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Background: Chagas disease is a neglected tropical disease. About 6 to 8 million people are chronically infected and 10% to 15% develop irreversible gastrointestinal disorders, including megaesophagus. Treatment focuses on improving symptoms, and isosorbide and nifedipine may be used for this purpose., Methodology: We conducted a systematic review to evaluate the effectiveness of pharmacological treatment for Chagas' megaesophagus. We searched MEDLINE, Embase and LILACS databases up to January 2018. We included both observational studies and RCTs evaluating the effects of isosorbide or nifedipine in adult patients with Chagas' megaesophagus. Two reviewers screened titles and abstracts, selected eligible studies and extracted data. We assessed the risk of bias using NIH 'Quality Assessment Tool for Before-After (Pre-Post) Studies with No Control Group' and RoB 2.0 tool. Overall quality of evidence was assessed using GRADE., Principal Findings: We included eight studies (four crossover RCTs, four before-after studies). Three studies evaluated the effect of isosorbide on lower esophageal sphincter pressure (LESP), showing a significant reduction (mean difference -10.52mmHg, 95%CI -13.57 to-7.47, very low quality of evidence). Three studies reported the effect of isosorbide on esophageal emptying, showing a decrease in esophageal retention rates (mean difference -22.16%, 95%CI -29.94 to -14.38, low quality of evidence). In one study, patients on isosorbide reported improvement in the frequency and severity of dysphagia (moderate quality of evidence). Studies evaluating nifedipine observed a decrease in LESP but no effect on esophageal emptying (very low and low quality of evidence, respectively). Isosorbide had a higher incidence of headache as a side effect than nifedipine., Conclusions: Although limited, available evidence shows that both isosorbide and nifedipine are effective in reducing esophageal symptoms. Isosorbide appears to be more effective, and its use is supported by a larger number of studies; nifedipine, however, appears to have a better tolerability profile., Trial Registration: PROSPERO CRD42017055143. ClinicalTrials.gov CRD42017055143., Competing Interests: The authors have declared that no competing interests exist.

Background: The rationale for medical therapy of initial achalasia and the results obtained over the last 20 years in our laboratory are presented., Methods: Achalasic patients were selected as candidates for medical therapy on the basis of the presence of a slight esophageal dilation (<5 cm) on X-rays and a good manometric response to nifedipine administration. These patients were asked to take 10-20 mg of nifedipine sublingually 30-45 min before each meal for 2 weeks. Chronic medical therapy was continued only in those with an 'excellent' or 'good' clinical response to nifedipine and a lack of severe side effects. X-ray controls were planned every 6 months and manometric examination after the first 6 months., Results: Of the 56 patients selected in the above-mentioned manner, 17 had an insufficient clinical response or severe side effects during the initial trial and did not continue medical therapy. Of the 39 patients who started chronic medical treatment, 13 are still on therapy and 26 stopped after an average of 2.8 years: 17 because they underwent dilation or myotomy; 4 for unknown reasons, and 5 apparently recovered. Esophageal manometry was carried out in 4 of the latter patients and revealed that the achalasic motor pattern had been replaced by a near-normal pattern., Conclusions: We believe that medical treatment of achalasia should be carried out not only in those patients who cannot undergo invasive procedures or do not respond well to them, but also in patients with initial achalasia selected using the above-mentioned criteria, because regression of the disease could take place in some of them.

Oesophageal motor activity was recorded manometrically with a low compliance system in 16 patients with achalasia and a slightly dilated oesophagus. After a basal recording period, nifedipine 20 mg was given sublingually to 9 patients and isosorbide dinitrate 5 mg to another 7 patients. Lower oesophageal sphincter pressure (LESp) and oesophageal body pressure wave amplitude were measured for 60 min after drug administration. Both drugs decreased LESp and pressure wave amplitude, but the effect of isosorbide dinitrate was faster and more intense than that of nifedipine. There was a lower inhibitory effect of nifedipine on the amplitude of pressure waves than on LESp, while isosorbide dinitrate inhibited with a similar intensity both LESp and pressure waves.

This study was carried out to demonstrate the possible return of esophageal peristalsis in patients affected by esophageal achalasia chronically treated with sublingual nifedipine and to investigate which parameters are correlated with the return of peristalsis. Thirty-two patients were treated with sublingual nifedipine 10-20 mg taken 30 min before meals. A clinical and manometric evaluation was performed before and after 6 months of therapy. Before treatment, in no patient was peristaltic activity recorded. After 6 months, peristalsis was observed in six patients. In this group, no pretreatment manometric parameter was different from that of the remaining achalasic patients; only the clinical history of dysphagia was significantly shorter (p < 0.001) and the esophageal diameter significantly less (p < 0.001). In conclusion, chronic treatment with sublingual nifedipine can induce a return of esophageal peristalsis in patients with a short clinical history of disease and slightly dilated esophagus.

The effects of sublingual nifedipine and isosorbide dinitrate on oesophageal emptying were compared in 11 patients with Chagasic achalasia. The oesophageal emptying of a radiolabelled test meal was assessed three times in each patient by a scintigraphic technique. No treatment preceded one of the studies (basal study). Nifedipine (20 mg) by the sublingual route 30 min before the meal, preceded one study. Isosorbide dinitrate, 5 mg by the sublingual route 5 min before the meal, preceded the third study. The order of the studies was allocated randomly for each patient. Oesophageal retention at the completion of the meal was significantly less (P less than 0.01) after isosorbide dinitrate (median: 54%, range: 5-87%) than after sublingual nifedipine (median: 78%, range: 7-99%) or after the control study (median: 83%, range: 5-100%). This difference persisted up to 20 min after the meal. Values measured in the control study and after sublingual nifedipine were not different (P greater than 0.10). These results show that isosorbide dinitrate, but not sublingual nifedipine, enhances oesophageal emptying in Chagasic achalasia.

Calcium channel blockers have been previously shown to decrease lower esophageal sphincter (LES) pressure and improve symptoms in achalasia. We performed a placebo-controlled, double-blind, crossover study to assess the effects of oral nifedipine and verapamil on LES pressure, amplitude of esophageal body contraction, and clinical symptomatology in eight patients with symptomatic achalasia diagnosed by endoscopy, barium swallow, and manometry. Patients were randomized to receive up to 20 mg nifedipine, 160 mg verapamil, or placebo and underwent esophageal manometry before (baseline) and after four weeks on each drug. Diary cards were kept to record and grade symptoms and drug plasma level determinations were correlated with manometric and clinical findings. Both nifedipine and verapamil caused a statistically significant decrease in mean LES pressure, but only nifedipine caused a significant decrease in the amplitude of contractions of the smooth muscle portion of the esophagus. No statistically significant differences in the overall clinical symptomatology were noted with any of the drugs, although some individual improvements in dysphagia and chest pain were noted. We conclude that, despite the reduction in LES pressure and contraction amplitude of the distal esophageal body, oral nifedipine and verapamil do not significantly alter the clinical symptomatology of patients with achalasia.

We studied the esophageal effects of nifedipine in 20 patients with achalasia (20 mg sublingually) and nine patients with high-amplitude peristaltic esophageal contractions (nutcracker esophagus) (20 mg orally). In patients with achalasia, nifedipine decreased lower esophageal sphincter (LES) pressure by approximately 30%. In ten patients with achalasia, plasma nifedipine concentrations were 45.3 +/- 17.7 and 57.4 +/- 12.8 ng/mL (means +/- SEM) at 30 and 60 minutes, respectively, after drug administration. In patients with nutcracker esophagus, nifedipine decreased LES pressure by approximately 50% and contraction amplitude in the body of the esophagus by approximately 25%. After comparison was made with our previous results in normal subjects, we concluded that (1) nifedipine decreased LES pressure in patients with achalasia to a similar extent to that noted in normal subjects; (2) plasma concentrations measured after 20 mg of nifedipine given sublingually to achalasic patients were similar to those found under similar circumstances in normal subjects; and (3) nifedipine decreased LES pressure and contraction amplitude in patients with nutcracker esophagus to a greater extent than was found in normal subjects. These results suggest that double-blind, placebo-controlled clinical trials of nifedipine in the treatment of achalasia or nutcracker esophagus are indicated.

The effects of sublingual isosorbide dinitrate (5 mg) and nifedipine (20 mg) were compared in 15 patients with achalasia. The parameters examined included the manometric measurement of the lower esophageal sphincter pressure, the radionuclide assessment of esophageal emptying and the clinical response. The mean basal lower esophageal sphincter pressure fell significantly after both drugs (p less than 0.01), with a maximum fall of 63.5% 10 min after receiving isosorbide dinitrate, but by only 46.7% 30 min after nifedipine. The esophageal radionuclide test meal retention was significantly less (p less than 0.01) only after receiving isosorbide dinitrate. The drug improved initial esophageal emptying by its effect on the lower esophageal sphincter and by relieving the test meal hold-up noted to occur at the junction of the upper and midesophagus. Eight patients cleared their test meal within 10 min after isosorbide dinitrate administration while only two did so after nifedipine. Subjectively, 13 patients had their dysphagia relieved by isosorbide dinitrate and 8 by nifedipine. However, this relief was not confirmed in 4 patients by the radionuclide study and they, as well as the other 3 patients who did not respond to therapy, were referred to pneumatic dilatation. Side effects were more prominent after nitrates. Three of the patients are currently receiving nifedipine and 5 patients received isosorbide dinitrate therapy for 8-14 mo. The radionuclide test meal is currently the best way of objectively evaluating drug therapy in patients with achalasia. Isosorbide dinitrate is more effective than nifedipine in relieving their symptoms.

We described an 84-year-old woman with symptomatic achalasia who refused both dilation and surgical treatment. She was treated with the calcium channel blocking drug nifedipine, with significant relief of symptoms. Objective evidence of response to the drug was confirmed by using an egg salad sandwich meal labeled with 99mTc-DTPA.

The effect of nifedipine on esophageal symptoms was evaluated in 20 patients with primary esophageal motor disorders. The patients were randomized to receive nifedipine (10 mg t.i.d.) or placebo for two weeks, and then crossed over to receive the other medication. Ten patients had hypertensive lower esophageal sphincter, four had diffuse esophageal spasm, three had vigorous achalasia, two had "nutcracker esophagus," and one patient had achalasia. The score of chest pain or dysphagia was recorded on a scale of 0 to 10 during each study. The patients who received nifedipine improved significantly compared to those who received placebo. This improvement was most marked in patients with hypertensive lower esophageal sphincter. No significant side effects or changes in blood pressure were encountered in any of the study groups. Our results indicate that patients with primary esophageal motor disorders have a good clinical response to nifedipine therapy.

Manometric studies have been performed to determine the effect of nifedipine on lower oesophageal sphincter (LOS) pressure and distal oesophageal motility in healthy subjects, in patients with diffuse oesophageal spasm, and in a patient with achalasia. Significant reductions in LOS pressure and in the amplitude of peristaltic oesophageal contractions were observed. In the patients with diffuse oesophageal spasm the amplitude and frequency of non-peristaltic (spasm) contractions were also reduced. Nifedipine did not significantly influence gastric emptying rates of solid and liquid components of a test meal in normal subjects nor in patients who had undergone gastric surgery.

Utilizing the rationale that the calcium channel blocker nifedipine decreases lower esophageal sphincter pressure, we performed a double-blind, placebo-controlled, crossover trial of sublingual nifedipine in achalasia, a disorder whose treatment depends on reduction in lower esophageal sphincter pressure. Ten patients participated in this trial, completed diaries, underwent manometric determinations of lower esophageal sphincter pressure, and had testing of esophageal emptying rates by a solid-meal radionuclide method. Nifedipine, titrated to a dose of 10-30 mg before meals, was well tolerated. Compared with placebo, nifedipine significantly reduced the frequency of dysphagia, but some symptoms of dysphagia, regurgitation, or nocturnal cough were still present most days. Nifedipine significantly reduced lower esophageal sphincter pressure by 28%, a value approximately one-half that achieved by successful pneumatic dilatation or myotomy. Esophageal emptying rates, as determined by the radionuclide method, were unchanged by nifedipine. We concluded that 1) nifedipine reduces symptoms of achalasia, but substantial symptoms do remain during such therapy; 2) the suboptimal effect results from the limited, although statistically significant, effect of nifedipine on reduction of lower esophageal sphincter pressure; and 3) although we believe that nifedipine may be recommended as treatment for achalasia in the subset of patients whose overall medical condition places them at high risk for forceful dilatation or surgery, it cannot be recommended as a standard alternative to these other modalities.

Four adolescents with achalasia were treated with nifedipine. All the patients' symptoms improved dramatically. On manometric evaluation, following oral nifedipine, the lower esophageal sphincter pressure decreased approximately 50%. No change in esophageal peristaltic activity was noted. Side effects were minimal; two patients had mild headache initially. Nifedipine, which is commonly used in adult patients with achalasia, may be beneficial for short-term symptomatic relief in children until more definitive therapy can be performed.

The effect of a new calcium antagonist, nifedipine, which has a spasmolytic activity on smooth muscle cells, was studied on the esophageal function of 20 patients with achalasia of mild and moderate degree. The study was carried out by using constantly perfused catheters and recording the pressure variations at the lower esophageal sphincter, before and after sublingual administration of 10-20 mg of nifedipine. The drug significantly decreased the lower esophageal sphincter pressure for more than 1 h. A clinical trial was also carried out by assessing the improvement of symptoms in achalasia patients taking sublingually a dose of 10-20 mg of nifedipine before each meal. After 6-18 mo of nifedipine therapy these patients underwent a placebo treatment, whereas an additional group of 9 achalasia patients was treated first with placebo followed by nifedipine. The nifedipine treatment gave excellent or good results in a large majority of patients of both groups. The moderate results were only 5 and the poor responses only 3. The clinical improvement induced by nifedipine was statistically significant when compared, not only with the pretreatment clinical state, but also with the results of the placebo treatment. No tachyphylaxis and few side effects were seen either during the manometric recordings or the longest periods of therapy. This study suggests that nifedipine may be advantageously used in the medical treatment of achalasia of mild or moderate degree.

The effect of nifedipine, one of calcium antagonists, was studied on esophageal function of 10 patients with achalasia. Lower esophageal sphincter pressure (LESP) was measured with constantly perfused catheter before and after sublingual administration of 10 mg nifedipine. Nifedipine decreased LESP both in achalasia patients and normal controls except one patient. The fall of LESP by nifedipine seems to correlate with initial resting LESP. A clinical trial of nifedipine on patients with achalasia was carried out taking nifedipine sublingually in a daily dosage of 30 to 60 mg before meal. Nifedipine therapy gave good results in 8 patients, and poor response in one and no effects in one patient. Nifedipine improved symptoms of achalasia, but did not improve the degree of esophageal dilatation. Side effect was observed in only one patient, which was flushing of extremities caused by vasodilation, and it is not hazardous to continue nifedipine therapy. Sublingual administration of nifedipine in patients with achalasia is very useful way of medical treatment in two respects, 1) nifedipine decreases LESP, and 2) sublingual administration does not need to pass through the drug through esophagogastric junction which pressure is abnormally high in achalasia patients.