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PubMed1983

Reactivity to alcohol cues in alcoholics and non-alcoholics: implications for a stimulus control analysis of drinking.

The present study is an attempt to identify responses to alcohol-related stimuli which might differentiate alcoholics from non-alcoholics. The assumption was that alcoholics would be more reactive to alcohol cues because of prior conditioning history with respect to alcohol and drinking. Eight alcoholics in treatment were compared with ten non-alcoholic controls and two recovering alcoholics, using swallowing and salivation as the principal dependent measures. (The concordance of swallowing and salivation was validated using dental rolls with an independent group of ten alcoholics.) Five-minute "sniff-trials" were provided in which subjects smelled either cedar chips or their favorite alcoholic beverage, in a labelled container. Swallowing (salivation) and craving (desire to drink alcohol) were significantly elevated in alcohol-sniffing trials for alcoholics in treatment compared with non-alcoholics; cardiac rate and galvanic skin response duration were also elevated in alcoholics in treatment, though not significantly. Recovering alcoholics resembled alcoholics in treatment more closely than they resembled non-alcoholics. The data were examined in the context of conditioned withdrawal resembled non-alcoholics. The data were examined in the context of conditioned withdrawal and homeostatic protective mechanisms. Implications for the stimulus control analysis of drinking were discussed.

Adult↗
PubMed1996

Peripheral effects of three novel non-peptide tachykinin NK1 receptor antagonists in the anaesthetized rat.

Three novel non-peptide tachykinin NK1 receptor antagonists were assessed on the transient fall in mean arterial blood pressure and the salivation induced by i.v. substance P (0.65 nmol/kg) in the urethane-anaesthetized rat. LY303241 ((R)-1-[N-(2-methoxybenzyl)acetylamino]-3-(1H-indol-3-yl)-2-[N-(2-(4- phenylpiperazin-1-yl)acetyl)amino]propane), LY303870 ((R)-1-[N-(2-methoxybenzyl)acetylamino]-3-(1H-indol-3-yl)-2-[N-(2-(4-(++ +piperidin-1 -yl)piperidin-1-yl)acetyl)amino]propane) and LY306740 ((R)-1-[N-(2-methoxybenzyl)acetylamino]-3-(1H-indol-3-yl)-2-[N-(2-(4 -cyclohexylpiperazin-1-yl)acetyl)amino]propane) (65 nmol-9 micromol/kg i.v.; 5 min earlier) inhibited both the vasodepressor and salivary responses to substance P in a dose-dependent manner. LY303241 and LY306740 were more potent in inhibiting the vascular response to substance P while LY303870 was more potent in inhibiting the salivary response. LY303870 and LY306740 were devoid of direct effects while LY303241 decreased blood pressure and heart rate for 1 and 10 min, respectively. The antagonists act in a stereoselective and specific manner since the opposite (S) enantiomers of LY303870 (LY306155) and LY306740 (LY307679) failed to block the effects of substance P. In addition, LY303241, LY303870 and LY306740 neither affected the hypotension and the salivation induced by carbachol nor the increases in mean arterial pressure and heart rate induced by the tachykinin NK2 receptor agonist [beta-Ala8]neurokinin A-(4-10). Only LY303241 attenuated the decreases in mean arterial pressure and heart rate evoked by the tachykinin NK3 receptor agonist senktide. LY303870 and LY306740 appear to be the most interesting antagonists since they act in a specific and selective manner at the tachykinin NK1 receptor. The difference in the order of potency of the three antagonists to inhibit the hypotension and salivation elicited by substance P could be ascribed to their pharmacodynamic features or to the existence of different signal transduction mechanisms or receptor subtypes.

Anesthesia↗
PubMed1999

A comparison of the cuffed oropharyngeal airway (COPA) with the laryngeal mask airway (LMA) during manually controlled positive pressure ventilation.

STUDY OBJECTIVE: To examine the cuffed oropharyngeal airway (COPA) during positive pressure ventilation (PPV) and to compare its reliability and efficacy with the laryngeal mask airway (LMA). DESIGN: Prospective, randomized, controlled trial. SETTING: University Hospital. PATIENTS: 60 adult ASA physical status I and II patients scheduled for urologic surgery. INTERVENTIONS: Patients were randomly assigned to be ventilated with a COPA (n = 33) or a LMA (n = 27) during a standardized anesthetic procedure. Following preoxygenation and induction with alfentanil and propofol, the respective airways were inserted. Patients were ventilated manually with the reservoir bag of the anesthesia respirator. Inspiratory airway pressure was limited to 20 cm H2O, and the target tidal volume was 7 ml/kg. Respiratory rate was adjusted to achieve an end-tidal pressure of carbon dioxide of 35 mmHg. Anesthesia was maintained with propofol, nitrous oxide in oxygen, and alfentanil, as appropriate. MEASUREMENTS AND MAIN RESULTS: We evaluated ease of insertion (nominal scale: easy, moderate, difficult, or impossible) and recorded the number of maneuvers performed during insertion until an airtight seal of the airway was achieved. Reliability for "hands free" ventilation--defined as ventilation without the need to further augment the position of the airway device manually--was determined (nominal scale: adequate ventilation, adequate ventilation with manual assistance, and inadequate ventilation leading to airway change). Ventilation and oxygenation parameters were derived from the anesthesia respirator and a capillary blood gas sample, respectively. The incidence of laryngopharyngeal discomfort and the amount of salivation were assessed by nominal scales. The COPA was easier to insert than the LMA (p < 0.001), but more positional maneuvers (p < 0.001) were necessary with this device. "Hands free" ventilation was achieved less often with the COPA (p < 0.02). Ventilation and oxygenation were comparable with both devices. The COPA was associated with less salivation (p < 0.01) and laryngopharyngeal discomfort (p < 0.05) than the LMA. CONCLUSION: Although effective ventilation can be accomplished with both devices, the LMA is more reliable for "hands free" ventilation than the COPA. The lower incidence of laryngopharyngeal discomfort and salivation with the COPA may be beneficial for patients at risk for developing laryngospasm.

Adolescent↗
PubMed1993

Synthesis and antimuscarinic activity of some 1-cycloalkyl-1-hydroxy-1-phenyl-3-(4-substituted piperazinyl)-2-propanones and related compounds.

A new class of substituted 1-phenyl-3-piperazinyl-2-propanones with antimuscarinic activity is reported. As part of a structure-activity relationship study of this class, various structural modifications, particularly ones involving substitution of position 1 and the terminal piperazine nitrogen, were investigated. The objective of this study was to derive new antimuscarinic agents with potential utility in treating urinary incontinence associated with bladder muscle instability. These compounds were examined for M1, M2, and M3 muscarinic receptor selectivity in isolated tissue assays and for in vivo effects on urinary bladder contraction, mydriasis, and salivation in guinea pigs. Potency and selectivity in these assays were influenced most notably by the nature of the substituent group on the terminal nitrogen of the piperazine moiety. Benzyl substitution was particularly advantageous in producing compounds with functional M3 receptor (smooth muscle) and bladder selectivity; it provided several candidates for clinical study. In vivo, 3-(4-benzyl-piperazinyl)-1-cyclobutyl-1-hydroxy-1-phenyl-2-propanone (24) demonstrated 11- and 37-fold separations in its effect on bladder function versus mydriatic and salivation responses, respectively. The corresponding 2-chlorobenzyl derivative 25 was more than 178-fold selective for M3 versus M1 and M2 muscarinic receptors. 3-(4-Benzylpiperazinyl)-1,1-diphenyl-1-hydroxy-2-propanone (51) was 18-fold selective for M3 versus M1 and 242-fold selective for M3 versus M2 receptors. It was also selective in guinea pigs, where it displayed 20- and 41-fold separations between bladder function and effect on mydriasis and salivation, respectively. In general, the results of this study are consistent with the proposition that the described piperazinylpropanones interact with muscarcinic receptors in a hydrogen-bonded form that presents a conformation similar to that apparently adopted by classical antimuscarinic agents.

Animals↗
PubMed1980

Anticholinergic effects and plasma desipramine levels.

Anticholinergic effects of the tricyclic antidepressant desipramine were studied in 12 outpatients. Objective measurements of salivation and pulse rate and subjective ratings of mouth dryness and palpitations were made before and during treatment with desipramine at a final daily dosage of 150 mg. There were significant changes after 3 wk of treatment in all parameters except ratings of palpitation. Subjects with moderate or high plasma desipramine levels had more suppression of salivation than those with low levels. Changes in salivation and pulse did not correlate, nor did they correlate with subjective reports.

Adult↗
PubMed1997

Serum leptin and short-term regulation of eating in obese women.

1. Leptin is generally thought to play a key role in the regulation of eating. However, its real role in human eating behaviour is still poorly known. Therefore, the role of leptin in the regulation of eating was examined in obese binge- and non-binge-eating women during exposure to food and food-related stimuli. 2. Eleven binge- and ten non-binge-eating obese women took part in the study. In addition to serum leptin, serum insulin, non-esterified fatty acids, plasma glucose, salivation, the feeling of hunger and the desire to eat were repeatedly measured during the experiment. 3. Serum leptin levels did not differ between the binge- and non-binge-eating women. Neither were leptin levels associated with the feeling of hunger or the desire to eat food, nor with the amount or composition of food eaten. During food exposure leptin levels did not change, whereas at the same time serum insulin levels increased and serum non-esterified fatty acid levels decreased. The change in salivation during food exposure was inversely associated with the fasting leptin level. 4. This study indicates that serum leptin does not play a role in the regulation of eating in obese women, at least not in the short term. Furthermore, leptin levels are not different in obese binge-eating women as compared with obese non-binge-eating women. Interestingly, high fasting leptin levels may be associated with a decreased salivation response in the presence of food and food-related stimuli.

Adult↗
PubMed2006

Salivary secretions by aphids interacting with proteins of phloem wound responses.

Successful phloem feeding requires overcoming a number of phloem-related plant properties and reactions. The most important hurdle is formed by the phloem wound responses, such as coagulating proteins in the phloem sieve elements of the plant and in the capillary food canal in the insect's mouth parts, i.e. the stylets. It seems that in order to prevent protein clogging inside a sieve element, ejection of watery saliva plays an important role. This ejection is detected in the electrical penetration graph (EPG) as E1 salivation and always precedes phloem sap ingestion. During this feeding from sieve elements, another regular and concurrent salivation also occurs, the watery E2 salivation. This E2 saliva is added to the ingested sap and, it probably prevents phloem proteins from clogging inside the capillary food canal. Whatever the biochemical mode of action of the inhibition of protein coagulation might be, in some plants aphids do not seem to be able to prevent clogging, which may explain the resistance to aphids in these plants. The relevance of this hypothesis is demonstrated by new experimental results and is related to new EPG results from plants with phloem-located resistance.

Animals↗
PubMed2001

Smoking expectancy mediates the conditioned responses to arbitrary smoking cues.

Smokers' responses to smoking cues may be the result of a classical conditioning process. There is evidence that classical conditioning may not proceed in human subjects unless subjects are consciously aware of the stimulus (CS)-reinforcer (UCS) contingencies. In two experiments the role of CS<-->UCS contingency awareness in the expression of conditioned responses (craving, salivation, and skin conductance) was studied. A discriminative classical conditioning paradigm was used during which subjects were presented with one stimulus (the CS +) always paired with cigarette smoking (the UCS) and another (the CS -) never paired with cigarette smoking. Half of the subjects were given instructions to discover the CS<-->UCS contingencies (group 'aware', AWR), whereas the other half were not (group 'unaware', UWR). In experiment 1, all subjects responded to the CS + with increased cigarette craving relative to the CS -; this effect was more pronounced in the AWR group compared to the UWR group. A lower amount of salivation in response to the CS + compared to the CS - was found in the UWR group. These between-group differences were interpreted as a consequence of the enhanced expectancies of smoking in the presence of CS + in group AWR compared to group UWR. In experiment 2, the observed craving responses to CS + and CS - were consistent with those seen in experiment 1, but no discriminative salivary response to the stimuli was found. When, after conditioning training, subjects' expectancies of smoking were removed by instructions, and their responses to CS + and CS - were again measured, the discriminative craving response to CS + and CS - was eliminated and all subjects demonstrated a lower amount of salivation in response to the CS + compared to the CS -. These data suggest that presentation of arbitrary cues previously paired with cigarette smoking can elicit CRs and that facilitation of awareness of the CS<-->UCS contingency by instructions can potentiate craving CRs. In addition, these data suggest that craving CRs can be eliminated, whereas compensatory CRs can be facilitated, when cigarette expectancy is removed with instructions.

Adolescent↗
PubMed2005

Monoaminergic drugs and directly observable signs of LAAM withdrawal in rhesus monkeys.

Monoaminergic ligands modified a naltrexone discriminative stimulus in rhesus monkeys dependent on 2 mg/kg per day of the mu opioid L-alpha-acetylmethadol (LAAM). This study examined a role for monoamines in the directly observable and physiologic manifestations of LAAM withdrawal induced by naltrexone in the same monkeys. The effects of saline, clonidine (0.032 mg/kg), haloperidol (0.032 mg/kg), cocaine (1.0 mg/kg), amphetamine (1.0 mg/kg) and imipramine (10.0 mg/kg) were examined in LAAM-dependent monkeys that subsequently received saline or naltrexone (0.0001-1.0 mg/kg). Naltrexone dose-dependently increased respiration, abdominal rigidity and salivation. Clonidine attenuated each of these withdrawal signs, whereas haloperidol increased some (i.e. respiration) and decreased others (i.e. salivation). When administered alone, cocaine and amphetamine increased respiration and also increased the respiratory stimulant effects of naltrexone; cocaine and amphetamine did not attenuate any measure of withdrawal. With the exception of a decrease in naltrexone-induced salivation, imipramine was without effect. These results are strikingly different from results in these same LAAM-dependent monkeys showing that cocaine and amphetamine, but not clonidine, markedly attenuated a naltrexone discriminative stimulus. That monoaminergic ligands differentially alter the directly observable and discriminative stimulus effects of naltrexone in LAAM-dependent monkeys supports the view that monoamines differentially mediate the physical manifestations (norepinephrine) and subjective experience (dopamine) of opioid withdrawal.

Adrenergic alpha-Agonists↗
PubMed1985

Comparison of the effects of binodaline and amitriptyline on peripheral autonomic functions in healthy volunteers.

Twelve healthy male volunteers participated in five experimental sessions separated by weekly intervals. At the beginning of each session the subjects received one single oral dose of the following drugs, according to a double-blind, balanced cross-over design: binodaline hydrochloride (50 mg or 100 mg); amitriptyline hydrochloride (50 mg or 100 mg); lactose placebo. Salivation and resting pupil diameter were assessed before and 2 h after the ingestion of the drugs; baseline sweating, carbachol- or phenylephrine-evoked sweating were measured 2 h following drug taking. Binodaline, like placebo, had little effect on salivary output, whereas amitriptyline caused a dose-dependent decrease in salivation. None of the drugs caused any significant change in resting pupil diameter or in baseline sweating. Carbachol-evoked sweating did not differ significantly following the ingestion of binodaline or placebo; on the other hand responses to carbachol were significantly reduced following amitriptyline. Phenylephrine-evoked sweating was reduced by both binodaline and amitriptyline. The lack of effect of binodaline on salivation, resting pupil diameter, baseline and carbachol-evoked sweating is in agreement with the results of animal experiments indicating the lack of an interaction of this drug with cholinergic mechanisms. The reduction in phenylephrine-evoked sweating would be indicative of an alpha-adrenoceptor blocking property of this drug.

Adult↗
PubMed1986

Glycopyrrolate during ketamine/diazepam anaesthesia. A double-blind comparison with atropine.

In a double-blind study, the effects of atropine and glycopyrrolate (dosage ratio 2:1) following i.m. and i.v. administration were compared with respect to salivation, heart rate, and blood pressure before, during and after i.v. infusion anaesthesia with ketamine and diazepam for alloplastic hip or knee surgery in 30 patients above the age of 50 years. Given with the premedicant, the two drugs were equally effective in reducing salivation. A slight increase in heart rate was seen after atropine only (P less than 0.005). Increases in heart rate and blood pressure during induction of anaesthesia were similar in the two groups. A second dose of the test drug was given with neostigmine for reversal of neuromuscular blockade. Again, there were no statistically significant differences with respect to salivation, blood pressure, heart rate, nausea and/or vomiting, unpleasant dreams and arousal time.

Aged↗
PubMed1994

The effect of Salinum on the symptoms of dry mouth: a pilot study.

The effect of a new saliva substitute, Salinum, was tested in 37 patients with severe symptoms of reduced salivation. The majority of the patients had suffered from hyposalivation and dry mouth for more than 8 years. The saliva substitute consisted of a water soluble extract of linseed. The physical properties of this extract are similar to those of the glycoproteins of the salivary secretions. The patients used the saliva substitute for a seven days period. Prior to the use of the extract the patients reported that the most severe symptoms of decreased salivation were a feeling of dryness in the mouth and burning sensations in the tongue, pharynx and oesophagus, The majority of the patients reported that the use of Salinum reduced the symptoms of hyposalivation. Great variation in effect occurred from patient to patient. Generally the patients with the most severe symptoms experienced the greatest relief of the symptoms when they used Salinum. Although of short duration the results of this pilot study indicate that an extract of linseeds may compensate for some aspects of the consequences of reduced salivation. Further studies are needed to elucidate the feasibility of the extract as saliva replacement.

Adult↗
PubMed2005

Comparative study on pharmacological effects of DM-phencynonate hydrochloride and its optical isomers.

AIM: The 3-azabicyclo(3,3,1)nonanyl-9-alpha-yl-alpha-cyclopentyl-alpha-phenyl-alpha-glycolate (DM-phencynonate hydrochloride, DMCPG) is a demethylated metabolite of 3-methyl-3-azabicyclo(3,3,1)nonanyl-9-alpha-yl-alpha-cyclopentyl-alpha-phenyl-alpha-glycolate (phencynonate hydrochloride, CPG). (+/-)DMCPG had one chiral center and two enantiomers [R(-) and S(+)DMCPG]. Here we carried out a comparative study of the pharmacological profiles of these optical isomers. METHODS: Affinity and relative efficacy were tested using a radioligand-binding assay with muscarinic acetylcholine receptors from the rat cerebral cortex. Pharmacological activity was assessed in three individual experiments: (1) potentiating the effect of a sub-threshold hypnotic dose of sodium pentobarbital; (2) inhibiting oxotremorine-induced salivation; and (3) inhibiting the contractile response to carbachol. RESULTS: In the competitive binding assay, R(-)DMCPG (K(i)=763.75 nmol/L) was 4- and 2-fold more potent than (+/-)DMCPG (K(i)=3186 nmol/L) and S(+)DMCPG (K(i)=1699 nmol/L) in inhibiting the binding of [(3)H]QNB. The R(-) and S (+) configurations showed positive cooperation (n(H)>1) with the muscarinic receptor, whereas (+/-)DMCPG had a negative cooperation (n(H)<1) relationship with the muscarinic receptor in a radio-binding assay. Both the R(-) and S(+) configurations could potentiate the effect of sub-threshold hypnotic dose of sodium pentobarbital in a dose-dependent manner (the ED(50) values were 2.53 and 18.65 mg/kg, respectively), but (+/-)DMCPG did not display significant central depressant effects at doses from 10 to 29.15 mg/kg (P>0.05). (+/-)DMCPG and its optical isomers suppressed the guinea pig ileum contractile response to carbachol. The IC(50) values were 7.78 x 10(-9), 1.88 x 10(-7), and 1.038 x 10(-7) nmol/L, respectively. In the anti-salivation study, (+/-)DMCPG and its enantiomers depressed oxotremorine- induced salivation in a dose-dependent manner, and the order of potency was R(-)DMCPG (ED(50)=0.44 mg/kg) > (+/-)DMCPG (ED(50)=2.88 mg/kg) >S(+)DMCPG (ED(50)=5.05 mg/kg). CONCLUSION: (+/-)DMCPG and its optical isomers have differences in their pharmacological potencies as anticholinergic agents, and the R(-) configuration is more active than the S(+) configuration.

Animals↗
PubMed1996

The effects of 5-hydroxydopamine on salivary flow rates and protein secretion by the submandibular and parotid glands of rats.

The secretory effects of 5-hydroxydopamine (5-OHDA) were tested in Nembutal-anaesthetized adult male Sprague-Dawley rats injected I.V. over a wide range of doses, with and without various autonomic antagonists and Ca2+ channel blockers. Polyacrylamide disc gel (15%) and iso-electric focusing (IEF) electrophoresis by the PhastSystem were used to separate and determine the types of protein in submandibular saliva. Amylase activity of parotid saliva was determined by the blue dextran method. Salivation by the submandibular glands following application of 5-OHDA was completely abolished by both prazosin and propranolol, whereas salivation by the parotid glands was completely abolished by propranolol alone. Following application of 5-OHDA, there was a dose-related increase in flow rates and total output of protein, but not in the protein concentration and amylase activity, from both salivary glands. The effect of 5-OHDA on submandibular saliva was significantly reduced by alpha-adrenoceptor blockers, but not by beta-adrenoceptor and cholinergic blockers, nor by any Ca2+ channel blocker. The effect of 5-OHDA on the parotid gland was not significantly altered by atropine and phentolamine. However, after pretreatment with reserpine, a 95% reduction was observed in the salivation from the submandibular gland. This implies that 5-OHDA is mostly acting indirectly via release of noradrenaline. The proteins in submandibular saliva following treatment with 5-OHDA alone or 5-OHDA in combination with beta-adrenoceptor blockers were mainly of the alpha-type, whereas after treatment with 5-OHDA in combination with alpha-adrenoceptor blockers they were of the beta-type. The alpha-type was found in saliva after treatment with each of three Ca2+ channel blockers.

Adrenergic alpha-Antagonists↗
PubMed2003

Regulation mode of evaporative cooling underlying a strategy of the heat-tolerant FOK rat for enduring ambient heat.

Compared with other rat strains, the inbred FOK rat is extremely heat tolerant. This increased heat tolerance is due largely to the animal's enhanced saliva spreading abilities. The aims of the present study were to 1) quantify the heat tolerance capacity of FOK rats and 2) determine the regulatory mode of the enhanced salivary cooling in these animals. Various strains of rats were acutely exposed to heat. In the heat-intolerant strains, saliva spreading was insufficient and the core temperature (Tc) rose rapidly. In contrast, FOK rats maintained an elevated Tc plateau (39.5 +/- 0.7 degrees C) for 5-6 h over a wide range of ambient temperatures (Ta) (37.5-42.5 degrees C). In hot environments the FOK rats secreted copious amounts of saliva and spread it over more than the entire ventral body surface. FOK rats had a low Tc threshold for salivation, and the salivation rate increased linearly in proportion to the Tc deviation from the threshold. No strain difference or temperature effect was observed in the saliva secretion rate from in vitro submandibular glands perfused by sufficient doses of ACh. These results suggest that 1) the ability of FOK rats to maintain a moderate steady-state hyperthermia (39.5 +/- 0.7 degrees C) over a wide Ta range is enabled by a lowered threshold Tc for salivation and functional negative-feedback control of saliva secretion and 2) strain differences in ability to endure heat stress are mainly attributable to changes in the thermoregulatory control system rather than altered secretory abilities of the salivary glands.

Adaptation, Physiological↗
PubMed2001

Differences in parasympathetic vasodilator and salivary responses in the cat submandibular gland between lingual and chorda-lingual nerve stimulation.

Experimental activation of parasympathetic vasodilatation and salivation in the submandibular gland by a "pseudoreflex" method has definite advantages over other commonly used methods. However, it is unclear which stimulation sites allow for avoidance of direct activation of the parasympathetic efferents to this gland. We examined this question in heavily anesthetized (alpha-chloralose and urethane), artificially ventilated, cervically vago-sympathectomized cats, using the intersection of the chorda-lingual nerve and the submandibular gland duct ("the intersection") as our reference point. Both vasodilatation and salivation evoked by electrical stimulation of the lingual nerve were abolished by section of the chorda-lingual nerve (10 mm proximal to the intersection), provided the stimulation site was distal to the intersection by 4 mm or more. This salivation was abolished by the muscarinic receptor antagonist, scopolamine. Thus, by careful choice of stimulation site, submandibular gland responses mediated solely by reflex parasympathetic mechanisms can be evoked by lingual nerve stimulation in this preparation.

Adrenergic alpha-Antagonists↗
PubMed1995

A pharmacokinetic and pharmacodynamic study of intravenous pilocarpine in humans.

Pilocarpine (P) is of potential utility in the treatment of xerostomia. Because optimal development of P dosage forms for humans requires that its pharmacokinetics and pharmacodynamics be defined, this intravenous study of its disposition and associated salivary responses was performed. In a hospital setting, two healthy female subjects were given a series of graded doses of intravenous P or placebo to stimulate salivary secretion. Plasma levels of P, heart rate, blood pressure, and respiratory rate were simultaneously monitored. Other objective and subjective physiological parameters were assessed. Plasma concentrations of P declined either mono- or bi-exponentially with time, and brisk initial salivation was followed by prolonged salivation at doses > or = 1 mg. At doses between 0.5 and 3.5 mg, dose-independent pharmacokinetic parameters included a small steady-state volume of distribution (2.4 to 3.0 L/kg), a high plasma clearance (0.026 to 0.03 L/kg/min), and a mean residence time of approximately 100 min. The cumulative volume of whole saliva secreted during the first 3 h post-dose was linearly related to the area under the plasma concentration-time curve. Plasma concentrations from 1 to 42 ng/mL were associated with significant levels of salivation. The pharmacokinetic linearity of the system and proportionality between the area under plasma concentration-time curves and overall salivary response have important implications for the design and utilization of pilocarpine dosage forms.

Adult↗
PubMed2005

Efficacy of an adenosine A1 receptor agonist compared with atropine and pralidoxime in a rat model of organophosphate poisoning.

The objective of this study was to evaluate the effects of an adenosine A1 agonist, phenylisopropyl adenosine (PIA), on metamidophos poisoning compared to specific antidotes. Rats were poisoned with metamidophos (30 mg/kg, oral) and observed for 24 hours. One group received sodium chloride (1 mL/kg) and four experimental groups received atropine (5 mg/kg), pralidoxime (PAM, 20 mg/kg), atropine/PAM (5/20 mg/kg) or PIA (1 mg/kg) intraperitoneally. Atropine reduced salivation and prevented respiratory distress when compared to sodium chloride-treated rats. Treatment with PAM did not cause any suppression of cholinergic signs. Atropine and PAM combination prevented salivation, convulsion and respiratory distress. PIA delayed initial time of the salivation, convulsion and time to death. However, PIA was found ineffective against the metamidophos-induced cholinergic symptoms and mortality. All treatments, except PIA, lead to survival of these animals. Acetylcholinesterase (AChE) activity was not normalized by PIA or PAM. PIA prevented metamidophos-induced diaphragmatic muscle necrosis as much as PAM. In conclusion, a single dose of PIA was unable to protect the rats from metamidophos toxicity. Further studies are needed involving a combination of PAM and/or atropine with repeated doses of PIA to clarify the efficacy of adenosine agonists in OP poisoning.

Adenosine A1 Receptor Agonists↗