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Patients seeking medical advice for chronic constipation were investigated over a 24 month period in the outpatient clinics of the participating centres.

Inclusion criteria were patients aged 18–75 years and presenting with chronic constipation, defined in accordance with the Rome diagnostic criteria (less than two bowel movements (bm) a week for at least 12 months or the presence of two or more of the following complaints when laxatives and/or enemas were not used: less than three bowel movements a week; straining at defecation; sense of incomplete evacuation; and hard stools on at least 25% of occasions). Other criteria were: negative tests for organic disorders of the digestive tract; no anorectal lesions; no abnormality at barium enema or colonoscopy; and normal laboratory tests (routine laboratory examinations and serum calcium, phosphorus, T3, T4, and TSH).

Exclusion criteria were: patients not meeting the inclusion criteria; inflammatory bowel disease; pregnant women or women not using effective contraceptive measures; previous surgery on the gastrointestinal tract, except appendicectomy and cholecystectomy; chronic use of drugs affecting gastrointestinal motility; and chronic systemic, metabolic, neurological, and psychiatric illnesses. The study was approved by the local ethics committee. All subjects gave written informed consent.

This was a multicentre (five centres) trial. The study was subdivided into two consecutive periods. In the first initial period of four weeks' duration, all patients received active treatment (PMF-100). In the second period of 20 weeks duration', responders to the initial treatment entered into a trial run according to a randomised, double blind, placebo controlled, parallel group design.

After a medical history and physical examination were performed at visit 1, patients entered the initial four week period during which they were treated with PMF-100 and were instructed to standardise their diet so as to have a mean daily intake of 15 g of fibre and 1500 ml of water and to refrain from laxatives, rectal evacuants, and enemas. Patients who responded at the end of the initial four week period (visit 2) were allocated to receive, in a double blind manner for the following 20 weeks, active treatment with PMF-100 (group I) or placebo (group II), according to a randomisation code independent for each centre. Patients were defined as responders at visit 2 if they referred and reported on the diary card that during the previous two weeks of treatment they had at least 2 bm/week and no other defecatory disturbances or at least 3 bm/week with or without defecatory disturbances.

During the study no other medication was allowed. Laxatives were allowed only when patients had no bowel movements for at least five consecutive days. After each four week period of treatment and at the end of the study, patients were required to attend for a visit (visits 3–7).

At each visit, patients were given 56 sachets for the subsequent four week period and four weekly diary cards on which they reported daily the number of sachets taken, number of evacuations, stool consistency (soft, firm, hard, pellety), straining (absent or present) at defecation, use of laxatives (oral, suppository) or enemas, and the following symptoms: abdominal pain, abdominal bloating, flatulence, borborygmi. The presence of the abdominal symptoms were specifically asked for by the physician who rated them as: absent; mild, not interfering with daily activities; moderate, interfering with daily activities; moderately severe, requiring medication; severe, requiring urgent medical assistance. At visits 2, 3, 4, 5, 6, and 7, patients returned the completed diary cards and the remaining sachets.

At visits 1, 4 and 7, patients underwent a physical examination, and heart frequency and blood pressure were recorded, together with the following laboratory analyses: full blood count, serum concentrations of sodium, potassium, creatinine, glucose, transaminases, and alkaline phosphatases, and BUN. Serum levels of calcium and phosphorus, and ESR were assessed at visit 1.

At visits 2 and 7, patients were asked about tolerability of the PEG solution in terms of taste (pleasant, indifferent, unpleasant); daily volume ingested (low, adequate, excessive); and modality of preparation (easy, difficult).

Active treatment (PMF-100; Normopeg (Selg 250 in Italy), Promefarm Srl Milan, Italy) was supplied as a granular preparation contained in sachets. Each 17.5 g sachet contained the following active ingredients: polyethylene glycol 4000 14.6 g; anhydrous sodium sulphate 1.42 g; sodium bicarbonate 0.42 g; sodium chloride 0.36 g; potassium chloride 0.18 g; simethicone (activated dimethicone) 0.01 g; and orange flavour. Placebo, containing 16.92 g of orange flavoured maltodextrine, was supplied in an identical form, and the smell, colour, and taste of both preparations were similar. Patients were instructed to dissolve the contents of each sachet in 250 ml of water before ingestion. The dose was one sachet twice daily; patients were allowed to reduce the dose to once daily according to bowel movement frequency. In no case were they allowed to increase the dose.

Bowel frequency, straining at defecation, stool consistency, use of oral and rectal laxatives or enemas, and relevant symptoms were collected from data reported on the diary card and assessed at each visit. Bowel frequency was expressed as the number of evacuations per week, and normal frequency was considered to be at least three evacuations per week.

The severity of each symptom was scored by the physician on a five-point scale: absence of symptoms (0), mild (1), moderate (2), moderately severe (3), and very severe (4). The score for each symptom was evaluated separately.

Treatment compliance was assessed by direct interview of the patient, checking the diary cards on which the daily number of sachets taken was recorded, and counting the sachets brought back by the patient at each visit.

To assess the therapeutic effectiveness of PMF-100, the primary criteria were complete remission of constipation consisting of ⩾3 bm/week, no use of laxatives, no straining at defecation, feeling of complete evacuation, and no hard/pellety stools. Secondary criteria were: bowel frequency and normalisation of bowel frequency, use of laxatives, straining at defecation, stool consistency, and presence of other symptoms.

It was hypothesized that patients assigned to the placebo group could more likely interrupt the study than those treated with PMF-100. Thus the number of drop outs caused by no response to treatment was assessed and used as an additional criterium to evaluate the therapeutic effectiveness of PMF-100.

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