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[Long-term results with timolol].

The results of an 18-month study with Timolol in 36 patients with glaucoma or ocular hypertension are presented. Patients with ocular hypertension were well controlled with Timolol alone, while in the glaucoma group most patients needed combined treatment with a parasympathomimetic drug. Some trends suggest a continuous diminution of the hypotensive effect to Timolol, especially in the glaucoma group. No severe reactions were observed, although slight bradycardia could represent a risk for patients with severe heart conditions. Minor local and systemic side effects are mentioned.

Clinical Trials as Topic↗

Prinzmetal's variant angina. Coronary arteriogram and left ventriculogram during angina attack induced by methacholine.

Recently, in Prinzmetal's variant angina, many cases with normal coronary arteries have been reported. The anginal attacks frequently relapse after aortocoronary bypass grafting. It is frequently possible to induce an anginal attack by parasympathomimetic agents such as methacholine and pilocarpine. In this study, methacholine (0.13 mg per kilogram) was injected subcutaneously in three cases of this disease to induce an angina attack, and coronary arteriograms and left ventriculograms were recorded. In all cases a coronary arterial spasm corresponding to the site of the ST-segment elevation in the electrocardiogram was observed. Complete occlusion due to the spasm was observed even in the normal coronary artery. Asynergy was seen in the left ventricular wall corresponding to the site of the ST-segment elevation in the electrocardiogram.

Angina Pectoris↗

The influence of pilocarpine and biperiden on pH value and calcium, phosphate, and bicarbonate concentrations in saliva during and after radiotherapy for head and neck cancer.

OBJECTIVE: The purpose of the present study was to investigate the influence of parasympathomimetic pilocarpine and anticholinergic biperiden on salivation, pH value, and calcium, phosphate, and bicarbonate concentrations in saliva in patients irradiated for malignant tumors of the head and neck region. STUDY DESIGN: Sixty-nine patients were randomly assigned into 3 groups. Group A consisted of patients receiving pilocarpine, group B of those who were receiving biperiden during radiotherapy and pilocarpine for 6 weeks after its completion, and group C comprised patients receiving neither of the mentioned drugs. The quantity of secreted unstimulated saliva, its pH value, as well as calcium, phosphate, and bicarbonate concentrations in saliva were measured before the beginning of radiotherapy, after 30 Gy of irradiation, at completed irradiation, and 3, 6, and 12 months after completion of radiotherapy. RESULTS: Saliva secretion was found to be the least affected in the group of patients receiving biperiden throughout the course of radiotherapy. One year after completion of therapy, the quantity of secreted saliva could only be measured in the patients receiving biperiden during radiotherapy; it amounted to 16% of the average initial quantity of saliva secreted before the beginning of irradiation. In all 3 groups of patients, mean pH value decreased during radiotherapy and started to increase again after completion of irradiation. In group B the decrease in pH value after radiotherapy was statistically significantly smaller than that in group C (P =.01). During and after irradiation, calcium concentration was increased in all 3 groups of patients. Phosphate concentration decreased during radiotherapy in all 3 groups. In group B it started to increase again 3 months after completion of radiotherapy. Bicarbonate concentration showed a slight increase during radiotherapy and started to decrease again after completion of irradiation. CONCLUSION: The results of our study indicate that the inhibition of saliva secretion during radiotherapy and its stimulation after completion of treatment can contribute not only to some preservation of the quantity of saliva but also to at least partial preservation of its quality in terms of pH value and calcium, phosphate, and bicarbonate concentrations.

Administration, Oral↗

Functional characteristics of dispersed rat submandibular cells.

Rat submandibular gland cells have been obtained through enzymatic dispersion using chromatographically purified collagenase (EC 3.4.24.3) and hyaluronidase (EC 3.2.1.35) and gentle mechanical force. The recovery of viable cells after the isolation procedure was 59% on the basis of total glandular DNA content. Approximately 60% of the total cell population consisted of acinar cells; less than 8% were immature granular duct cells; and the remainder were intercalated duct, striated duct, and myoepithelial cells. Most of the acinar cells were in acinar-intercalated duct complexes. The integrity of the isolated cells was substantiated by their exclusion of trypan blue, intracellular electrolyte composition, incorporation of [14C]glucosamine into trichloroacetic acid + phosphotungstic acid precipitable material at a linear rate for 1.5 hr, secretory responses to parasympathomimetic and sympathomimetic stimulation, and morphologic integrity as determined by light and electron microscopy. The cholinergic receptors were characterized through investigation of the net transmembrane flux of K+ in response to carbamoylcholine. The alpha-adrenergic receptors were characterized by investigating the net transmembrane flux of K+ in response to norepinephrine stimulation and the beta-adrenergic receptors were characterized by determining the rate of secretion of 14C-labeled mucin after isoproterenol stimulation. A high degree of sensitivity to both cholinergic and adrenergic secretagogues was observed.

Animals↗

Acetylcholine, melatonin, and potassium depolarization stimulate release of luteinizing hormone-releasing hormone from rat hypothalamus in vitro.

We have examined the release of radioimmunoassayable luteinizing hormone-releasing hormone (LH-RH) from fragments of rat medial basal hypothalamus. These fragments were cultured overnight in medium containing serum and then preincubated in groups of three for 10 min in medium resembling cerebrospinal fluid in its electrolyte constituents and containing bacitracin. This was followed by 30-min incubation periods during which some of the hypothalami were exposed to test substances. Potassium depolarization, effected by the addition of 56 mM potassium chloride to the incubation medium, caused a marked stimulation in LH-RH release, but only in the presence of calcium. Acetylcholine at 10 nM and the parasympathomimetic anticholinesterase agent neostigmine at 1 microM markedly stimulated LH-RH release. Hexamethonium, a nicotinic antagonist, at 1 microM abolished the acetylcholine-induced increment in LH-RH release. Melatonin, a pineal indolamine, caused significant stimulation of LH-RH release at a concentration as low as 10 nM. Bacitracin (21 microM) was employed in all these experiments. It had no effect on LH-RH release but did prevent the degradation of LH-RH in this system. We conclude that acetylcholine and melatonin are capable of inducing LH-RH release from the rat medial basal hypothalamus. These actions may account for some of the progonadotropic properties previously ascribed to these agents.

Acetylcholine↗

Absorptive and mucus-secreting subclones isolated from a multipotent intestinal cell line (HT-29) provide new models for cell polarity and terminal differentiation.

A clone HT29-18 has been isolated from the parent cell line HT-29, which derived from a human colon adenocarcinoma (Fogh, J., and G. Trempe, 1975, Human Tumor Cells in Vitro, J. Fogh, editor, Plenum Publishing Corp., New York, 115-141). This clone is able to differentiate as the parent cell line does. Differentiation occurs when glucose is replaced by galactose in the culture medium (Pinto, M., M.D. Appay, P. Simon-Assman, G. Chevalier, N. Dracopoli, J. Fogh, and A. Zweibaum, 1982, Biol. Cell., 44:193-196). We demonstrate here that the differentiated cloned population HT29-18/gal is heterogenous: although 90% of the cells show morphological characteristics of "absorptive cells", only 20-30% of them display sucrase-isomaltase in their apical microvillar membranes. About 10% of the entire cell population consists of cells containing mucous granules similar to intestinal goblet cells. We have isolated two subclones, HT29-18-C1 and HT29-18-N2, from the differentiated HT29-18/gal cells. HT29-18-C1 cells show morphological characteristics of polarized absorptive cells, when growing either in glucose- or in galactose-containing media, but the sucrase-isomaltase is not expressed in the cells grown in glucose-containing medium. The clone HT29-18-N2 is also polarized in both culture conditions and is similar to globlet cells in vivo. It grows as a monolayer, exhibits tight junctions, and contains numerous mucous granules whose exocytosis can be triggered by carbachol, a parasympathomimetic drug. We conclude that the clone HT29-18 first isolated was a multipotent cell population from which we isolated several subclones that differentiate either as absorptive (HT29-18-C1) or as mucous (HT29-18-N2) cells. In contrast to the parent HT-29 cell line, the subclones retain most of their differentiated properties in glucose-containing medium.

Adenocarcinoma↗

Polarized secretion of transgene products from salivary glands in vivo.

Previously (Kagami et al. Hum. Gene Ther. 1996;7:2177-2184) we have shown that salivary glands are able to secrete a transgene-encoded protein into serum as well as saliva. This result and other published data suggest that salivary glands may be a useful target site for vectors encoding therapeutic proteins for systemic delivery. The aim of the present study was to assess in vivo if transgene-encoded secretory proteins follow distinct, polarized sorting pathways as has been shown to occur "classically" in cell biological studies in vitro. Four first-generation, E1-, type 5 recombinant adenoviruses were used to deliver different transgenes to a rat submandibular cell line in vitro or to rat submandibular glands in vivo. Subsequently, the secretory distribution of the encoded proteins was determined. Luciferase, which has no signal peptide, served as a cell-associated, negative control and was used to correct for any nonspecific secretory protein release from cells. The three remaining transgene products tested, human tissue kallikrein (hK1), human growth hormone (hGH), and human alpha1-antitrypsin (halpha1AT), were predominantly secreted (>96%) in vitro. Most importantly, in vivo, after a parasympathomimetic secretory stimulus, both hK1 and hGH were secreted primarily in an exocrine manner into saliva. Conversely, halpha1AT was predominantly secreted into the bloodstream, i.e., in an endocrine manner. The aggregate results are consistent with the recognition of signals encoded within the transgenes that result in specific patterns of polarized protein secretion from rat submandibular gland cells in vivo.

Adenoviridae↗

The therapy of Adie's syndrome with dilute pilocarpine hydrochloride solutions.

Impressed by the benefit two patients with Adie's Syndrome derived from topical 0.1% pilocarpine therapy, we performed the present study to examine the measurable effects of 0.1% pilocarpine in several patients with this syndrome. Our study suggests those patients with Adie's Syndrome who lack stereoacuity may benefit from long term therapy with dilute pilocarpine if their stereoacuity may benefit from long term therapy with dilute pilocarpine if their stereoacuity improves following a single drop of 0.1% pilocarpine. Therefore, we recommend measuring stereoacuity during pupil diagnostic testing with 0.1% pilocarpine hydrochloride. Potential problems concerning medical therapy of Adie's Syndrome with parasympathomimetics are discussed.

Adie Syndrome↗

The molecular mode of action of Clostridium perfringens enterotoxin.

While certain strains of Clostridium perfringens have been associated with food poisoning outbreaks for the past 30 years, it has been only during the past 10 years that progress has been made in describing the disease process. And only within the past 5 years has meaningful progress been made in understanding the mechanism by which the disease is caused. Early observations, that the protein enterotoxin can cause erythema, increase capillary permeability, and exhibit parasympathomimetic properties, have been greatly added to in more recent studies. It is now believed tht the enterotoxin can alter intestinal transport of fluid, ions, and glucose, cause tissue damage in the gut and inhibit metabolic processes in intestinal tissue. Furthermore, the enterotoxin is thought to act very quickly (in a matter of minutes, compared to hours for other known enteropathogenic factors) and to affect basic function (macromolecular synthesis) and structure (membrane damage to microvillus brush borders) of individual cells. These findings have opened up many new questions that hopefully, when answered, will further the understanding of how this enterotoxin acts, as well as other enterotoxins being studied today.

Animals↗

Glaucoma and its treatment: a review.

PURPOSE: A review of glaucoma and its treatment is presented. SUMMARY: Glaucoma is a common eye disease that can cause irreversible blindness if left undiagnosed and untreated. Glaucoma is a leading cause of blindness in the United States and other industrialized countries. In most cases, the symptoms of early-stage glaucoma are minimal or nonexistent. There are several different types of glaucoma, and they have been classically divided into the categories of primary or secondary open-angle or angle-closure glaucoma. Secondary forms of glaucoma are caused by various ocular or systemic diseases. Every available treatment to prevent progressive glaucomatous optic neuropathy has potential adverse effects and involves a certain amount of risk and financial expense. Conventional first-line treatment of glaucoma usually begins with the use of a topical selective or nonselective beta-blocker or a topical prostaglandin analog. Second-line drugs of choice include alpha-agonists and topical carbonic anhydrase inhibitors. Parasympathomimetic agents, most commonly pilocarpine, are considered third-line treatment options. For patients who do not respond to antiglaucoma medications, laser trabeculoplasty and incisional surgery are further methods that can be used to lower intraocular pressure. The results of clinical trials have reaffirmed the utility of antiglaucoma medications in slowing the progression of the disease. CONCLUSION: Glaucoma is a common eye disease that is usually associated with an elevated intraocular pressure. Treatment options for patients with glaucoma include medications, laser therapy, and incisional surgery. The risks and benefits of each type of treatment must be carefully considered to maximize the treatment's benefits while minimizing adverse effects.

Administration, Topical↗

Effect of adenosine triphosphate on the accessory pathways.

To determine the site of the anterograde and retrograde conduction in the Wolff-Parkinson-White syndrome (WPW), 40 mg of adenosine triphosphate (ATP) was injected during electrophysiological studies in 53 patients with ventricular preexcitation. In 40 cases, the accessory pathway was evident (group 1) and in 13 cases it was concealed (group 2). In 10 cases in group 1, anterograde conduction was abolished with disappearance of the features of preexcitation. In 7 patients of group 1 and in 4 patients of group 2, retrograde conduction in the accessory pathway was prolonged or abolished. These effects were unexpected because ATP is a parasympathomimetic drug. There was a correlation between the Kent effective refractory period (ERP) and the action of ATP. When the drug did not change the anterograde and retrograde conduction in the Kent bundle, the anterograde accessory pathway ERP was always less than 230 ms. When ATP only decreased retrograde conduction in the Kent bundle, anterograde accessory pathway ERP was always more than 280 ms.

Adenosine Triphosphate↗

Effects of angiotensin converting enzyme inhibition: a clinical point of view.

Angiotensin converting enzyme inhibitors were developed to prevent the in vivo generation of angiotensin II and thereby to reduce peripheral vasoconstriction. However, these compounds exert some additional effects that may or may not be angiotensin dependent. These include potential sodium diuresis, bradykinin accumulation, prostaglandin release, blunting of sympathetic activity, parasympathomimetic actions, central effects, redistribution of blood flow toward some particularly important organs. Only the comprehensive assessment of the many complex interactions that exist between the renin-angiotensin and several other regulatory systems reveals the complete therapeutic profile of this class of pharmacologic agents.

Angiotensin I↗

Spectral analysis of heart rate variability as a quantitative measure of parasympatholytic effect--integrated pharmacokinetics and pharmacodynamics of three anticholinergic drugs.

The time course and concentration-effect relationship of parasympatholytic effects of three anticholinergic drugs were investigated using spectral analysis of heart rate (HR) variability. Single intravenous (i.v.) doses of atropine (10 microg/kg), glycopyrrolate (5 microg/kg), scopolamine (5 microg/kg), and placebo were given to eight healthy volunteers in a double-blind, randomized cross-over study. Electrocardiogram (ECG) was recorded at baseline and 2.5, 5, 10, 20, and 30 minutes, and 1, 1.5, 2, 3, 4, 5, and 6 hours after drug administration, while the subjects breathed at a fixed 0.25 Hz frequency. The powers of two frequency bands (low frequency [LF] = 0.07-0.15 Hz and high frequency [HF] = 0.15-0.40 Hz) were calculated using stationary time series of R-R intervals (RRI) free from ectopic beats. To perform pharmacokinetic-pharmacodynamic (PK-PD) modeling, venous plasma drug concentrations were measured. Atropine and glycopyrrolate, and, to a lesser extent, scopolamine induced decreases in HF power and increases in LF/HF ratio of HR variability, indicating parasympatholytic activity and corresponding changes in sympathovagal balance. Maximal average decreases in HF power were 99%, 94%, and 82%, respectively, but in two scopolamine subjects, a parasympathomimetic effect was dominant. Interindividual variability was least for the Hayano index of HF power (square root (RRI HF-power)/RRI*100), and profound and consistent decreases were seen after atropine and glycopyrrolate. Pharmacokinetics were best fitted to a two-compartment open model, and effect compartment link modeling using the Hayano index was performed with the atropine and glycopyrrolate data. The best description of the PK-PD relationship for both drugs was achieved using the sigmoidal Emax model. Mean (+/-SD) EC50, sigmoidicity factor (gamma), and equilibration rate constant (k(e0)) estimates were 1.35 (+/-0.27) ng/mL, 6.07 (+/-1.98) and 11.0 (+/-5.28) l/h for atropine and 1.35 (+/-0.49) ng/mL, 4.34 (+/-1.55) and 2.26 (+/-0.81) l/h for glycopyrrolate. Spectral analysis of HR variability appears to be a powerful tool in monitoring parasympatholytic drug activity. A sigmoidal Emax model with an extremely steep concentration-response relationship was revealed for atropine and glycopyrrolate. The effects of scopolamine were more incongruous.

Adult↗

Fludarabine induced intestinal pseudo-obstruction: case report and literature review.

Intestinal pseudo-obstruction is a recognized but rare complication of chemotherapy. Vinca alkaloids and cytarabine have been reported to be associated with intestinal pseudo-obstruction. We report a case of fludarabine induced severe intestinal pseudo-obstruction in a 66-year-old man suffering from non-Hodgkin's lymphoma, and describe our successful management of this with a combination of parasympathomimetic and mechanical decompression, after failure of conservative management.

Aged↗

Intravenous naphazoline intoxication.

Nine pale perspiring drug addicts with drowsiness, nausea, headache, normal blood pressure and marked sinus bradycardia with premature ventricular beats were seen at the Casualty Department soon after alleged i.v. cocaine administration. Eight were treated with atropine, as the bradycardia suggested intoxication with a parasympathomimetic compound. Seven were discharged in good condition after a few hours' observation. One patient developed a blood pressure of 150/120 mmHg after atropine. Subsequently, a hemiparesis was found and an intracerebral haematoma was evaluated at surgery. Another patient was admitted forthwith to the CCU. He did not receive any medication and recovered within two days. Urinalysis of these two patients disclosed contents of naphazoline, a powerful alpha-adrenergic agent. Samples of the alleged cocaine contained 97% naphazoline HCl. A conscious rabbit was injected with naphazoline and thereafter with atropine. I.v. naphazoline doubled mean arterial pressure (MAP) and reduced heart rate (HR) from 167 to 30 beats/min. Atropine doubled HR, but caused a marked rise in MAP, too, stressing the adverse effects of atropine in these cases. When confronted with patients after alleged cocaine abuse, the role of substitute drugs, especially alpha-adrenergic compounds, should be considered as this should influence the therapeutic approach.

Adult↗

Effect of sympathetic and parasympathetic mediators on the release of calcitonin gene-related peptide and prostaglandin E from rat dura mater, in vitro.

Although not without controversy, an influence of the autonomic nervous system in headache is a matter for current debate. A possible contact site of autonomic and sensory nerves is the dura mater, where they form a dense network accompanying blood vessels. We investigated interactions between autonomic and nociceptive fibres by measuring release of calcitonin gene-related peptide (CGRP) and prostaglandin E2 (PGE2) from the dura mater, in vitro. The parasympathomimetic agent carbachol did not change basal release of CGRP or PGE2, whereas it diminished release induced by a mixture of inflammatory mediators. Norepinephrine did not change induced release of CGRP or PGE2, nor basal release of CGRP. However, basal release of PGE2 was enhanced by norepinephrine, and this enhancement was reduced by serotonin through 5-HT(1D) receptors. We conclude that sympathetic transmitters may control nociceptor sensitivity via increased basal PGE2 levels, a possible mechanism to facilitate headache generation. Parasympathetic transmitters may reduce enhanced nociceptor activity.

Animals↗

Central nervous system control of intraocular pressure.

Normal intraocular pressure (IOP) is the result of an equilibrium between aqueous humor (AH) production, AH outflow and episcleral venous pressure. Most available antiglaucoma agents produce their effects by interacting with autonomic mechanisms (beta-blockers, epinephrine or parasympathomimetics). In contrast, the role of the central nervous system (brain and nerves) in the regulation of IOP remains unclear in view of the complex haemodynamic, metabolic or hormonal changes which occur under experimental conditions. In this paper, we discuss a basic understanding of the anatomic and physiological relationships between central nervous system and IOP and describe how the brain can affect functions in ciliary body and trabeculum meshwork.

Animals↗

The action of atropine on pancreatic secretion.

The action of atropine, in preventing pancreatic secretion in response to a parasympathomimetic drug, is analysed. Atropine does not appear to affect the uptake of glycine by the pancreatic cell, or the incorporation of radioactive amino acids into the total pancreatic tissue proteins, or into the proteins of the zymogen granules. The rate of amylase resynthesis in stimulated glands is not affected by atropine. It is suggested that atropine blocks pancreatic secretion in rats by blocking the extrusion of zymogen granules.

Amino Acids↗