[Malacoplakia in the ureter and bladder].

We report a case of malacoplakia in the ureter and bladder. A 78-year-old woman was admitted to our department for detailed examination of hydronephrosis. A small-fingertip-sized tumorous yellowish white lesion was detected by cytoscopy at a site that appeared to be the right side of the ureteral orifice. Transurethral resection was performed on the same site. Flat yellowish white protruding lesions were seen at two sites on the right ureter. Michaelis-Gutmann bodies were observed in biopsy specimens from both the bladder and ureter, and a diagnosis of malacoplakia was made. Ascorbic acid and bethanechol chloride were administered postoperatively. Endoscopy performed three months after the operation showed that the protruding lesions in the bladder and ureter had disappeared. Narrowing of the ureter or vesicoureteral reflux has not been seen to date.

Abomasal and duodenal motility in yearling cattle after administration of prokinetic drugs.

Effects of the following treatments on abomasal and duodenal myoelectric activity in yearling cattle were studied: 2 ml of 0.9% sodium chloride solution (NACL); 0.07 mg of bethanechol (BET)/kg of body weight; 0.1 mg of metoclopramide (MET)/kg; and 0.07 mg of bethanechol and 0.1 mg of metoclopramide (BETMET)/kg. All treatments were administered SC during the early part of phase I of the migrating myoelectric complex. Myoelectric signals were recorded for 4 hours after administration of the treatments from 1 electrode in the antrum and 3 electrodes in the duodenum. For the antral spike rate (ASR), there was no significant difference among treatments during the first hour, but the ASR was significantly (P < 0.05) greater during hours 2 to 4 after treatment with BETMET, compared with ASR for MET alone. The duodenal spike rate (DSR) was significantly (P < 0.05) greater during the first hour after administration of BETMET than after the other treatments. After administration of BET, DSR was significantly (P < 0.05) greater than after MET or NACL. There was no difference in DSR after MET, compared with DSR after NACL. There was no significant difference in DSR among treatments during the second and third hours. The total antegrade propagating spike (TAPS) count was greater after administration of BETMET in all hours, compared with the other treatments. The ratio of TAPS to total spikes on the orad-most duodenal electrode was significantly (P < 0.05) greater after BETMET during hours 1 and 2.

[Prostatic malacoplakia: a case report].

We report a case of prostatic malacoplakia in a 68-year-old man complaining of fever, residual urinary sensation and small urinary stream. Culture of the urine showed E. coli and Enterococcus faecalis. Digital examination and transrectal ultrasound of the prostate were most compatible with carcinoma. However, transrectal needle biopsy revealed the histopathological features of malacoplakia. The patient had been treated with trimethoprim-sulfamethoxazole, bethanechol and ascorbic acid for 5 months. Twenty-seven cases of prostatic malacoplakia in the Japanese literature are reviewed.

Cortical biopsy in Alzheimer's disease: diagnostic accuracy and neurochemical, neuropathological, and cognitive correlations. Intraventricular Bethanecol Study Group.

Neurochemical assessments were performed on biopsy samples taken from the right frontal lobe of patients diagnosed with Alzheimer's disease (AD), before the implantation of a ventricular catheter and pump assembly for the infusion of bethanechol chloride as an experimental therapy. The pathologically diagnosed patients with AD (n = 35; mean age, 67 +/- 1.5 yr) were compared with a group of samples from normal age-equivalent autopsied controls (n = 22; mean age, 68 +/- 2 yr) and autopsied AD brains (n = 11; mean age, 73 +/- 2 yr). Samples were assayed for choline acetyltransferase (ChAT), acetylcholinesterase, binding to [3H]quinuclidinyl benzilate as an index of total muscarinic cholinergic binding, and [3H]pirenzepine binding as an index of M1 cholinergic receptor subtype binding. Mean levels of ChAT activity were decreased in the biopsied patients to 36% of age-matched autopsied controls. The loss of ChAT activity correlated significantly with the Mini-Mental State Examination, an index of global cognitive function. Mean ChAT activity in autopsied AD cortex was further decreased compared with controls, indicating continuous decline through the course of the disease. Acetylcholinesterase followed a similar, less dramatic decline. No differences were found in [3H]quinuclidinyl benzilate binding or [3H]pirenzepine binding between biopsied and autopsied controls. Neuritic plaque counts did not correlate with either the Mini-Mental State Examination or ChAT activity in the biopsy specimens.(ABSTRACT TRUNCATED AT 250 WORDS)

L-365,260, a potent CCK-B/gastrin receptor antagonist, suppresses gastric acid secretion induced by histamine and bethanechol as well as pentagastrin in rats.

We evaluated the effects of a potent cholecystokinin (CCK)-B/gastrin receptor antagonist, L-365,260 (3R(+)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin - 3-yl)-N'-( 3-methylphenyl) urea); a selective CCK-A receptor antagonist, devazepide (L-364,718); and cimetidine on gastric acid secretion induced by pentagastrin, histamine and bethanechol in anesthetized rats. We also evaluated the effects of L-365,260 and cimetidine on acid secretion in pylorus-ligated rats. Intravenous administration of L-365,260, L-364,718 and cimetidine dose-dependently reduced acid secretion induced by pentagastrin (20 nmol/kg/hr), with ED50 values of 0.63, 19.1 and 2.5 mumol/kg, respectively. Of interest was the finding that L-365,260, like cimetidine, dose-dependently inhibited acid secretion induced by histamine (100 mumol/kg/hr) and bethanechol (5 mumol/kg/hr) with ED50 values of 5.9 and 4.3 mumol/kg, respectively. L-364,718, even at 30 mumol/kg, i.v., had only a slight effect on histamine- or bethanechol-induced acid secretion. Gastric acid secretion was suppressed by treatment with L-365,260 (3-100 mumol/kg, i.v.) and cimetidine (11.9-396.4 mumol/kg, i.v.) in pylorus-ligated rats, with ED50 values of 13.3 and 96.9 mumol/kg, respectively. These results indicate that L-365,260 suppresses acid secretion induced by histamine and bethanechol in rats and that the gastrin receptor plays an important role in acid secretion in pylorus-ligated rats.

The development of polyanhydrides for drug delivery applications.

This paper reviews the development of the polyanhydrides as bioerodible polymers for drug delivery applications. The topics include design and synthesis of the polymer, physical properties, techniques to fabricate the polymer into drug delivery devices, evaluation of biocompatibility, and example applications of the polyanhydrides. Discussion of the interrelationship between the physical-chemical properties of the polyanhydrides, fabrication methods, and drug release rates is included. One section is devoted to a case study to provide a historical perspective of the development a polyanhydride-based drug delivery treatment from the conception of the idea to the final stages of human clinical trials. This section includes an outline of the extensive in vitro and in vivo testing that is necessary for development of a new material for biomedical applications.

Influence of the bathing medium on the contractile responses of the rabbit urinary bladder.

This study examined contractile responses of the in vitro rabbit whole-bladder preparation to field stimulation, bethanechol and KCl in Tyrode's solution and minimum essential medium (MEM). We found frequency-dependent increases in intravesical pressure in bladders incubated in Tyrode's solution and MEM. However, bladders incubated in MEM consistently responded with greater increases in intravesical pressure compared to those incubated in Tyrode's solution. Similarly, there were frequency-dependent increases in the rate of pressure generation in bladders incubated in Tyrode's solution and MEM, and bladders incubated in MEM responded with greater rates of pressure generation than those incubated in Tyrode's solution at frequencies of 1, 2 and 4 Hz. In addition, there were significant increases in intravesical pressure generated in response to administration of 500 mmol/l bethanechol and 186.4 mmol/l KCl in bladders incubated in MEM compared to Tyrode's solution but no changes in the rate of pressure generation. The influence of L-methionine, one of the constituents of MEM, on the responses of whole bladders to nerve stimulation was also investigated. L-methionine at concentrations of 0.1 and 1.0 mmol/l had no effects on the increase in intravesical pressure or rate of pressure generation following nerve stimulation. It is speculated that the increases in contractile responsiveness of bladders incubated in MEM are related to the combination of amino acids, vitamins and other constituents of the cell culture medium.

Stable bimodal response to cholinomimetic drugs in Alzheimer's disease. Brain mapping correlates.

We investigated quantitative EEG brain mapping as a physiologic marker of drug response while studying the stability of intersubject variability in patients with Alzheimer's disease (AD) who were receiving bethanechol through intracerebroventricular (ICV) shunts. Two of the patients had previously demonstrated cognitive and behavioral improvements on medication; the third had cognitive deterioration complicated by agitated depression. All three patients were reexamined in a dose-response paradigm. Serial brain mapping examinations were performed along with brief cognitive testing. All patients showed drug responses that were comparable with responses during their initial dose-response phase. There were strong linear correlations between global decreases in 2 to 6 Hz slow-wave activity and cognitive improvement. Brain mapping demonstrated that slowing decreased in magnitude and field with increasing dose until optimal dose was reached; with supra-optimal doses, the magnitude and field of the slowing increased dramatically. These results suggest that the quality of cholinomimetic drug responses are stable over time in individual patients, and that magnitude and pattern of slow-wave activity as measured by brain mapping may be useful in monitoring treatment with cholinomimetic agents.

Cumulative dose-response curves for bethanechol-induced electrogenic secretion in rat jejunum in vitro: is tachyphylaxis a significant factor?

Electrogenic secretion was monitored as the short-circuit current (Isc) by an automatic voltage clamp across the isolated rat jejunum incubated in vitro. Responses to consecutive additions of bethanechol (1 mM) to the serosal surface showed tachyphylaxis. Addition of prostaglandin E2, however, after a single dose of 1 mM-bethanechol, induced an undiminished Isc response indicating that the tachyphylaxis was homologous. Dose-response curves for serosal applications of bethanechol obtained by serial-cumulative addition did not show tachyphylaxis when compared with those from a non-cumulative technique. The method of automatically recording the intestinal Isc with serial-cumulative addition of a serosal secretagogue gives dose-response curves free from tachyphylaxis.

Uso de medicamentos proquinéticos del tubo digestivo en niños / Use of prokinetic drugs of the digestive tract in children

Se revisan las bases anatómicas, bioquímicas y neurofisiológicas del aparato digestivo. Asimismo, se analiza la farmacología de las principales drogas con acción procinética a nivel del tracto gastrointestinal, sus indicaciones, efectos secundarios y dosis en pediatría.

[Efficacy of combination of Ea-0643 (bunazosin hydrochloride) and bethanechol chloride in patients with neurogenic bladder].

Bethanechol chloride, a cholinergic agent and bunazosin hydrochloride, an alpha adrenergic blocking agent were administered orally to 28 patients with neurogenic bladder due to peripheral nerve disorders. To compare the effect of the two drugs, one of the drugs was initially administered orally for 2 weeks, and then both of them were administered for the next 2 weeks. Since there were some significant differences in the patient background between the two groups, it was difficult to compare the two drugs. However combined use of these drugs resulted in both objective and subjective good responses in those patients.

Intracerebroventricular bethanechol for Alzheimer's disease. Variable dose-related responses.

Five male patients participated in a pilot open-label study of dose-related aspects of response to intracerebroventricular bethanechol in Alzheimer's disease. No patient had remission of symptoms, but three patients improved symptomatically and on tests of memory. Improvement was evident over a restricted range of doses for each subject, and symptoms were worse at doses below and above the optimal range. There was little overlap in the range of doses producing improvement among these three. Two patients had no consistent improvement in memory, and agitation, depression, paranoia, and seizures developed during treatment. Qualitative differences and variability in dosages producing responses complicate the identification of true drug response in the treatment of Alzheimer's disease.

Evidence for a respiration-modulated cholinergic action on the activity of medullary respiration-related neurons in the rabbit. An iontophoretic study.

Effects of the iontophoretically administered cholinergic agonists acetylcholine, bethanechol and DMPP on the activity of medullary respiration-related neurons were examined in urethane-anaesthetized rabbits. Inhibitory effects prevailed over excitatory effects. Analysis of cholinergic effects by cycle-triggered averaging revealed three major types of neuronal responses: (i) constant alterations of spike-density throughout the whole period of activity ("constant effects"), (ii) effects increasing during the progression of the burst of discharge or effects restricted to a particular fraction of the burst ("phasic effects") and (iii) effects which were characterized by an excitation during one respiratory phase and an inhibition during the other phase ("bi-phasic effects"). The latter type of effects was observed in phase-spanning respiration-related neurons. Phasic effects were mainly observed in inspiration-related neurons which were predominantly inhibited by stimulation of muscarinic receptors. Inspiratory R beta-neurons in no case were phasically affected by cholinergic agents. The mean muscarinic inhibition of inspiration-related neurons increased with the progression of inspiration. The mean nicotinic inhibition of expiration-related neurons decreased with the progression of expiration. Results suggest that the efficacy of (i) a central inspiration terminating mechanism and (ii) the onset of discharge of expiratory neurons is modulated by acetylcholine.

Intracerebroventricular bethanechol chloride infusion in Alzheimer's disease. Results of a collaborative double-blind study.

The use of intracerebroventricular bethanechol chloride infusion in patients with Alzheimer's disease was first reported in 1984. An initial trial in four patients demonstrated the feasibility of this approach for cholinergic drug delivery to the brain, but objective improvement in cognitive function was not documented. A collaborative placebo-controlled double-blind crossover study has now been carried out in 49 patients with biopsy-documented Alzheimer's disease. The results demonstrate a statistical improvement in Mini-Mental State scores and significantly slower performance on Trails A testing during drug infusion. Other neuropsychological test scores were not similarly affected. The degree of improvement was not sufficient to justify further treatment of Alzheimer's disease patients by intracerebroventricular infusion of bethanechol chloride. The drug delivery system used in the study was well tolerated, with two irreversible complications in more than 50,000 patient days.

The necessity of human trials of putative therapies for Alzheimer's disease.

The absence of a suitable animal model for Alzheimer's disease leaves therapeutic trials in human subjects as a necessity. Reasonable criteria can be formulated for deciding which therapies should be tested. Scientific rationale and likelihood of success should be major considerations. Novel approaches of delivering drugs to the central nervous system should not be discouraged so long as complication rates can be shown to be low.

Novel CNS-directed drug delivery systems in Alzheimer's disease and other neurological disorders.

Increasing knowledge of the neurochemical aspects of central nervous system function raises the possibility of treating Alzheimer's disease (AD) and other neurological diseases by the appropriate manipulation of neurotransmitters, neuromodulators, neurohormones or neurotrophic factors. Clinical application of this knowledge may, however, be inhibited by long standing problems with drug delivery to the central nervous system (CNS). Novel, CNS-directed, drug delivery systems might be used to overcome many of these problems. The problems encountered in drug delivery to the brain, present experience with the clinical use of some novel drug delivery systems and the advantages and disadvantages of these systems will be discussed.

Methodological considerations in cognitive disorders or: "the baby needs enough bath water".

Establishing treatment efficacy for neuropsychiatric disorders is an often protracted process due to vagaries of symptoms, course, and probably the inherent variability of the central nervous system. No single study design is likely to be definitive. Thorough evaluation of intracranial drug infusion for illnesses such as Alzheimer's Disease will require extended, multidisciplinary work before true evaluation can confidently be made.

Evidence for cholinergic modulation of aldosterone secretion in man.

Acetylcholine stimulates aldosterone secretion in bovine glomerulosa cells in vitro via specific cholinergic receptors. In this study we examined the effect of peripheral muscarinic blockade with atropine on metoclopramide-, angiotensin-II-, and ACTH-stimulated aldosterone secretion in man. Atropine (0.6 mg, iv) administered 10 min before MCP delayed the onset of the plasma aldosterone response and attenuated the mean peak response from 502 +/- 103 (+/- SE) to 322 +/- 72 pmol/L (P less than 0.05) without affecting zero time mean plasma aldosterone levels (144 +/- 28 vs. 136 +/- 36 pmol/L for control and atropine, respectively). This inhibitory effect was not mediated by changes in PRA or plasma potassium or ACTH (as reflected by cortisol) concentrations. Atropine also attenuated the plasma aldosterone response to a low dose angiotensin II infusion (2 ng/kg.min; control, 449 +/- 99 pmol/L; atropine, 297 +/- 78 pmol/L; P less than 0.05). In contrast, atropine had no effect on the plasma aldosterone response to a bolus dose (250 micrograms) of ACTH. Neither atropine (0.6 mg, iv) nor the cholinergic muscarinic agonist bethanechol (5 mg, sc) alone elicited a change in plasma aldosterone. Collectively, these data provide evidence for cholinergic modulation of aldosterone secretion in man. We conclude that cholinergic mechanisms may facilitate the aldosterone responses to angiotensin-II and metoclopramide, but not to ACTH.

Intracerebral drug delivery in rats with lesion-induced memory deficits.

Pharmacological treatments directed at increasing cortical acetylcholine activity in patients with Alzheimer's disease have largely been disappointing, perhaps because denervated areas of brain may not be exposed to adequate amounts of drug. A new method has been developed to enable localized intracerebral delivery of neurotransmitter substances using a polymeric drug delivery system. Microspheres of a polyanhydride sebacic acid copolymer were impregnated with bethanechol, an acetylcholinesterase-resistant cholinomimetic. Twenty rats received bilateral fimbria-fornix lesions, producing cholinergic denervation of the hippocampus and marked impairment in spatial memory. The animals were trained for 2 weeks to run after which they received bilateral intrahippocampal implants of saline (five rats), blank polymer (five rats), or bethanechol-impregnated polymer (10 rats). Following implantation, spatial memory was assessed by radial-maze performance testing for 40 days. Untreated lesioned rats showed persistently poor spatial memory, entering maze arms with near random frequency. Similarly, animals treated with saline and blank polymer did not improve after implantation. Rats treated with bethanechol-impregnated microspheres, however displayed significant improvement within 10 days after implantation; this improvement persisted for the duration of the experiment (p less than 0.05, Student's t-test). Histological analysis of regional acetylcholinesterase staining showed widespread loss of activity throughout the hippocampus bilaterally in all animals. The microsphere implants were visible within the hippocampus, with minimal reactive changes in surrounding brain. It is concluded that intracerebral polymeric drug delivery successfully reversed lesion-induced memory deficits, and has potential as a neurosurgical treatment method for Alzheimer's disease and other neurodegenerative disorders.

Substance P and vasoactive intestinal peptide influence polyamine metabolism in salivary glands of the rat.

In parotid, sublingual and submaxillary glands stimulated by continuous intravenous infusion of the neuropeptides substance P or vasoactive intestinal peptide at various doses for 3 h, the concentrations of the polyamines putrescine, spermidine, spermine and N1-acetylspermidine as well as the activity of ornithine decarboxylase were determined. This enzyme catalyses the synthesis of putrescine and is the key enzyme in polyamine formation. Vasoactive intestinal peptide induced the most marked effects, and the most conspicuous findings were made in the sublingual glands, where the ornithine decarboxylase activity was found to have increased more than 100-fold, accompanied by an increased level of putrescine in those glands which were removed immediately after the end of the infusion. When, instead, the glands were removed 5 h after the end of the infusion there was no longer any increase in the activity of ornithine decarboxylase or in putrescine concentration, but now spermidine and spermine were found to be increased. Interestingly, the parasympathetic non-adrenergic, non-cholinergic regulation of polyamine metabolism in the major salivary glands of the rat is most predominant in the sublingual glands.