Efficacy of epidural lidocaine combined with tramadol or neostigmine on perineal analgesia in the horse.

REASONS FOR PERFORMING STUDY: Short duration of analgesia is among the limitations of a single epidural injection with lidocaine in horses. OBJECTIVES: To evaluate the effectiveness and safety of epidural lidocaine in combination with either tramadol or neostigmine for perineal analgesia in horses. METHODS: Epidural catheters were placed in 6 saddle horses that then were given 3 treatments: 2% lidocaine (0.2 mg/kg bwt) alone, 2% lidocaine (0.2 mg/kg bwt) plus tramadol (0.5 mg/kg bwt), and 2% lidocaine (0.2 mg/kg bwt) plus neostigmine (1.0 µg/kg bwt). The order of treatments was randomised. Haemodynamic variables, respiratory rate, rectal temperature, analgesia, motor block and behaviour scores were compared among the 3 treatments. These parameters were determined before drug administration (baseline), at 5, 10, 15, 30, 45, 60, 75 and 90 min, and every 30 min thereafter until loss of analgesia. RESULTS: Duration of analgesia was longer with lidocaine plus tramadol (210 ± 12 min) compared with lidocaine plus neostigmine (150 ± 35 min) or lidocaine alone (70 ± 12 min; P<0.05). All treatments produced mild or moderate motor block without behavioural changes. Other adverse effects were not observed in any of the horses. CONCLUSION AND POTENTIAL RELEVANCE: Further studies are required to demonstrate whether tramadol or neostigmine have a role in the management of post operative pain when coadministered with lidocaine.

Neostigmine for the treatment of gastrointestinal atony: a report of one case.

BACKGROUND: A case of severe constipation is described in a 75-year- old cancer patient receiving methadone for pain. Her constipation was refractory to the current treatment and she suffered severe discomfort and cognitive impairment. Due to the severity of the clinical situation and after excluding mechanical obstruction, low doses of subcutaneous neostigmine were administered, having bowel movements with evacuation of stools in a few hours after its administration. DISCUSSION: The results suggest that subcutaneous neostigmine could be an alternative choice in a group of selected patients with advanced cancer and opioid-induced constipation.

The ACB technique: a biomagentic tool for monitoring gastrointestinal contraction directly from smooth muscle in dogs.

The aim of this paper was to verify whether AC biosusceptometry (ACB) is suitable for monitoring gastrointestinal (GI) contraction directly from smooth muscle in dogs, comparing with electrical recordings simultaneously. All experiments were performed in dogs with magnetic markers implanted under the serosa of the right colon and distal stomach, and their movements were recorded by ACB. Monopolar electrodes were implanted close to the magnetic markers and their electric potentials were recorded by electromyography (EMG). The effects of neostigmine, hyoscine butylbromide and meal on gastric and colonic parameters were studied. The ACB signal from the distal stomach was very similar to EMG; in the colonic recordings, however, within the same low-frequency band, ACB and EMG signals were characterized by simultaneity or a widely changeable frequency profile with time. ACB recordings were capable of demonstrating the changes in gastric and colonic motility determined by pharmacological interventions as well as by feeding. Our results reinforce the importance of evaluating the mechanical and electrical components of motility and show a temporal association between them. ACB and EMG are complementary for studying motility, with special emphasis on the colon. ACB offers an accurate method for monitoring in vivo GI motility.

Role of cholinergic, opioidergic and GABAergic neurotransmission of the dorsal hippocampus in the modulation of nociception in guinea pigs.

AIMS: Several physiological, pharmacological and behavioral lines of evidence suggest that the hippocampal formation is involved in nociception. The hippocampus is also believed to play an important role in the affective and motivational components of pain perception. Thus, our aim was to investigate the participation of cholinergic, opioidergic and GABAergic systems of the dorsal hippocampus (DH) in the modulation of nociception in guinea pigs. MAIN METHODS: The test used consisted of the application of a peripheral noxious stimulus (electric shock) that provokes the emission of a vocalization response by the animal. KEY FINDINGS: Our results showed that, in guinea pigs, microinjection of carbachol, morphine and bicuculline into the DH promoted antinociception, while muscimol promoted pronociception. These results were verified by a decrease and an increase, respectively, in the vocalization index in the vocalization test. This antinociceptive effect of carbachol (2.7 nmol) was blocked by previous administration of atropine (0.7 nmol) or naloxone (1.3 nmol) into the same site. In addition, the decrease in the vocalization index induced by the microinjection of morphine (2.2 nmol) into the DH was prevented by pretreatment with naloxone (1.3 nmol) or muscimol (0.5 nmol). At doses of 1.0 nmol, muscimol microinjection caused pronociception, while bicuculline promoted antinociception. SIGNIFICANCE: These results indicate the involvement of the cholinergic, opioidergic and GABAergic systems of the DH in the modulation of antinociception in guinea pigs. In addition, the present study suggests that cholinergic transmission may activate the release of endorphins/enkephalin from interneurons of the DH, which would inhibit GABAergic neurons, resulting in antinociception.

Parasympathetic dysfunction is associated with baroreflex and chemoreflex impairment in streptozotocin-induced diabetes in rats.

This study explored physiological mechanisms of diabetic dysfunction in baroreceptors and chemoreceptors-mediated hemodynamic responses, and cholinergic neurotransmission in 30-day diabetic rats (n = 14) and controls (n = 14). Basal hemodynamic data and vagal response to electrical stimulation and methacholine injection were also evaluated. Muscarinic receptors were characterized using a radioligand receptor binding assay ([3H]N methylscopolamine). Experimental diabetes (50 mg/kg of STZ, i.v.) decreased systolic, diastolic, and mean arterial pressure and basal heart rate. Heart rate (HR) responses to vagal electrical stimulation (16, 32, and 64 Hz) were 15%, 11%, and 14% higher in diabetics vs non-diabetics, as were HR responses to methacholine injection (-130+/-24, -172+/-18, -206+/-15 bpm vs. -48+/-15, -116+/-12, -151+/-18 bpm, P < 0.05). Muscarinic receptor density was higher (267.4+/-11 vs 193.5+/-22 fmol/mg/prot, P < 0.05) in the atria of diabetic rats than in those of controls; the affinity was similar between groups. Diabetes-induced reduction of reflex responses to baro- (reflex bradycardia: -3.4+/-0.3 and -2.7+/-0.2 bpm/mm Hg; reflex tachycardia: -1.6+/-0.1 and -1.4+/-0.07 bpm/mm Hg, in control and diabetics, P < 0.05) and chemoreceptor stimulation, enhancement of HR responsiveness to cardiac vagal electrical stimulation and methacholine stimulation, plus an increase in the number of atrial muscarinic receptors indicates reduced parasympathetic activity, which is probably derived from central nervous system derangement.

Inhibition of salivary secretion by activation of cannabinoid receptors.

It is known that marijuana use decreases saliva secretion. Therefore, we hypothesized that cannabinoid receptors (CBs) are located in salivary glands to mediate that effect. In these experiments, we used the submandibular gland (SMG) of male rats, which is one of the major salivary glands. Mammalian tissues contain at least two types of CBs, CB1 and CB2, mainly located in the nervous system and peripheral tissues, respectively. Both receptors are coupled to Gi protein and respond by inhibiting the activity of adenylyl cyclase. We demonstrated that both CB1 and CB2 are present in the SMG, each showing specific localizations. The best-known endocannabinoid is anandamide (AEA), which binds with high affinity to CB1 and CB2. We showed that AEA markedly reduced forskolin-induced increase of cAMP content in vitro. This effect was blocked by AM251 and AM630 (CB1 and CB2 antagonists, respectively), indicating that both receptors are implicated in SMG physiology. In addition, we showed that AEA injected intraglandularly to anesthetized rats inhibited norepinephrine (NE)- and methacholine (MC)-stimulated saliva secretion in vivo and that both AM251 or AM630 prevented the inhibitory action of AEA. Also, the intraglandular injection of AM251 increased saliva secretion induced by lower doses of NE or MC. This increase was synergized after coinjection with AM630. Therefore, we concluded that AEA decreases saliva secretion in the SMG acting through CB1 and CB2 receptors.

Terapéutica en el glaucoma crónico de ángulo abierto / Therapeutic in the open angle chronic glaucoma

El objetivo fundamental del tratamiento en el glaucoma es evitar la progresión de la neuropatía óptica glaucomatosa. El tratamiento farmacológico está dirigido básicamente a disminuir la producción de humor acuoso en el epitelio ciliar, aumentar su evacuaciòn por la vía uveo escleral o por la vía trabecular. El glaucoma se encuentra entre las primeras causas de ceguera en el mundo. En este trabajo presentamos los medicamentos más recomendados en el glaucoma primario de ángulo abierto...

Evaluation, prevention and management of radiotherapy-induced xerostomia in head and neck cancer patients.

PURPOSE OF REVIEW: As part of the multidisciplinary approach to head and neck cancer patients, radiation therapy plays an essential role, improving locoregional control. Radiation therapy-induced xerostomia is a late side-effect that increases the risk for developing dental caries and compromises oral mucosal integrity, resulting in oral pain, loss of taste, difficulties with swallowing and chewing, sleep disorders and worse quality of life. This review focuses on evaluation, prevention and management of radiation therapy-induced xerostomia. RECENT FINDINGS: In terms of xerostomia prevention, some clinical trials evaluating amifostine and intensity-modulated radiation therapy have shown positive results. Pilocarpine is a useful agent as a treatment of radiation-induced xerostomia in head and neck cancer patients. SUMMARY: Despite some advances in radiation therapy-induced xerostomia prevention, its treatment is an area in which advances are urgently needed.

Intracerebroventricular physostigmine facilitates heat loss mechanisms in running rats.

The aim of this study was to evaluate the participation of central cholinergic transmission in the regulation of metabolic rate, core temperature, and heat storage in untrained rats submitted to exercise on a treadmill (20 m/min, 5% inclination) until fatigue. The animals were separated into eight experimental groups, and core temperature or metabolic rate was measured in the rats while they were exercising or while they were at rest after injection of 2 microl of 5 x 10(-3) M physostigmine (Phy) or 0.15 M NaCl solution (Sal) into the lateral cerebral ventricle. Metabolic rate was determined by the indirect calorimetry system, and colonic temperature was recorded as an index of core temperature. In resting animals, Phy induced only a small increase in metabolic rate compared with Sal injection, without having any effect on core temperature. During exercise, the Phy-treated animals showed a lower core heating rate (0.022 +/- 0.003 degrees C/min Phy vs. 0.033 +/- 0.003 degrees C/min Sal; P < 0.02), lower heat storage (285 +/- 37 cal Phy vs. 436 +/- 34 cal Sal; P < 0.02) and lower core temperature at fatigue point than the Sal-treated group (38.5 +/- 0.1 degrees C Phy vs. 39.0 +/- 0.1 degrees C Sal; P < 0.05). However, despite the lower core heating rate, heat storage, and core temperature at fatigue, the Phy-treated rats showed a similar running time compared with the Sal-treated group. We conclude that the activation of the central cholinergic system during exercise increases heat dissipation and attenuates the exercise-induced increase in core temperature without affecting running performance.

Bethanecol chloride for treatment of clomipramine-induced orgasmic dysfunction in males.

PURPOSE: To investigate whether bethanecol chloride may be an alternative for the clinical management of clomipramine-induced orgasmic dysfunction, reported to occur in up to 96% of male users. METHODS: In this study, 12 fully remitted panic disorder patients, complaining of severe clomipramine-induced ejaculatory delay, were randomly assigned to either bethanecol chloride tablets (20 mg, as needed) or placebo in a randomized, double-blind, placebo-controlled, two-period crossover study. A visual analog scale was used to assess severity of the orgasmic dysfunction. RESULTS: A clear improvement was observed in the active treatment period. No placebo or carry-over effects were observed. CONCLUSION: These findings suggest that bethanecol chloride given 45 minutes before sexual intercourse may be useful for clomipramine-induced orgasmic dysfunction in males.

Bethanecol chloride for treatment of clomipramine-induced orgasmic dysfunction in males

OBJETIVO: Investigar se o uso do cloridato de betanecol é uma alternativa útil no manejo clínco da disfunção orgásmica induzida pela clomipramina, relatada por até 96 % dos usuários do sexo masculino. MÉTODOS: Foram estudados 12 pacientes do sexo masculino em remissão completa de transtorno de pânico porém com queixas de disfunção orgásmica grave secundária ao uso da clomipramina. Os pacientes foram aleatoriamente distribuídos ao tratamento com cloridrato de betanecol (20 mg quando necessário) ou placebo em um estudo duplo cego "crossover" de dois períodos. RESULTADOS: Foi observado um benefício claro no período de uso da droga ativa. Não foram observados efeito placebo ou "carry-over" nos pacientes inicialmete alocados ao medicamento ativo. CONCLUSÕES: Os resultados deste estudo sugerem que o cloridato de betanecol, usado em doses únicas, 45 minutos antes da relação sexual, pode ser útil em pacientes do sexo masculino apresentado disfunção orgásmica secundária ao uso da clomipramina.

Antinociceptive effect of low-dose intrathecal neostigmine combined with intrathecal morphine following gynecologic surgery.

BACKGROUND: The purpose of this study was to determine whether combination of 1-5 microg intrathecal neostigmine would enhance analgesia from a fixed intrathecal dose of morphine. METHODS: A total of 60 patients undergoing gynecologic surgery were randomized to one of five groups. Patients received 15 mg bupivacaine plus 2 ml of the test drug intrathecally (saline, 100 microg morphine, or 1-5 microg neostigmine). The control group received spinal saline as the test drug. The morphine group received spinal morphine as test drug. The morphine + 1 microg neostigmine group received spinal morphine and 1 microg neostigmine. The morphine + 2.5 microg neostigmine group received spinal morphine and 2.5 microg neostigmine. Finally, the morphine + 5 microg neostigmine group received spinal morphine and 5 microg neostigmine. RESULTS: The groups were demographically similar. The time to first rescue analgesic (minutes) was longer for all patients who received intrathecal morphine combined with 1-5 microg neostigmine (median, 6 h) compared with the control group (median, 3 h) (P < 0.02). The morphine group (P < 0.05) and the groups that received the combination of 100 microg intrathecal morphine combined with neostigmine (P < 0.005) required less rescue analgesics in 24 h compared with the control group. The incidence of perioperative adverse effects was similar among groups (P > 0.05). CONCLUSIONS: The addition of 1-5 microg spinal neostigmine to 100 microg morphine doubled the duration to first rescue analgesic in the population studied and decreased the analgesic consumption in 24 h, without increasing the incidence of adverse effects. The data suggest that low-dose spinal neostigmine may improve morphine analgesia.

Neuropharmacological actions of some binuclear lanthanide(III) complexes.

Binuclear lanthanide(III) compounds are of great interest because of the potential of their mutual Ln(3+)-Ln(3+) electronic couplings to produce unusually sharp images in magnetic resonance and fluorescence imaging of biological tissue. The toxicity and neuropharmacological properties of the water soluble and stable neutral binuclear complex [La(api)](2) were compared with those of binuclear complexes with lower water stability, and the components used in their syntheses. The order of the 24-h LD(50) (mg/kg body wt.) of the compounds in mice was: salicylaldehyde (2.24)160). These compounds induced convulsions, urination and defecation in mice. Due to the relatively very low toxicity of [La(api)](2), its mode of action was explored. Its proconvulsant action may possibly involve an interaction of undissociated complex with muscarinic receptors, and is reversed by atropine.

Baroreceptor control of heart rate in the awake toad: peripheral autonomic effectors and arterial baroreceptor areas.

Systemic injection of sodium nitroprusside (30 microg/kg, i.v.) in the awake Bufo paracnemis toad induced a fall in arterial blood pressure and tachycardia. This tachycardia, but not the hypotension, was significantly reduced in toads with bilateral electrolytic lesion of the caudal and commissural regions of the solitary tract nucleus and in animals with transection of the spinal cord, 2 mm below the obex. This indicates that the tachycardia is reflex, depends on the integrity of the solitary tract nucleus and is due to descending spinal autonomic activation. Pretreatment with propranolol (4 mg/kg, i.v.) significantly reduced the tachycardia but did not block it completely, showing the importance of beta-adrenoceptors in its genesis. The reflex increase in heart rate induced by nitroprusside was not statistically significant in animals with bilateral section of the laryngeal nerve, whose baroreceptor fibers originate from the pulmocutaneous artery or in animals in which the bilateral section of the laryngeal nerve was performed together with section of the glossopharyngeal nerves, which incorporate fibers originating from the carotid labyrinth. The reduction of the reflex tachycardia was significant in toads with aortic arch denervation alone or combined with section of the laryngeal nerves or in animals with complete denervation of the three baroreceptors areas. These results suggest that the region of the aortic arch, when submitted to unloading, is the most important baroreceptor zone for cardiac compensation in toads.

Colinomiméticos / Terapeutic effects of cholonergic substances

Atualizaçäo sobre a fisiologia, terapêutica e toxicidade dos colinomiméticos sobre o homem.

The monoterpene alkaloid cantleyine from Strychnos trinervis root and its spasmolytic properties.

Cantleyine, a monoterpene alkaloid isolated from the root bark of Strychnos trinervis, was submitted to a broad spectrum pharmacological screening, in which the principal effect observed was a nonspecific relaxation of isolated smooth muscles. Cantleyine relaxed (IC50 2.1 x 10(-4) M) the guinea-pig trachea, pre-contracted by carbachol and antagonized in a nonspecific manner; carbachol (IC50 2.1 x 10(-4) M) and histamine (IC50 1.4 x 10(-4) M) induced contractions in the guinea-pig ileum; and phenylephrine (IC50 3.8 x 10(-4) M) responses in the rat aorta. Cantleyine antagonized (pD'2, 3.82) cumulative concentration response curves to histamine in the ileum in a noncompetitive, reversible (slope, 4.84) and concentration dependent manner. The tonic contractions induced by histamine and KCl were also inhibited in a concentration-dependent and reversible manner (IC50 7.2 x 10(-5) and 1.8 x 10(-4) M, respectively), suggesting that cantleyine should be acting on voltage-dependent Ca2+ channels. This hypothesis was confirmed by the observation that cantleyine inhibited (pD'2, 3.35), in a concentration dependent manner, the CaCl2 induced contraction in depolarizing medium. These results suggest that cantleyine produces nonspecific spasmolytic effects in smooth muscle and that in guinea-pig ileum this effect is, in part, due to the inhibition of Ca+2 influx through voltage-dependent Ca2+ channels.

Partially folded intermediates during trypsinogen denaturation.

The equilibrium unfolding of bovine trypsinogen was studied by circular dichroism, differential spectra and size exclusion HPLC. The change in free energy of denaturation was delta GH2O = 6.99 +/- 1.40 kcal/mol for guanidine hydrochloride and delta GH2O = 6.37 +/- 0.57 kcal/mol for urea. Satisfactory fits of equilibrium unfolding transitions required a three-state model involving an intermediate in addition to the native and unfolded forms. Size exclusion HPLC allowed the detection of an intermediate population of trypsinogen whose Stokes radii varied from 24.1 +/- 0.4 A to 26.0 +/- 0.3 A for 1.5 M and 2.5 M guanidine hydrochloride, respectively. During urea denaturation, the range of Stokes radii varied from 23.9 +/- 0.3 A to 25.7 +/- 0.6 A for 4.0 M and 6.0 M urea, respectively. Maximal intrinsic fluorescence was observed at about 3.8 M urea with 8-aniline-1-naphthalene sulfonate (ANS) binding. These experimental data indicate that the unfolding of bovine trypsinogen is not a simple transition and suggest that the equilibrium intermediate population comprises one intermediate that may be characterized as a molten globule. To obtain further insight by studying intermediates representing different stages of unfolding, we hope to gain a better understanding of the complex interrelations between protein conformation and energetics.

Stability of pilocarpine ophthalmic solutions.

The stability of pilocarpine and pilocarpine-timolol eyedrop preparations available on the Argentine market was studied. A high-performance liquid chromatographic method that allows the estimation of pilocarpine in the presence of degradation products was used for the study according to the preestablished design. It was found that pilocarpine solutions are stable, while pilocarpine in association with timolol shows significant degradation.

Partially folded intermediates during trypsinogen denaturation

The equilibrium unfolding of bovine trypsinogen was studied by circular dichroism, differential spectra and size exclusion HPLC. The change in free energy of denaturation was delta GH2O = 6.99 + ou - 1.40 kcal/mol for guanidine hydrochloride and delta GH2O = 6.37 + ou - 0.57 kcal/mol for urea. Satisfactory fits of equilibrium unfolding transitions required a three-state model involving an intermediate in addition to the native and unfolded forms. Size exclusion HPLC allowed the detection of an intermediate population of trypsinogen whose Stokes radii varied from 24.1 + ou - 0.4 angstron to 26.0 + ou - 0.3 angstron 1.5 M and 2.5 M guanidine hydrochloride, respectively. During urea denaturation, the range of Stokes radii varied from 23.9 + ou - 0.3 angstron to 25.7 + ou - 0.6 angstron for 4.0 M and 6.0 M urea, respectively. Maximal intrinsic fluorescence was observed at about 3.8 M urea with 8-aniline-1-naphthalene sulfonate (ANS) binding. These experimental data indicate that the unfolding of bovine trypsinogen is not a simple transition and suggest that the equilibrium intermediate population comprises one intermediate that may be characterized as a molten globule. To obtain further insight by studying intermediates representing different stages of unfolding, we hope to gain a better understanding of the complex interrelations between protein conformation and energetics.