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Effects of autonomic drugs on the cardiovascular system: dogs with achalasia (under halothane anesthesia).

The parasympathetic and sympathetic components of the autonomic systems as they relate to cardiovascular function were studied on dogs with achalasia of the esophagus. This was accomplished by administering the parasympathomimetic drugs methacholine (0.2 mg/kg, subcutaneously), 2 doexy-D-glucose (100 mg/kg, intravenously (IV), the parasympatholytic drug atropine (0.2 mg/kg, IV), the sympathomimetic agent epinephrine (2.5 microng/kg, IV), and the beta adrenergic blocker propranolol (0.5 mg/kg, IV); and then measuring cardiac output, stroke volume, heart rate, mean arterial pressure, pulse pressure, central venous pressure, total peripheral resistance, PaCO2, PaO2, pH, and base deficit. Cardiovascular responses to the administration of the parasympathomimetic drugs, methacholine and 2 deoxy-D-glucose, or the parasympatholytic drug, atropine, were similar to those observed in normal dogs. Cardiovascular responses to the administration of the sympathomimetic drug epinephrine and the sympatholytic drug propranolol or beta blocker were also consistent with those observed in normal dogs. It can be interpreted from this pharmacologic evidence that parasympathetic and sympathetic innervations to the cardiovascular system are present in dogs with achalasia of the esophagus. Fewer cardiovascular variables were significantly altered in dogs with achalasia than in normal dogs. Since this was true for both the sympathetic and the parasympathetic values, it is interpreted as reflecting their general health rather than a specific lesion.

Anesthesia, Inhalation↗

[Lactones. 22. Synthesis and reduction of alpha-aminomethylene-delta,delta-diphenyl-delta-valerolactones].

Treatment with tris-(dimethylamino)-methane resp. formylation and reaction with piperidine transfer 1 to 5a,b, which can not be reduced to the corresponding alpha-aminomethyllactones 4a,b, in contrast to the homologue 6 and other alpha-aminomethylene-gamma- and delta-lactones. Isolation of products and gc/ms-investigations verify the reaction course: The aminomethyl moiety in alpha-position of delta,delta-diarylated delta-lactones is instable and eliminates amine to give 7 (NaCNBH3) or 9 (H2/Pt). Only cleavage of the lactone ring enables the formation of stable aminomethyl compounds (10,11). 5a shows weak parasympatholytic and no H1-antihistaminic activity at the isolated guinea-pig ileum.

Animals↗

Airway mucus membrane: effects of beta-adrenergic and anticholinergic stimulation.

Mucus hypersecretion and non-continuous clearance of tracheobronchial mucus contribute to airflow obstruction in several pulmonary disease entities. Bronchospasm, which is frequently associated with bronchial asthma, can present simultaneously with mucus transport abnormalities. Therapy designed to dilate airways may produce secondary effects, which are deleterious to effective transport of lung mucus. Sympathomimetic agents, such as beta-adrenergic agonists, reduce the tone of bronchial smooth muscle and enhance the flow of mucus within lung airways. Parasympatholytic agents also improve airflow in the lungs, but their effects at the mucus membrane of the airways may not be beneficial. Atropine, an anticholinergic agent, apparently has dose-dependent effects on human mucociliary function and, administered orally, can reduce large airway mucus transport. However, newer anticholinergic agents, such as ipratropium bromide, are effective bronchodilators and do not exhibit unfavorable effects on lung mucus transport in either subjects with normal mucus secretion or those with hypersecretory disease entities, such as bronchitis. In mildly symptomatic asthmatic patients, aerosolized ipratropium decreased airway obstruction without consistent positive or negative influence on lung mucociliary function.

Adrenergic beta-Agonists↗

Pharmacologic evidence for a parasympathetic role in seizure-induced neurocardiac regulatory abnormalities.

PURPOSE: We evaluated whether postictal cardiac arrhythmia can be prevented by pharmacologic blockage of peripheral muscarinic receptors in an experimental model of epilepsy in rats. METHODS: Rats were prepared for chronic electrocardiograph recording and pretreated with atropine methyl bromide (2 or 10mg/kg i.p.) or saline prior to exposure to maximal electroshock (MES). The resulting seizure severity and duration of cardiac arrhythmia were measured. RESULTS: Atropine methyl bromide did not significantly affect seizure severity in comparison to control animals but reduced the arrhythmia at a dose of 2mg/kg, and completely suppressed arrhythmia at 10mg/kg. CONCLUSIONS: Postictal arrhythmia following MES-induced seizures may be blocked by pretreatment with atropine methyl bromide, a peripherally acting parasympatholytic agent. Our findings support previous observations that suggest strong participation of the parasympathetic system in postictal arrhythmia. This may be important for clinical suppression of cardiac arrhythmia in persons with uncontrolled epilepsy, who are at risk for sudden unexpected death.

Animals↗

Usefulness of low doses of atropine to quantify the vagal stimulus-response relation in patients with congestive heart failure.

The response of low doses of atropine is reported to be attenuated in patients with congestive heart failure (CHF). Judging from the main site of action of low doses of atropine, we may be able to assess the functional state of the vagal center in the central nervous system. This study examines the clinical significance of heart rate (HR) response to a low dose of atropine in patients with CHF. Low and high doses of atropine were administered intravenously in 72 patients with CHF. HR after a low (parasympathomimetic) dose injection was assessed by the ratio Rm (minimal HR/basal HR), and after a high (parasympatholytic) dose by the ratio R1 (augmented HR/basal HR). Rm and R1 were related to indexes of CHF. Rm increased with progression of CHF (0.92 +/- 0.03 in New York Heart Association functional class I, 0.98 +/- 0.05 in class II, and 1.00 +/- 0.04 in class III). It also correlated with ejection fraction (r = -0.48, p <0.01) and more importantly, with peak oxygen uptake (r = -0.59, p <0.01). R1 exhibited weak correlation with basal HR (r = -0.33, p <0.05) and ejection fraction (r = 0.31, p <0.05), but had no correlation with other indexes. The vagal center may be already blunted in New York Heart Association class II with respect to increased Rm, which may be related to depressed exercise capacity. A low dose of atropine injection offers a simple and safe method for providing important information on the functional state of the vagal center in the central nervous system in patients with CHF.

Adult↗

[Therapy of allergic rhinitis].

Nasal allergy is due to a change in the immunoreactivity of an individual. B-lymphocytes produce allergen-specific IgE antibodies after the antigen is presented to T-helper cells. IgE bound to mast cells leads to mast cell activation in the case of antigen contact. Mast cells release mediators and induce local inflammation. The symptoms of allergic rhinitis are caused by various factors and are different in individuals, and hence therapy must be in accordance with the necessities in the individual. There are four principles of therapy in allergic rhinitis. The first and best is allergen avoidance. It is the first choice in animal allergy and important in mite allergy. It is difficult for mold allergy and impossible for pollen allergy. The second is immunotherapy. Immunotherapy is a specific form of controlled allergen admission that changes immunoreactivity into allergen tolerance in a major part of patients. Immunotherapy is a very important tool if performed by a physician with experience. The third principle is drug therapy. With todays drugs, it is still symptomatic. alpha-sympathomimetic vasoconstrictors administered systemically (and, still better, locally) relieve nasal stuffiness. Parasympatholytic drugs can abort pathological secretions. Cromoglycate (DNCG) is a local prophylactic drug improving all symptoms of allergic rhinitis. DNCG is the first choice in pollinosis. Antihistamines are usually given systemically, and the modern drugs have no sedative effect. Clinical effects are comparable to DNCG, and there are new substances available for local therapy. Steroids given systematically improve all symptoms of allergy and inflammation after a certain delay. Due to side effects, local steroids are preferred today.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Cortex Hormones↗

[Angel trumpet: a poisonous garden plant as a new addictive drug?].

BACKGROUND AND OBJECTIVE: Angel's trumpet (Species Brugmansia) is widely used as a garden plant because it is easily kept and the luxuriance of its flowering. Belonging to the Family Solanacea it contains a large amount of alkaloids (parasympatholytics). Because of its hallucinogenic action, its leaves and flowers are increasingly used by young people as a substitute for the hallucinogen LSD (lysergic acid diethylamide). In the summer of 1997, one of a group of youths died after they had ingested its flowers which they had gathered from front gardens. An investigation was undertaken to identify the alkaloids and measure their concentration in the various parts of the plant. METHODS: Four young and one eight-year old plant were kept outdoors from May until October, and its flowers and leaves were removed for analysis weekly. All samples were deep-frozen at -20 degrees C and later, at the same time, thawed out, weighed and extracted in methanol. The alkaloids were identified by high pressure liquid chromatography (HPLC), diode array detector, separated by means of a Hypersil HyPurity cartridge, and measured at a wave-length of 220 nm. RESULTS: All 66 flowers, 32 leaves and 2 speed capsules contained tropane alkaloids, mainly scopolamine. The highest concentrations were found in the seed capsules, lower ones in the flowers, while the leaves contained only small amounts. Total alkaloid content per flower of the younger plants averaged 0.94 mg, of the younger ones 1.81 mg. The flowers of the old plant contained up to 3 mg scopolamine. CONCLUSION: The ingestion of even a few flowers of Angel's trumpet can cause symptoms of poisoning. Easy availability of the plant thus presents a danger. Because of the increasing incidence of deliberate ingestion by young people, poisoning by Angel's trumpet should be included in the differential diagnosis in patients with confusion and hallucinations of uncertain origin, especially during the summer months.

Adolescent↗

[Parasympathicolytic treatment of abnormal neurogenic bladder function: a urodynamic study (author's transl)].

The effect of two parasympatholytic drugs, trospium chloride and hyoscine-N-butylbromide, was studied by urodynamic tests in 20 patients with spastic neurogenic bladder function. After intravenous injection of 0.6 mg trospium chloride or 60 mg hyoscine-N-butyl bromide bladder capacity increased significantly, while the degree of spasm and the response in the ice water test decreased significantly. Maximal sphincter pressure, resting bladder pressure, maximal bladder filling pressure and abdominal pressure remained unchanged.

Benzilates↗

Atrioventricular block after administration of atropine in patients following cardiac transplantation.

BACKGROUND: Atropine is widely used as a parasympatholytic agent during diagnostic and therapeutic procedures. We observed an unexpected paradoxical response to atropine after cardiac transplantation. METHODS: In a study investigating the occurrence of autonomic reinnervation after cardiac transplantation, atropine, at 0.015 mg/kg body weight, was given intravenously to 23 patients (mean age, 56+/-8 years) 98 days to 6.4 years after transplantation. RESULTS: Two patients experienced a witnessed syncope 40 and 150 min after administration of atropine. Second-degree atrioventricular (AV) block was documented in the first patient immediately afterward, and third-degree AV block was seen on 24-hr electrocardiogram monitoring in the second patient. A third patient developed documented AV block 15 min after atropine but experienced no sequelae because of a previously implanted pacemaker. CONCLUSIONS: Although the underlying mechanism is not clear, these findings suggest that atropine may paradoxically cause high-degree AV block in patients after transplantation. Accordingly, it should be used with caution and appropriate monitoring in these patients.

Adult↗

Pulmonary function changes induced by three regimens of bronchodilating agents in calves with acute respiratory distress syndrome.

Two aerosolised bronchodilators, one sympathomimetic and one parasympatholytic, were tested either alone or in combination for their ability to improve the pulmonary function of double-muscled calves suffering from acute respiratory distress syndrome. In control animals treated with 0.9 per cent saline the parameters of pulmonary function and signs of clinical distress did not change significantly within the hour following the first treatment. Among the other animals, both at one hour and seven days after the first treatment, the most clinical improvement was observed in the animals treated with both bronchodilators and the least in the animals treated with clenbuterol hydrochloride. One hour after the first treatment the respiratory system compliance of the animals treated with ipratropium bromide and the arterial oxygen tension of the animals treated with both bronchodilators were significantly enhanced. After seven days the resistive parameters, the rectal temperature and the respiratory rate were also significantly improved in the animals treated with ipratropium bromide or both bronchodilators whereas only the respiratory rate and rectal temperature were significantly reduced in the animals treated with clenbuterol hydrochloride.

Acute Disease↗

The potential for mental status changes associated with systemic absorption of anticholinergic ophthalmic medications: concerns in the elderly.

Several cases have been reported of anticholinergic toxicity following the administration of commonly used parasympatholytic cycloplegics and mydriatics. Cases have been reported in children, adults, and the elderly. The risk of developing mental status changes secondary to anticholinergic ophthalmic medications is of particular concern in the elderly. Drug-induced mental status or behavior changes should not be mistaken for exacerbation of an underlying disorder or the onset of a new disease (e.g., Alzheimer's disease, dementia). Clinicians should be aware of these potential complications, monitor for changes in mental status, and take appropriate action.

Absorption↗

A rat mammary tumor model induced by the organophosphorous pesticides parathion and malathion, possibly through acetylcholinesterase inhibition.

Environmental chemicals may be involved in the etiology of breast cancers. Many studies have addressed the association between cancer in humans and agricultural pesticide exposure. Organophosphorous pesticides have been used extensively to control mosquito plagues. Parathion and malathion are organophosphorous pesticides extensively used to control a wide range of sucking and chewing pests of field crops, fruits, and vegetables. They have many structural similarities with naturally occurring compounds, and their primary target of action in insects is the nervous system; they inhibit the release of the enzyme acetylcholinesterase at the synaptic junction. Eserine, parathion, and malathion are cholinesterase inhibitors responsible for the hydrolysis of body choline esters, including acetylcholine at cholinergic synapses. Atropine, a parasympatholytic alkaloid, is used as an antidote to acetylcholinesterase inhibitors. The aim of this study was to examine whether pesticides were able to induce malignant transformation of the rat mammary gland and to determine whether alterations induced by these substances increase the cholinergic activation influencing such transformation. These results showed that eserine, parathion, and malathion increased cell proliferation of terminal end buds of the 44-day-old mammary gland of rats, followed by formation of 8.6, 14.3, and 24.3% of mammary carcinomas, respectively, after about 28 months. At the same time, acetylcholinesterase activity decreased in the serum of these animals from 9.78 +/- 0.78 U/mL in the control animals to 3.05 +/- 0.06 U/mL; 2.57 +/- 0.15 U/mL; and 3.88 +/- 0.44 U/mL in the eserine-, parathion-, and malathion-treated groups, respectively. However, atropine alone induced a significant (p < 0.05) decrease in the acetylcholinesterase activity from the control value of 9.78 +/- 0.78 to 4.38 +/- 0.10 for atropine alone, to 1.32 +/- 0.06 for atropine in combination with eserine, and 2.39 +/- 0.29 for atropine with malathion, and there was no mammary tumor formation. These results indicate that organophosphorous pesticides induce changes in the epithelium of mammary gland influencing the process of carcinogenesis, and such alterations occur at the level of nervous system by increasing the cholinergic stimulation.

Acetylcholinesterase↗

Pharmacotherapy of nasal disease.

Rhinitis may be classified as infectious (purulent), seasonal allergic, perennial allergic, perennial nonallergic (vasomotor) and nasal polyps. Pharmacotherapy can be local or systemic. A variety of compounds are available, including alpha adrenergic agonists, mast cell stabilizing agents, Beta-2 agonists, antihistamines, cholinergic antagonists and corticosteroids. In terms of histamine receptors, H1 receptors predominate in the epithelium and glands but both H1 and H2 receptors are present in nasal blood vessels. Trigeminus-reflex mediated nasal secretions, can be treated by parasympatholytic drugs.

Adrenergic alpha-Agonists↗

[Acupuncture - has it a demonstrable bronchospasmolytic effect in bronchial asthma (author's transl)].

In 12 patients with bronchial asthma the effects of acupuncture (45 tests altogether) on airway resistance have been investigated. In 9 patients there was a significant decrease of airway resistance 10 minutes, 1 hour and 2 hours after the end of acupuncture. The lowest level for airway resistance (70,1% of control value) was reached during the first hour after acupuncture. The possibility of a merely suggestive effect could be excluded, because "placebo-acupunctures" did not change airway resistance significantly. The comparison with a parasympatholytic acting drug as a metered aerosol (Atrovent) demonstrated that acupuncture had a some-what weaker bronchospasmolytic effect. 3 patients showed after repeated acupunctures no reaction whatever.

Acupuncture Therapy↗

Organophosphorous pesticides in breast cancer progression.

Environmental substances may be involved in the etiology of breast cancers. Many studies have found an association between cancer in humans and exposure to agricultural pesticides. Organophosphorous pesticides have been used to control mosquito plagues. Parathion and malathion, organophosphorous pesticides are cholinesterase inhibitors responsible for the hydrolysis of body choline esters, including acetylcholine at cholinergic synapses. Their primary target of action in insects is the nervous system whereby they inhibit the enzyme acetylcholinesterase at synaptic junction. Atropine is a parasympatholytic alkaloid used as an antidote to acetylcholinesterase inhibitors. We have established an experimental breast cancer model, where epithelial cells in the rat mammary gland underwent a stepwise transformation into malignant cells by exposure to pesticides (Cabello et al, 2001). The aim of this work was to examine whether pesticides were able to induce progression of malignant transformation of a human breast epithelial cell line, MCF7. These results showed that parathion and malathion increased PCNA and induced mutant p53 protein expression of MCF7 cells in comparison to controls and atropine inhibited such action. These results indicated that organophosphorous pesticides can induce more changes in this malignant breast cell line, inducing another step in the progression of the transformation process and atropine on the other hand inhibited the effect of such substances.

Adenocarcinoma↗

Studies on the metabolic clearance of ciclotropium to alpha-phenylciclopentylacetic acid using a new enantiospecific metabolite assay.

Ester hydrolysis represents an important biotransformation pathway for various parasympatholytic agents. Cleavage of the ciclotropium ester bond results in the formation of alpha-phenylciclopentylacetic acid (PCA). The relevance of this metabolic route for ciclotropium bromide (HIT-PCE, CAS 85166-20-7) including its stereochemical aspects was studied in a preliminary pharmacokinetic study. An enantiospecific assay for biological material was developed that is based on chiral derivatization of PCA with N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide (EDAC) and the primary amine S-FLOPA, a chiral coupling component for carboxylic acids derived from S-flunoxaprofen, followed by HPLC resolution. R-(--)-Ibuprofen was used as internal standard. From plasma or urine PCA can be extracted into n-hexane/ethanol (9:1) at pH 4 under addition of sodium chloride. Derivatization with EDAC/FLOPA was performed under addition of 1-hydroxybenzotriazole in anhydrous dichloromethane that contained trace amounts of pyridine (ambient temperature; 2 h reaction time). The chromatographic separation was performed on a silica gel stationary phase (Zorbax Sil) using n-hexane-chloroform-ethanol (100:10:1, by vol.) as mobile phase (flow rate, 2 ml/min; fluorescence-detection, 305/355 nm; elution order of the derivatives, (-) before (+)). Limit of quantification was 1.0 ng/ml for plasma and 10 ng/ml for urine. In the pharmacokinetic study in two healthy volunteers who received a single i.v. dose of 10 mg ciclotropium race-mate the PCA concentrations in plasma were below the detection limit, but approx. 1.5% of the administered dose were excreted into urine as the respective glucuronides.(ABSTRACT TRUNCATED AT 250 WORDS)

Bridged Bicyclo Compounds, Heterocyclic↗

[Pulmonary artery wedge pressure and heart rate measurement during pharmacological stress induction for left cardial function diagnosis in horses with and without heart disease].

In 18 horses, the pulmonary artery wedge pressure and the heart rate were measured during pharmacological stress load. 12 horses were healthy (4 trained, 8 untrained) and 6 horses had a heart disease (3 trained, 3 untrained). Pharmacological stress induction was carried out with the sympathomimetic drug dobutamine at a dosage rate of 7.5 microg/kg/min over 10 minutes of infusion. At the fourth minute, the parasympatholytic drug atropine was administered (5 microg/kg bw), and the heart rate and the pulmonary artery wedge pressure were continuously measured over 26 minutes. During sole dobutamine infusion, a significant decrease in heart rate and a significant increase in pulmonary artery wedge pressure were observed. After the application of atropine in the fourth minute, a significant increase in heart rate (from 35.7 +/- 6 up to 106 +/- 38/ min) and in pulmonary artery wedge pressure (from 15.7 +/- 3 up to 24 +/- 8.6 mmHg) were visible in the group of healthy horses. The horses with heart diseases had a significantly higher increase in both parameters (heart rate and pulmonary artery wedge pressure) with a significantly positive correlation (r = 0.7). The heart rate increased in the horses with heart diseases from 35.2 +/- 2,8 beats/min up to 132 +/- 45.7 beats/min and the pulmonary artery wedge pressure increased from 17.3 +/- 3,2 mmHg up to 32.7 +/- 13 mmHg. The cardiac status (healthy or heart disease) as well as the training level of the horses (untrained or trained) had a significant influence on the heart rate and the pulmonary artery wedge pressure. The untrained horses (healthy and heart disease) showed significantly higher values over a longer period of time than did the trained horses with the same cardiac status. Additionally the influence of pharmacological stress induction on echocardiographic parameters was investigated. The left atrial size (p = 0.015) and left ventricular diameter were significanly different in the systole (p = 0.008) and in the diastole (p = 0.001) between healthy horses and horses with heart diseases. All horses showed a positive correlation between the pulmonary artery wedge pressure and the left atrial size (r = 0.8), as well as between the left ventricular systolic (r = 0.6) and the diastolic diameter (r = 0.6). The correlation between the pulmonary artery wedge pressure and the left atrial size was nearly the same in the healthy horses (r = 0.74) and in the horses with heart diseases (r = 0.76). Regarding the training level, all untrained horses had a significantly higher correlation between the pulmonary artery wedge pressure and the left atrial size (r = 0.87) in comparison to the trained horses (r = 0.74). Particularly in the untrained horses with heart diseases, this correlation was remarcable (r = 0.99).

Animals↗

[Terodiline in the treatment of stress incontinence in women].

Terodiline combines simultaneously a parasympatholytic and a calcium antagonistic effect and can be used positively for the treatment of urge-incontinence of women. 44 female patients with an urge-incontinence have been examined urodynamically before and after a six-week treatment with terodiline. After therapy the urodynamic parameters ameliorated significantly. A subjective amelioration or even a healing of the urge symptomatic occurred in 86.4% of the patients. The side effects were minor.

Adult↗