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Difenoximide (SC-26100) is closely related to the antidiarrheal agent, diphenoxylate, which is a chemical congener of meperidine. It has been shown to have a greater ability than methadone to suppress opiate withdrawal in addicted mice, and it has produced less physical dependence than morphine and methadone in laboratory animals. In this study difenoximide was administered to nine active heroin addicts. A dose of 4 mg administered 4 times per day for 3 days effectively suppressed opiate withdrawal, while a dose of 8 mg produced symptoms resembling those of narcotic excess in subjects who had recently self-administered heroin. No side effects were observed at the therapeutic dosage level, and the drug was well accepted by subjects. Difenoximide was shown to be a potentially useful narcotic treatment agent in this inpatient study.

Clonidine (0.01 to 0.16 mg/kg) and lofexidine (0.01 to 0.64 mg/kg) produced a dose-dependent inhibition of diarrhea induced by castor oil treatment in the rat. Both drugs were more potent and longer acting than diphenoxylate. Pre- and posttreatment with naloxone (5 mg/kg) failed to prevent or antagonize the antidiarrheal effect of clonidine and lofexidine. These data suggest that clonidine and lofexidine may provide potent antidiarrheal activity of a nonnarcotic nature.

Drug effects on the intestine are traditionally explained in terms of action on the muscle layers and the nerves that control them. This is particularly true in the case of the opioids but research starting two decades ago has identified the intestinal mucosa as the site of action of the antidiarrhoeal opioids. Continued research using the intestinal mucosa offers a fresh approach to solving some old problems. For example it could lead to more confident predictions to be made about the wanted and unwanted effects of opioid drugs on the intestine and may help to find better drug treatments for alleviating withdrawal diarrhoea in addicts. Eventually it may help to explain how the general process of opioid dependence occurs at a cellular level.

The effect on ileostomy function of codeine phosphate, Lomotil, or Isogel was tested in 20 subjects at home living a normal life, studied over two three-day periods on and off treatment. Codeine phosphate 60 mg three times daily was associated with a reduction in the mean total weight of ileostomy output and the ileostomy outputs of water, sodium, and potassium (p < 0·05). The proportion of faecal solids increased on codeine and the effluent appeared thicker but the output of faecal solids remained unchanged. Mean faecal fat increased on codeine. The transit rate from mouth to stoma was slower in four of the five subjects on codeine and a further two subjects withdrew from the trial with temporary intestinal obstruction while on the drug. Lomotil two tablets three times daily was associated with a small and statistically not quite significant fall in the mean total weight of ileostomy output and the ileostomy output of water. Sodium and potassium outputs in the effluent fell on Lomotil (p < 0·05) but the other parameters remained unchanged. Isogel 15 ml three times daily was associated with an increase in the mean total weight of ileostomy output and the ileostomy outputs of water, sodium, potassium, and faecal solids (p < 0·01). Although the effluent looked more viscid on Isogel, the proportion of faecal solids was unchanged. These results suggest that codeine phosphate has a beneficial effect on ileostomy function, reducing the loss of water and electrolytes, while Lomotil has a similar but less effective action in the dosage tested. By contrast, Isogel increases the ileostomy loss of water and electrolytes and will aggravate their depletion in patients with excessive fluid effluents. The increase in faecal fat associated with taking codeine phosphate suggests that it should be stopped before collecting specimens for faecal fat estimations.

The effect of aspirin (ASP), chlorpromazine (CPZ), diphenoxylate (DP), ethylene glycol tetraacetate (EGTA), hydrocortisone (HC), loperamide (LPA), methylprednisolone (MP), phenotolamine mesylate (PTM), propranolol (PR), and trifluoperazine (TPZ) on the secretory activity induced by Escherichia coli heat-stable (ST) enterotoxin in infant mice was studied. LPA and DP, which are used therapeutically for diarrhea, did not inhibit the effect of ST enterotoxin; MP and HC, known inhibitors of cholera enterotoxin, and two adrenergic agents (PR and PTM) had no effect on ST-induced secretory activity. TPZ, EGTA, ASP, and CPZ caused a significant (P

Gastrointestinal physiology, and the pathophysiology, diagnosis, symptoms and treatment of acute and chronic diarrhea are reviewed. Drugs used in the treatment of diarrhea include opiates (morphine, codeine), synthetic anti-diarrheals (diphenoxylate, loperamide), anticholinergics (atropine, propantheline), adsorbents (kaolin, pectin, cholestyramine resin) and Lactobacillus acidophilus. Chronic diarrhea and acute diarrhea caused by microorgansims, drugs and viruses are described. The management of diarrhea can be divided into three categories: (1) supportive therapy (fluid and electrolyte replacement); (2) symptomatic therapy which improves the consistency of the stool and reduces the frequency of bowel movements; and (3) specific therapy aimed at treating the cause (e.g., antibiotics for bacteria-induced diarrhea) or blocking the cellular mechanisms of fluid and electrolyte loss. Most acute diarrheal conditions can be managed successfully by avoiding oral solids and ingesting carbohydrate-electrolyte solutions. Synthetic antidiarrheals may increase the toxicity associated with bacterial diahhrea.

The official compendial USP method for the determination of Diphenoxylate HCI (DPHCI) and Atropine Sulphate (ATSO4) involves extensive sample manipulation followed by non-aqueous titration for (DPHCI) and gas chromatography for (ATSO4). Furthermore, the assay for individual tablets (content uniformity) is not specific. The proposed HPLC methodology offers substantial improvement in sensitivity, specificity and speed. The method provides simultaneous separation with minimum sample manipulation. The total elution time is less than ten minutes. The accuracy of the method was validated by comparing the results with those obtained by applying the USP XX method on commercial tablets. The specificity of the method was confirmed by the results of content uniformity of DPHCI which were more accurate than those obtained by the USP method.

Synthetic antidiarrheal agents like diphenoxylate and loperamide are characterized by strong opiate-like constipating activity with an almost complete lack of central morphinomimetic effects. The present investigation examines the pharmacological mechanisms underlying the action of such compounds.

Methods for the determination of diphenoxylate hydrochloride and atropine sulfate combinations in solutions and powdered tablet composites are presented. A semiautomated assay for diphenoxylate hydrochloride in individual tablets (content uniformity) also is presented. The USP XIX assays for these products are cumbersome and, in the case of solutions, inaccurate due to spectral interferences; the proposed methods offer substantial improvements in sensitivity, specificity, and speed. Results obtained by the USP and proposed methods are compared for several lots of commercial products. The accuracy and precision of the proposed methods are shown by standard recovery studies.

Suppositories of PGE 2 were utilized to induce abortion in 30 midtrimester patients. Side effects were reduced by a combination of premedication and concurrent medication consisting of chlorpromazine and lomotil. All gastrointestinal side effects, including nausea, emesis, and diarrhea, were significantly reduced with this combination of pre- and concurrent medication. Chlorpromazine did not significantly reduce fever in patients receiving PGE 2 .

As no adequate comparison of these widely used drugs has been made, we have performed a double-blind cross-over trial in 30 individuals with chronic diarrhea. Each underwent three randomized treatment periods of 4 wk duration. Patients were instructed to increase the daily dose gradually until control was achieved or side effects became intolerable. Stool frequency, consistency, urgency, and incontinence were then compared when a stable dose was reached. Though 2.3 capsules (4.6 mg) of loperamide, 2.3 capsules (103.5 mg) of codeine and 2.5 capsulses (12.5 mg) of diphenoxylate all reduced stool frequency to the same extent, diphenoxylate was significantly less effective in producing a solid stool. Before treatment 95% of patients experienced urgency, sometimes associated with fecal incontinence, often as their major diability. Loperamide and codeine were more effective in relieving this than was diphenoxylate. Side effects, particularly central nervous effects, were greatest with diphenoxylate and least with loperamide. Approximately equal numbers discontinued each preparation; poor control and central-nervous-system side effects were the usual reasons for stopping diphenoxylate and codeine, and abdominal pain and constipation for stopping loperamide. We conclude that both loperamide and codeine phosphate are superior to diphenoxylate in the symptomatic treatment of chronic diarrhea.

By means of a new behavioral procedure effectively controlling the narcotic stimulus properties of drugs, it was found that the oral administration of fentanyl, morphine, codeine and diphenoxylate produced the narcotic cue. The new antidiarrheal loperamide did not produce this cue in rats as sensitive as being able to detect 0.005 mg/kg s.c. fentanyl. The results are discussed in terms of drug abuse liability.

Abortion was successfully induced in 79 of 80 patients in midtrimester, by the serial administration of 250 microgram of 15 (S)-15 methyl PGF2alpha intramuscularly every second hour until abortion occurred. All 12 patients with missed abortion and 87% of the legal abortion patients aborted within 24 hours. The average period until abortion occurred in the missed abortion group was 8.2 hours (+/- 4.5 SD), and in the legal abortion group 16.4 hours (+/- 7.3 SD). All the patients were given prophylactic treatment for vomiting, using prochlorperazine. The average number of episodes of vomiting was 2.8 per ptient. All but 3 patients were given loperamide or diphenoxylate for "diarrhoea". The average number of episodes of diarrhoea was 2.5 per patient. The frequency of complications was low apart from a case of low uterine rupture.

45 children were admitted to hospital after ingesting varying quantities of diphenoxylate (Lomotil). One died and 44 recovered without any sequelae. Four patients were comatose, 32 were drowsy, and 9 suffered respiratory depression. No correlation was found between ingested dose and the severity of symptoms. Because of its action in rendering the gut atonic, removal of diphenoxylate by gastric lavage is mandatory, even in patients admitted at least 24 hours after drug ingestion. Naloxone is the narcotic antagonist of choice, and should be used in all cases where suspected diphenoxylate poisoning leads to respiratory depression or coma. The use of Lomotil as an antidiarrhoeal agent in children is difficult to justify.

A multicentre trial was conducted to compare Lomotil and Imodium in the treatment of acute non-specific diarrhoea in general practice. A total of eighty-three patients contributed to the study and were randomly allocated to one of the two treatments. No statistically significant differences were found between the drugs in their efficacy and speed of action in alleviating diarrhoea or in their palliative effect on nausea/vomiting and abdominal pain when present.

Fifteen patients with chronic diarrhea and fecal incontinence were admitted to a clinical research center and treated for 3 days with either placebo or diphenoxylate with atropine (Lomotil). The patients were then crossed over to the alternate medication. Lomotil had no effect on rectal or anal sphincter pressure or on continence for saline that had been infused into the rectum. However, Lomotil therapy reduced average stool frequency (from 4.9 to 2.6 times/day) and average stool weight (from 460 to 256 g/day). These results suggest that temporary or intermittent therapy with Lomotil and related drugs might benefit patients with chronic diarrhea and fecal incontinence. They should do this by virtue of a reduction in stool frequency and stool volume, without a deleterious effect on the defense mechanisms against incontinence.

Dihydroergotamine (DHE), an alpha-adrenergic blocking agent, rapidly improved 121 out of 123 diarrheal patients. A hypotonic sigmoid and a hyperreactive rectum were found in these patients. Manometric studies of the distal colon showed that DHE counteracts the rectal hyperactivity and increases sigmoidal tone. On the other hand, anticholinergic drugs and/or emotional stimuli accentuate the rectal hyperactivity of diarrheal patients. Both features could be due to an unbalanced neurologic control of the gastrointestinal tract with dominance of the alpha-adrenergic over the cholinergic activity. Diphenoxylate (DPO) suppressed the diarrhea in two patients not improved by DHE. Furthermore, DPO reinforced the therapeutic success of DHE in 11 lactose intolerance diarrheal patients, suggesting that the two drugs exert their effects by means of different mechanisms.

The distribution of basic drugs in blood differs qualitatively from that of acidic drugs. The binding of racemic, d-methadone, and l-methadone to human plasma and isolated protein fractions was studied by equilibrium dialysis at 37°. In plasma samples from 29 healthy subjects free fraction of dl-methadone was (x% ± SD) 10.62 ± 1.43. There were significant variations among subjects (p < 0.001). The free fraction of the d-isomer was 9.24 ± 1.61% and of the l-isomer, 12.44 ± 1.53%. Plasma albumin concentration and degree of binding do not correlate, but in normal hypoalbuminemic subjects the free fraction of dl-methadone correlates negatively with the concentration of α1-acid glycoprotein (α1-AGP), an acute-phase reactant protein. Percentage dl-methadone bound to purified human serum albumin (HSA) (4.1 gm/dl) was 36.60% (x ± SD). Isolated α1-AGP bound dl-methadone more avidly. As the α1-AGP increased from 0.05 to 2.0 gm/l, free fraction fell from 92.40% to 8.80%. Addition of α1-AGP (0.05 to 2.0 gm/l) to a physiologic concentration of purified HSA or to whole plasma progressively increased methadone binding. In eight monozygotic twin pairs, within-pair differences in binding of dl-methadone were less than in eight dizygotic twin pairs. Less than 20% of naloxone, codeine, morphine, heroin, pentazocine, and diphenoxylate bound to α1-AGP. Elevations of α1-AGP that occur in a variety of diseases may alter the kinetic and pharmacologic activity of methadone. Clinical Pharmacology and Therapeutics (1981) 29, 211–217; doi:10.1038/clpt.1981.34

1. 1. Medical management of narcotic dependence is discussed in terms of etiology, clinical syndrome, diagnosis, and specific treatment including methadone preparations and narcotic antagonists. 2. 2. Narcotic antagonists may prove to be useful in prevention, diagnosis, and treatment (including rehabilitation) of opiate dependence. The pharmacological actions of pure and partial antagonists are presented noting the differential properties that have practical application in helping to control opiate dependence and even prevent the development of a potential narcotic addict.

The antidiarrhoeal effect of difenoxin hydrochloride versus diphenoxylate was studied in a single-blind trial. The results obtained with these substances in the treatment of diarrhoea are described, and the effect of difenoxin hydrochloride on patients with chronic liver diseases is dealt with.

Loperamide, a novel antidiarrheal agent, was compared with diphenoxylate in a double blind crossover study of 23 patients with chronic diarrhea of various etiologies. Both agents were found to be capable of controlling or greatly reducing chronic diarrhea. Loperamide was superior to diphenoxylate in its ability to decrease the frequency and improve the consistency of the stools, even at a 2.5-fold lower dose level.

A series of 4-amino-2,2-diarylbutyronitriles (3) prepared for testing as inhibitors of gastrointestinal propulsive activity did not show any enhancement over such existing agents as diphenoxylate and loperamide. However, conversion of the nitrile group to a 2-methyl-1,3,4-oxadiazol-5-yl function led to compounds 5g and 5j, statistically equipotent to diphenoxylate and loperamide in the mouse and showing a very low order of analgesic activity. Structural modifications determined that the best separation of antipropulsive and analgesic effects was obtained when the amino group was bicyclic and the oxadiazole ring had a 2-methyl substituent. The most potent compounds were and analogues of diphenoxylate and loperamide where the oxadiazole ring was present, but these compounds had marked analgesic activity.

The absorption, excretion, and biotransformation of 14C-diphenoxylate hydrochloride (5 mg. containing 20.2 µc of 14C) when administered orally in ethanolic solution and without the presence of atropine sulfate was studied in 3 men. The mean urinary and fecal excretion of the total label in a 96 hour period was 13.65 ± 1.18 per cent and 49.20 ± 2.24 per cent, respectively. Thin-layer radiochromatographic analysis of the label in excreta indicated extensive biotransformation of the parent drug. In the urine, the maior metabolites were characterized as diphenoxylic acid and hydroxydiphenoxylic acid. These acids were present in both the free and coniugated fractions. Radioactivity in the plasma was associated largely with diphenoxylic acid and to a smaller extent with the unchanged drug. Pharmacokinetic analysis using a one-compartment open model showed a rapid absorption (t½ = 19.7 ± 1.7 minutes; peak level at 2.0 hours) of diphenoxylate followed by its rapid elimination (t½ = 2.50 ± 0.34 hours). The plasma half-life (t½ = 4.38 ± 1.04 hours) of diphenoxylic acid was higher than that of diphenoxylate.

A test was developed to quantify fecal output in rats. Narcotic analgesic (diphenoxylate, morphine), ganglionic blocking (mecamylamine) and anticholinergic drugs (atropine) decreased fecal output. Compounds with direct smooth muscle depressant properties (papaverine, mebeverine) did not alter fecal output. Several other drugs were also evaluated. The rat animal model is useful for assessing the effects of various drugs in altering fecal output.

A 42-year-old woman had dysentery caused by the Shiga bacillus, Shigella dysenteriae type 1, while taking diphenoxylate with atropine during and after her return from a trip to Mexico. Although she was treated with appropriate antibiotics, she suffered a prolonged and toxic acute course followed by intermittent bouts of diarrhea and abdominal cramping which persisted for two years. The risk of confusing Shiga dysentery with ulcerative colitis is illustrated by the presentation, management, and prolonged course of this patient's illness.

All children aged under 15 years admitted to hospital in Newcastle upon Tyne between 1974 and 1981 with a diagnosis of poisoning were studied. After the introduction in 1976 of child resistant containers for salicylates and paracetamol, salicylate poisonings fell dramatically. The other most important medicines to cause poisoning in young children were tricyclic antidepressants, benzodiazapines, Lomotil (diphenoxylate and atropine), and iron preparations; these should also be packaged in child resistant containers by regulation. Few children had symptoms after poisoning with household products, but bleach, turpentine, and paraffin might also be packaged in child resistant containers. The numbers of adolescent girls admitted after deliberate self poisoning and of teenage boys admitted after ingestion of alcohol increased over the study period.

The purpose of the study was to evaluate the validity of a model where intestinal transit is increased and decreased by motility modifying drugs. The measurement of breath hydrogen concentrations after ingestion of lactulose was used to estimate small intestinal transit time. After obtaining base-line values, eight healthy volunteers were pretreated on separate occasions with loperamide, diphenoxylate, metoclopramide and cisapride. Diphenoxylate caused a significant increase in small bowel transit time, whereas both metoclopramide and cisapride significantly shortened it. The H2 breath test therefore seems to accurately reflect the expected transit time. Loperamide did not alter significantly intestinal transit. Possibly this drug counteracts its own delaying influence on small bowel transit by hurrying gastric emptying. Alternatively, not enough time was allowed for it to exert its full effect.

A case study is presented of Lomotil toxicity in a 22-month-old following ingestion of eight to ten tablets (20-25 mg of diphenoxylate and 0.20-0.25 mg of atropine). Early symptoms are those of atropinism, followed later by dangerous central nervous system depression from the second component. Hospitalization, watchful supervision, and intelligent use of opiate antagonists are the essentials of good management.

To the Editor.— A recent report describing a fatal case of pseudomembranous colitis (242:749, 1979) warrants further comments. Antiperistaltic agents such as opiates and diphenoxylate hydrochloride with atropine sulfate (Lomotil) should not be used in pseudomembranous colitis, as these drugs prolong and worsen this condition by retarding the clearance of clostridial toxin in the stool. There are reports in the literature indicating a worse prognosis in patients with pseudomembranous colitis who are given the diphenoxylate and atropine mixture. I strongly believe that use of this drug had a bearing in the fatal outcome of the case in the aforementioned article. Finally, it should be stressed that there is no place for corticosteroids or corticotropin in the treatment of antibiotic-associated colitis. Because of the wide use of the mixture of diphenoxylate and atropine, heightened clinical awareness of its contraindication in pseudomembranous colitis is important.

A double-blind study of 20 patients with ulcerative colitis during treatment with diphenoxylate 5 mg three times daily and placebo is reported. There were two treatment periods of 14 days each, with cross-over technique and randomized sequence. Test variable for constipating effect was the mean number of defaecations per day. The criterion for inclusion of patients was the presence of 4 or more daily bowel movements; 2 patients did not complete the investigation. Significant difference (p less than 0.01) in constipating effect between diphenoxylase and placebo was demonstrated both during a period of 12 days and a period of 6 days (Tables II and III). The average number of bowel movements were reduced by 0.7 and 1.3 per day respectively. Side-effects during treatment with diphenoxylate were seen in 53% (Table III) with significant difference against placebo (p less than 0.05). On the basis of the small absolute reduction of defaecation frequency side-effects, it is concluded that diphenoxylate has no place in the routine treatment of ulcerative colitis.

We assessed the impact of twice daily instillations of 10 ml. liquid diphenoxylate hydrochloride and atropine sulfate (Lomotil) on the dynamics and function of continent urinary reservoirs constructed from intact cecum and ascending colon. Six patients were treated for 1 to 3 weeks at 3 to 8 months postoperatively. The treatments reduced the frequency of spontaneous reservoir contractions, as well as the basal and contraction pressures of the reservoirs. The reservoir capacities were increased modestly. These alterations in reservoir dynamics were accompanied by a decrease in the cramping characteristically associated with reservoir distension and increased intervals between reservoir catheterization. Two patients who had incontinence after initially successful operations regained continence during treatment. No systemic side effects were observed, although dilution of the drug may be required to prevent reservoir irritability. Diphenoxylate hydrochloride and atropine sulfate instillations may prevent acute and possibly long-term pressure-related complications of continent urinary reservoirs constructed from intact cecum and ascending colon.

The intestinal inhibitory activity of 1-(3-cyano-3,3-diphenylpropyl)-4-phenyl-4-piperidine-carboxylic acid ethyl ester (diphenoxylate) after a single oral dose of 5 mg was studied in 10 volunteers with X-ray diagnostic methods. The diphenoxylate treatment lengthened the transit time of the barium sulphate to caecum from 3.2 to 4.3 h. The X-ray cinematography showed the slower duodenal emptying in 5/10 of the subjects, but only in 1 of these the velocity of the peristaltic wave was clearly decreased. The results demonstrate directly the acute inhibitory action of diphenoxylate on intestinal motility with the dose used generally 3--4 times daily for the symptomatic treatment of diarrhoea.