptyline were given to five poor metabolizers of debrisoquin (INN; debrisoquine) with no functional CYP2D6 gene, five extensive metabolizers with one functional CY2D6 gene, five extensive metabolizers with two functional CYP2D6 genes, five ultrarapid metabolizers with duplicated CYP2D6*2 genes, and one ultrarapid metabolizer with 13 copies of the CYP2D6*2 gene. Plasma kinetics of nortriptyline and 10-hydroxynortriptyline were analyzed. Anticholinergic effects (inhibition of salivation and accommodation disturbances), sedation, blood pressure, and effect on supine and erect pulse rate were measured. RESULTS: There was a clear relation between the C gamma P2D6 genotype and the plasma kinetics of nortriptyline and 10-hydroxynortriptyline. The proportion between the apparent oral clearances of nortriptyline in the groups with 0, 1, 2, 3, and 13 functional genes was 1:1:4:5:17. The proportions between AUC(nortriptyline) to AUC(10-hydroxynortriptyline) ratios in the groups with 0, 1, 2, 3, and 13 functional genes were 36:25:10:4:1. Oral plasma clearance of nortriptyline and AUC(nortriptyline) to AUC(10-hydroxynortriptyline) ratio both correlated significantly with the debrisoquin metabolic ratio (rS = -0.89, p = 0.0001; rS = 0.92, p = 0.0001). Although ultrarapid metabolizer subjects were given double the nortriptyline dose (50 mg), inhibition of salivation was not more pronounced compared with the other genotype groups given 25 mg nortriptyline. CONCLUSION: The results of this study show the quantitative importance of the CYP2D6 genotype, especially the presence of multiple functional CYP2D6 genes for the pharmacokinetics of nortriptyline and 10-hydroxynortriptyline. Genotyping of subjects with multiple copies of functional genes may be of great value for differentiating ultrarapid metabolizers from patients who do not comply with the prescription and for assuring adequate drug choice and dosage for these patients.

Analysis of Variance↗

Comparison of the in vitro and in vivo profiles of tolterodine with those of subtype-selective muscarinic receptor antagonists.

Tolterodine [(R)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamine ] is a new potent and competitive muscarinic receptor antagonist developed for the treatment of urinary urge incontinence and other symptoms of overactive bladder. In vivo, tolterodine exhibits functional selectivity for the urinary bladder over salivary glands, a profile that cannot be explained in terms of selectivity for a single muscarinic receptor subtype. The aim of this study was to compare the in vitro and in vivo antimuscarinic profiles of tolterodine with those of muscarinic receptor antagonists with distinct receptor subtype-selectivity profiles: darifenacin [(S)-2-[1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl]-2,2-d iphenylacetamide; selective for muscarinic M3 receptors]; UH-AH 37 (6-chloro-5,10-dihydro-5-[(1-methyl-4-piperidinyl)acetyl]-11H-dibenzo-[b ,e][1,4]diazepine-11-one; low affinity for muscarinic M2 receptors); and AQ-RA 741 (11-([4-[4-(diethylamino)butyl]-1-piperidinyl]acetyl)-5,11-dihydro-6H-py rido[2,3-b][1,4]benzodiazepine-6-one; high affinity for muscarinic M2 receptors). The in vitro profiles of these compounds were in agreement with previous reports; darifenacin and UH-AH 37 demonstrated selectivity for muscarinic M3/m3 over M2/m2 receptors, while the converse was observed for AQ-RA 741. In vivo, AQ-RA 741 was more potent (1.4-2.7-fold) in inhibiting urinary bladder contraction than salivation in the anaesthetised cat (i.e., a profile similar to that of tolterodine [2.5-3.3-fold]), while darifenacin and UH-AH 37 showed the reverse selectivity profile (0.6-0.8 and 0.4-0.5-fold, respectively). The results confirm that it is possible to separate the antimuscarinic effects on urinary bladder and salivary glands in vivo. The data on UH-AH 37 and darifenacin support the view that a selectivity for muscarinic M3/m3 over M2/m2 receptors may result in a more pronounced effect on salivation than on bladder contraction. The data on AQ-RA 741 may indicate that muscarinic M2/m2 receptors may have a role in bladder contraction.

Animals↗

Gastric tube interposition as an esophageal substitute: comparative evaluation with gastric tube in continuity and gastric transposition.

BACKGROUND/PURPOSE: The aim of this study was to evaluate growth, hematologic and biochemical parameters, and histopathology after gastric tube interposition, gastric tube in continuity with or without posterior fundoplication, and gastric transposition in an experimental model. METHODS: Twenty-two postweaned, 28-day-old piglets were divided randomly into four groups: group 1 (n = 9) gastric tube interposition, group 2 (n = 4) gastric tube in continuity, group 3 (n = 5) gastric tube in continuity with posterior fundoplication, and group (n = 4) gastric transposition. The postoperative assessment included weekly measurement of weight, documentation of clinical symptoms, and deglutition difficulties. Hemoglobin, serum ferritin, albumin, globulins, total proteins, and red cell folate were measured. The pigs were killed and histopathologic assessment was made following a maximum observation period of 149 days. RESULTS: The four pigs with gastric transposition died within 96 hours postoperatively of respiratory embarrassment. The salient clinical features and histology are summarised. The salient clinical complications observed in the four groups were as follows. Group 1: vomiting (11%), minor leak (22%), and stricture (11%). There was no impairment of deglutition and the growth was normal. Group 2: vomiting (100%), excessive salivation (100%), and episodes of cyanosis (100%). Growth was impaired but there was no impairment of deglutition. Group 3: vomiting (80%), excessive salivation (80%), and episodes of cyanosis (20%). There was no impairment in deglutition or growth. Group 4: vomiting (100%), episodes of cyanosis (100%), and respiratory embarrassment (100%). Pigs in group 4 had to be sacrificed on day 3 or 4 postoperatively because of severe respiratory embarrassment, cyanosis, and presumed gastroesophageal reflux. At autopsy the anastomoses were intact, with no evidence of leak. The stomach and esophagus had good vascularity. Histopathology demonstrated esophagitis in 11% of the specimens in group 1, 100% of those in group 2, and 60% of those in group 3. Submucosal fibrosis was seen in 56% of group 1, 100% of group 2, and 80% of group 3. Hyperkeratosis was observed in 75% of group 2 and 40% of group 3 specimens. CONCLUSIONS: Gastric tube interposition in this animal model was associated with improved growth, fewer clinical complications, and fewer histopathologic changes than gastric tube in continuity with or without posterior fundoplication or gastric transposition.

Anastomosis, Surgical↗

A comparative study in rats of the in vitro and in vivo pharmacology of the acetylcholinesterase inhibitors tacrine, donepezil and NXX-066.

The in vitro and in vivo effects of the novel acetylcholinesterase inhibitors donepezil and NXX-066 have been compared to tacrine. Using purified acetylcholinesterase from electric eel both tacrine and donepezil were shown to be reversible mixed type inhibitors, binding to a similar site on the enzyme. In contrast, NXX-066 was an irreversible non-competitive inhibitor. All three compounds were potent inhibitors of rat brain acetylcholinesterase (IC50 [nM]; tacrine: 125 +/- 23; NXX-066: 148 +/- 15; donepezil: 33 +/- 12). Tacrine was also a potent butyrylcholinesterase inhibitor. Donepezil and tacrine displaced [3H]pirenzepine binding in rat brain homogenates (IC50 values [microM]; tacrine: 0.7; donepezil: 0.5) but NXX-066 was around 80 times less potent at this M1-muscarinic site. Studies of carbachol stimulated increases in [Ca2+]i in neuroblastoma cells demonstrated that both donepezil and tacrine were M1 antagonists. Ligand binding suggested little activity of likely pharmacological significance with any of the drugs at other neurotransmitter sites. Intraperitoneal administration of the compounds to rats produced dose dependent increases in salivation and tremor (ED50 [micromol/kg]; tacrine: 15, NXX-066: 35, donepezil: 6) with NXX-066 having the most sustained effect on tremor. Following oral administration, NXX-066 had the slowest onset but the greatest duration of action. The relative potency also changed, tacrine having low potency (ED50 [micromol/kg]; tacrine: 200, NXX-066: 30, donepezil: 50). Salivation was severe only in tacrine treated animals. Using in vivo microdialysis in cerebral cortex, both NXX-066 and tacrine were found to produce a marked (at least 30-fold) increase in extracellular acetylcholine which remained elevated for more than 2 h after tacrine and 4 h after NXX-066.

Acetylcholinesterase↗

Preclinical toxicity and teratogenicity studies with the narcotic antagonist analgesic drug TR5379M.

The narcotic antagonist TR5379M had po LD50 values of 365 and 750 mg/kg and iv LD50 values of 35.0 and 22.3 mg/kg in the mouse and rat, respectively. Subchronic (one month) po administration to rats at 40, 120, or 400 mg/kg/day and to cynomolgus monkeys at 20, 45, or 100 mg/kg/day showed the compound to be well tolerated at doses of 40 and 45 mg/kg, respectively. Deaths during the subchronic studies included one monkey following a single dose of 100 mg/kg and six rats following repeated doses of 400 mg/kg. Signs of toxicosis in rats included clonic convulsions (high-dose animals only) and mild dose-related salivation and hyperactivity. Signs of toxicosis in monkeys were limited to sporadic emesis and transiently decreased food consumption at all three dose levels. Emesis was not observed at doses of 20 or 45 mg/kg after the first week. Slightly increased weights (not significant at 40 mg/kg) for thyroid and adrenal glands occurred in male rats. Gross, microscopic, and clinical pathologic examinations revealed no treatment-related adverse effects at any dose level for either species. Administration of TR5379M to pregnant rats (20, 70, or 250 mg/kg/day on Days 6-15 of gestation) caused no teratogenicity or embryotoxicity and did not adversely affect any of the reproductive parameters examined. Dams given TR5379M at doses of 70 and 250 mg/kg salivated and had reduced weight gain. It was concluded from these studies that TR5379M has an adequate margin of safety to begin clinical investigations.

Abnormalities, Drug-Induced↗

Expression of biological activity of draculin, the anticoagulant factor from vampire bat saliva, is strictly dependent on the appropriate glycosylation of the native molecule.

Draculin, a glycoprotein isolated from vampire bat (Desmodus rotundus) saliva, is a natural anticoagulant which inhibits activated coagulation factors IX (IXa) and X (Xa). The observation that under captivity conditions, the anticoagulant activity present in vampire bat saliva is dependent upon the salivation protocol, led us to investigate the possible relationship between the expression of biological activity of native draculin and the post-translational glycosylation of the protein backbone. Daily salivation of vampire bats yields a saliva that progressively decreases in anticoagulant activity, without any significant change in overall protein content, or in the amount of protein specifically recognized by a polyclonal anti-draculin antibody. Anticoagulant activity of the saliva is restored after a 4-day period of rest. Besides the marked difference in anticoagulant activity, purified native draculin, obtained from high- and low-activity saliva, shows significant differences in: (a) composition of the carbohydrate moiety, and (b) Glycosylation pattern. Furthermore, controlled chemical deglycosylation of native draculin, under conditions that do not affect the polypeptide backbone, progressively leads to complete loss of the biological activity. Our present results implicate that correct glycosylation of draculin is a seminal event for the expression of the biological activity of this glycoprotein.

Animals↗

Health-related quality of life for nasopharyngeal carcinoma patients with cancer-free survival after treatment.

PURPOSE: To evaluate the health-related quality of life (HR-QOL) of nasopharyngeal cancer (NPC) patients with cancer-free survival after treatment and to investigate the factors correlated with their HR-QOL. METHODS AND MATERIALS: One hundred eighty-two NPC patients with cancer-free survival of more than 2 years after treatment were enrolled in the study. Data from the same number of people without a history of cancer, who had come to the hospital for health checkups, were also collected for comparison. The Chinese SF-36 questionnaire and nine items about head-and-neck functional impairments (HNFI) were self-reported by all participants at the clinics. Data relating to sociodemographic factors, cancer stage, and treatment of NPC survivors were analyzed. RESULTS: Psychometric tests revealed the excellent internal reliability (Cronbach's alpha: 0.87-0.96) and discriminative validity of the Chinese SF-36 used in Taiwan. Most functional domains of the Chinese SF-36 and all nine HNFI items were significantly worse in NPC survivors than in control subjects. No cancer or treatment-related variables significantly correlated with any functional domains of SF-36 or any items of HNFI for NPC survivors. Economic status, educational level, occupational status, and the number of comorbidities were the variables that significantly correlated with most functional domains of SF-36 for NPC survivors. Patients with more sufficient economic status, higher educational levels, with employment, or without comorbidity tended to enjoy better HR-QOL as detected by the SF-36. Salivation, hearing, and swallowing dysfunctions were the top three HNFI that disturbed NPC survivors. Economic status remained the most significant variable correlated with HNFI, including salivation, swallowing, neck stiffness, taste, and phonation. Survivors with better economic status reported less severe HNFI. CONCLUSIONS: NPC survivors had worse HR-QOL than healthy control subjects in the study. Socioeconomic status was the most significant variable that correlated with the HR-QOL of NPC survivors. This result might indicate that patients' superior individual characteristics and financial resources are important variables determining their ability to cope with cancer and treatment complications affecting their HR-QOL.

Adult↗

The effects of smoking cessation on food craving.

Weight gain is considered a frequent consequence of smoking cessation. Several psychological mechanisms may play an important role in weight gain following smoking cessation. The present investigation examined changes in food craving associated with smoking cessation using psychophysiologic (i.e., salivation), self-report, and behavioral (i.e., ad lib consumption) measures of reactivity to food cues in a prospective design. Although quitters (n = 16) evidenced weight gain (approximately 5 lbs.) at 1 week and 5 weeks post quit date and while control groups of smokers (n = 11) and nonsmokers (n = 16) did not, no support was found for increased craving assessed via self-report or salivation. The quitters did show evidence of increased craving as measured by ad lib consumption, while smokers and nonsmokers did not. However, the failure to find a significant Group by Session interaction limits our ability to make a strong statement concerning between-group differences on ad lib consumption.

Adult↗

Quantitative assessment of parkinsonian sialorrhea and results of treatment with botulinum toxin.

Aim: To assess quantitatively sialorrhea in Parkinson's disease (PD) and the efficacy of botulinum toxin (BOTOX) in its treatment.Material: 11 patients with a clinical diagnosis of idiopathic PD and drooling were assessed at least two points on the UPDRS Part II and 14 control subjects.Methods: Salivation was measured by weighing dental rolls before, and 2min after, insertion at six points of highest secretion of saliva in the mouth (buccal vestibule, and sublingual area). PD patients were assessed before and 1 week after injections of five units of BOTOX into each parotid salivary gland and the results were compared to the salivation production of controls.Results: Average secretion of saliva in PD patients was significantly higher than in controls-0.39+/-0.4g/2min. (range: 0.02-1.82) vs 0.19+/-0.16g/2min. (range: 0.02-0.98) (P=0.03). After treatment, the average secretion of saliva in PD patients decreased to 0.25+/-0.26g/2min. (range: 0.004-0.99) and did not differ significantly from controls. Nine patients improved also according to UPDRS. No side effects were observed in any of the patients injected.Conclusion: Botulinum toxin may be an effective and safe treatment of parkinsonian sialorrhea.

Journal Article↗

Role of parabrachial nucleus in submandibular salivary secretion induced by bitter taste stimulation in rats.

When rats lick a bitter taste solution such as quinine-hydrochloride, they secrete profuse amounts of saliva. The salivation has a higher flow rate than that induced by other qualities of taste stimulation: sweet, salty, and sour. The present study is aimed to clarify the neural mechanism of the quinine-evoked salivation by means of behavioral, neuroanatomical, and electrophysiological experiments. Behaviorally, submandibular salivary secretion and rejection behavior (gaping) were observed in normal rats, as well as in rats chronically decerebrated at the precollicular level. In chronically decerebrate rats, these quinine-evoked reactions were strongly suppressed by destruction of the medial part of the parabrachial nucleus, including the so-called taste area, and ventral part of the parabrachial nucleus, including the pontine reticular formation. Neuroanatomical study using a retrograde tracer, Fluoro-gold, revealed that the neurons sending their axons to the superior salivatory nucleus, parasympathetic secretory center, were located mainly in the pontine reticular formation ventral to the parabrachial nucleus, not in the parabrachial taste area. Extracellular neural activity was recorded from the parabrachial region in decerebrate rats, and responsiveness to taste stimulation, jaw movements, and electrical stimulation of the superior salivatory nucleus was examined. Neurons responsive to both taste stimulation and antidromic stimulation of the superior salivatory nucleus were found in the pontine reticular formation ventral to the parabrachial nucleus, which responded well to quinine and HCl taste stimuli. Neurons in the parabrachial taste area could respond to four qualities of taste stimulation, but not to antidromic stimulation of the salivary center. These results suggest that aversive taste information from the parabrachial taste area reaches the salivary secretory center via the reticular formation ventral to the parabrachial nucleus.

Animals↗

Synthesis and structure-activity studies of a series of spirooxazolidine-2,4-diones: 4-oxa analogues of the muscarinic agonist 2-ethyl-8-methyl-2,8-diazaspiro[4.5]decane-1,3-dione.

A series of spirooxazolidine-2,4-dione derivatives related to the putative M1 agonist 2-ethyl-8-methyl-2,8-diazaspiro[4.5]decane-1,3-dione (RS86; 1) were synthesized. The compounds were evaluated as cholinergic agents in in vitro binding assays and in in vivo pharmacological tests including antiamnesic effects using scopolamine-treated mice, hypothermia, and salivation in mice. Four compounds (5a,c,f and 17a) exhibited affinity for cortical M1 receptors and reversed scopolamine-induced impairment of mouse passive avoidance tasks, as did 1. Among these compounds, only 5a exhibited M1-receptor stimulating activity in pithed rats. Structural requirements for muscarinic activity in this series of spirooxazolidine-2,4-dione derivatives were as strict as those reported for spirosuccinimide derivatives including 1. The antiamnesic dose of 3-ethyl-8-methyl-1-oxa-3,8-diazaspiro[4.5]decane-2,4-dione (5a) was 2 orders of magnitude lower than the doses inducing hypothermia and salivation, in contrast to 1 for which the former dose was only 5-10-fold lower than the latter. These results suggest that the 8-azaspiro[4.5]decane skeleton represents a useful template for designing new muscarinic agonists as antidementia drugs.

Amnesia↗