Revisão sistemática e metanálise do uso de procinéticos no refluxo gastroesofágico e na doença do refluxo gastroesofágico em Pediatria / Systematic review and meta-analysis of the use of prokinetics in gastroesophageal reflux and in gastroesophageal reflux disease in Pediatrics

OBJETIVO: Avaliar, por meio de revisão sistemática e metanálise, estudos randomizados que comparam os procinéticos domperidona, bromoprida, metoclopramida e betanecol ao placebo no tratamento do refluxo gastroesofágico (RGE) e da doença do refluxo gastroesofágico (DRGE) em crianças. MÉTODOS: BUsca bibliográfica de ensaios clínicos randomizados (Medline, EMBASE, Biological Abstracts, ISI/Web of Science, CINAHL, Lilacs e Cochrane). O desfecho primário foi eficácia na modificação dos sintomas de refluxo, conforme definição de autores das fontes primárias. Outras variáveis de interesse foram: complicações relacionadas ao RGE, alterações nos exames laboratoriais de controle, qualidade de vida, eventos adversos e abandono do tratamento. RESULTADOS: Foram incluídos quatro estudos com domperidona, dois com metoclopramida, um com betanecol. Nenhum estudo com bromoprida foi localizado. O risco de não resposta ao tratamento foi significativamente menor para os procinéticos quando comparados ao placebo (RR 0,35; IC95 por cento 0,14-0,88). A vantagem terapêutica individual em relação ao placebo se manteve para a domperidona (n=126; RR 0,27; IC95 por cento 0,14-0,52; NNT 3; I2 0 por cento) e betanecol (n=44, RR 0,19, IC95 por cento 0,05-0,55, NNT 2), mas não para metoclopramida (n=71; RR 0,63; IC95 por cento 0,07-5,71, I2 92,2 por cento). CONCLUSÕES: A evidência para o uso de procinéticos no RGE e na DRGE em crianças é limitada, pois os poucos estudos são ensaios preliminares de resposta em curto prazo e com limitações metodológicas.

OBJECTIVE: To evaluate, by systematic review and meta-analysis, randomized studies comparing the prokinetics (domperidone, bromopride, metoclopramide and bethanechol) to placebo in the treatment of gastroesophagic reflux (GER) and gastroesophagic reflux disease (GERD) in children. METHODS: Bibliographic search for randomized clinical trials (Medline, EMBASE, Biological Abstracts, ISI/Web of Science, CINAHL, Lilacs e Cochrane). The primary outcome was the modification of reflux symptoms. Other outcomes were: GER-related complications, alterations in control exams, life quality, adverse events and abandon of treatment. RESULTS: The metanalysis included four studies on domperidone, two on metoclopramide, and one on bethanechol. No study of bromopride was retrieved. The risk of non-response to the treatment was significantly smaller in children that received prokinetics in comparison to placebo (RR 0.35, 95 percentCI 0.14-0.88). Individual therapeutic advantage regarding placebo was related to domperidone (n=126; RR 0.27; 95 percentCI 0.14-0.52, NNT 3; I2 0 percent) and bethanechol (n=44; RR 0.19; 95 percentCI 0.05-0.55; NNT 2), but not to metoclopramide (n=71; RR 0.63; 95 percentCI 0.07-5.71; I2 92.2 percent). CONCLUSIONS: The evidence for prokinetic use in GER and GERD in children is limited because the few studies report preliminary trials that evaluate short-term responses and show methodological limitations.

The treatment of nonobstructive urinary retention with high-frequency transvaginal electrical stimulation.

The usefulness of timed voiding, cholinergic medications, and high-frequency electrical stimulation in women with symptomatic urinary retention was evaluated. Results indicated that symptomatic urinary retention can be treated with behavioral modification and high-frequency electrical stimulation. Optimal results were found in younger women with stable bladders.

A clinical trial of bethanechol in patients with xerostomia after radiation therapy. A pilot study.

The effects of bethanechol in the treatment of dry mouth were assessed in patients with xerostomia after radiation therapy to the head and neck. Bethanechol possesses muscarinic and nicotinic-cholinergic activity that likely accounts for its mode of action. Bethanechol (25 mg, three times daily) was not associated with significant side effects. Statistically significant increases in whole resting saliva (p = 0.003) and whole stimulated saliva (p = 0.001) were seen. In patients with pretreatment stimulated saliva volumes greater than resting saliva volumes, a positive response to subsequent use of the sialagogue was seen.

Prokinetic agents in postgastrectomy patients.

Postgastrectomy syndromes are uncommon but, unfortunately, frustrating for both patient and physician, because treatment with prokinetic agents is often of limited benefit. This article examines the evidence for efficacy of available prokinetic drugs in the management of these difficult disorders.

Bilateral renal parenchymal malacoplakia presenting as fever of unknown origin: case report and review.

Malacoplakia is a rare inflammatory disorder seen most often in the urinary tract, where it is highly associated with coliform infection. Although first recognized by pathologists in 1902, it has received little attention from the infectious disease community. While there remains much uncertainty regarding the specific cause of malacoplakia, it appears to be associated with a defect in intracellular killing of ingested microorganisms by macrophages. We report a case of bilateral renal parenchymal malacoplakia that presented as fever of unknown origin, and we review 33 previously identified cases. Renal malacoplakia has traditionally been associated with high morbidity and mortality. More recently, treatment with antimicrobial agents such as trimethoprim or ciprofloxacin has yielded a better outcome than had been documented with other therapy. Malacoplakia should be considered in the evaluation of fever of unknown origin or of relapsing or refractory urinary tract infection. Therapy with antimicrobial agents capable of intracellular penetration is recommended.

Cholinergic dysfunction in Shy-Drager syndrome: effect of the parasympathomimetic agent, bethanechol.

To determine the frequency, severity and organ distribution of cholinergic dysfunction in the Shy-Drager syndrome, eleven patients were prospectively studied. In addition to documenting adrenergic insufficiency, a battery of twelve tests was employed to assess cholinergic function. Six tests demonstrated pupillary, lacrimal, salivary, urinary bladder, sexual and sudomotor dysfunction in the majority of patients. Cardiac vagal function as studied by the heart rate response to deep breathing, the Valsalva manoeuvre, cold face test, apnoeic facial immersion and atropine test was affected in all patients. Oesophageal motility was abnormal in six patients. Cholinergic dysfunction in patients with the Shy-Drager syndrome was widespread but of variable severity and distribution. Subcutaneous administration of the parasympathomimetic agent bethanechol demonstrated hyperresponsiveness of lacrimal, salivary, oesophageal, bowel, bladder and sudomotor functions. It is suggested that the Shy-Drager syndrome is primarily a preganglionic cholinergic disorder with transsynaptic degeneration accounting for the development of postganglionic cholinergic as well as adrenergic dysfunction.

Prosexual drugs: empirical status of the "new aphrodisiacs".

The search for an effective aphrodisiac has been a perennial pursuit of most societies throughout history. In the past decade, attention has focused increasingly on the prosexual effects of oral pharmacological agents with central neurotransmitter actions. The role of various dopaminergic, adrenergic, and serotonergic agents, in particular, has been intensively investigated in both human and animal studies. Some of these drugs have been considered for their potential role in the treatment of sexual dysfunction, while others have contributed to our understanding of basic neurophysiological processes in sexual arousal. This review provides a critical evaluation of current laboratory and clinical research on the "new aphrodisiacs," including studies in both patient populations and normal volunteers. Several conceptual and methodological problems are addressed, such as the definition and measurement of sexual response, the need to separate specific and nonspecific drug effects on sexual response, and the lack of studies in women. Although no single drug has proven to be clinically safe and reliably effective for human use, several promising candidates have been identified. Overall, research on prosexual drugs has contributed significantly to our understanding of basic mechanisms in sexual response, as well as providing new treatment options for common sexual disorders.

Treatment of nortriptyline's side effects in elderly patients: a double-blind study of bethanechol.

A double-blind, placebo-controlled study of bethanechol was conducted in 26 elderly depressed patients being treated with nortriptyline. Patients receiving bethanechol had reduced subjective complaints of anticholinergic side effects and showed a trend toward improvement on an objective measure of salivary flow. The potential use of bethanechol in older patients to reduce morbidity and improve compliance with medication regimens is discussed.

Bethanechol in the treatment of stuttering.

A double-blind trial of bethanechol for the treatment of stuttering that used a crossover experimental design failed to find the drug superior to placebo. However, two of the patients who did respond favorably elected to continue with the medication and have remained more fluent after taking the drug for 6 months. The notion of "bethanechol responders" is advanced.

Chronic pulmonary aspiration in children.

According to established diagnostic and therapeutic guidelines for chronic pulmonary aspiration, clinical suspicion is raised by coughing and choking with feeding, coughing during sleep, recurrent pneumonia, failure to thrive, and radiologic signs of chronic lung injury. The upper gastrointestinal series accurately defines anatomy and function, can differentiate between direct and reflux aspiration, and identifies conditions that predispose to aspiration. Gastroesophageal scintigraphy lacks anatomic detail but increases observation time, may differentiate between direct and reflux aspiration, and identifies delayed gastric emptying and gastroesophageal reflux. The lipid-laden macrophage index improves identification of aspiration, but cannot differentiate between direct and reflux aspiration. The esophageal pH probe identifies gastroesophageal reflux. Treatment options include medical therapy (thickened feedings, prone positioning, and metoclopramide) and surgical intervention (gastrostomy, fundoplication, and definitive correction of predisposing conditions). Therapy is determined by severity of illness and results of diagnostic evaluation.

Pilocarpine and other cholinergic drugs in the management of salivary gland dysfunction.

Sialagogues constitute an important component in the management of salivary gland dysfunction. Of the pharmacologic agents available, pilocarpine has been used extensively over the last century. Many clinical trials have documented the efficacy of this alkaloid, with doses that range from 1 to 15 mg normally taken four times a day. There is considerable individual variation in response although it is usually possible, in the presence of sufficient responsive exocrine tissue, to establish a therapeutic regimen that promotes increased salivation without significant side effects.

Nortriptyline in the hospitalized elderly: tolerance and side effect reduction.

This article describes two separate but related studies regarding the use of nortriptyline (NT) in the treatment of depressed elderly inpatients. The first study assesses medication tolerance to NT during the acute treatment of late-life depression. The second describes a placebo-controlled study of the effect of bethanechol in reducing antimuscarinic side effects of NT. Antidepressant pharmacotherapy was considered for 72 patients with late-life depression; 17 (24%) did not receive NT; 5 (7%) because of absolute or relative medical contraindications. Of the 55 patients who started on NT, 9 percent had side effects that necessitated medication discontinuation. A separate sample of 26 elderly depressed patients being treated with NT participated in a double-blind, placebo-controlled trial of bethanechol. Patients receiving bethanechol had reduced subjective complaints of anticholinergic side effects and showed improvement on an objective measure of salivary flow.

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.

Gastroesophageal reflux: diagnosis and management.

The pathologic potential of chronic esophagitis cannot be overemphasized. Persistent reflux causing cycles of mucosal damage followed by healing may eventually lead to end-stage disease, with development of peptic stricture. The most effective drugs available are those that inhibit acid production. Drugs that will enhance lower esophageal function are still in the future.

A syndrome resembling feline dysautonomia (Key-Gaskell syndrome) in a dog.

Dysautonomia, or autonomic nervous system dysfunction, was diagnosed in a 1-year-old dog. Clinical signs of disease included diarrhea, vomiting, prolapse of nictitating membranes, and urinary incontinence. Bilateral keratoconjunctivitis sicca, xerostomia, and decreased anal sphincter tone were also observed. On the basis of response to atropine, results of intradermal histamine testing and gastric motility studies, and ocular response to parasympathomimetics and sympathomimetics (direct and indirect acting), autonomic nervous system function was determined to be abnormal. Treatment with metoclopramide hydrochloride and bethanechol chloride resulted in improved attitude, appetite, Schirmer tear test response, and decrease in frequency of vomiting within 24 hours. Bladder function and anal tone improved within 3 weeks.

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.