PrDICETEL(r)
50 mg & 100 mg film-coated tablets Gastrointestinal calcium antagonist Date of Revision: September 7, 2007 Control #: 114792
PrDICETEL(r) (Pinaverium Bromide) 50 mg & 100 mg film-coated tablets
Gastrointestinal calcium antagonist
(pinaverium bromide) is a calcium antagonist which inhibits the calcium influx by blocking the voltage-dependent calcium channel at the smooth muscle cell level. It possesses a high degree of selectivity for the intestinal smooth muscle.
Many studies showed that pinaverium bromide induces a relaxation of the gastrointestinal and the biliary tracts and mainly of the colon, an inhibition of the motor colonic response to food and/or pharmacological stimulations, implying the action of the drug in irritable bowel syndrome. 4,9,37,47
DICETEL(r)
(pinaverium bromide) is indicated:
for the treatment and relief of symptoms associated with irritable bowel syndrome (IBS): abdominal pain, bowel disturbances and intestinal discomfort. for the treatment of symptoms related to functional disorders of the biliary tract.
(pinaverium bromide) is contraindicated in patients with known hypersensitivity to pinaverium bromide or any of the excipients.
No other contraindications have been identified at this time.
Contact of DICETEL(r) (pinaverium bromide) with the oesophageal mucosa may be irritating. Therefore, it is strongly recommended that the tablet be taken with a glass of water during mealtime. The tablet must be swallowed without being chewed or sucked. If more than three tablets are prescribed per day, the additional tablet(s) should be taken concurrently with a glass of water and a snack.
(pinaverium bromide) should not be administered for the relief of motility dysfunction due to underlying organic disease.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medication.
Use in pregnancy:3 No clinical data on exposed pregnancies are available. Animal studies are insufficient with respect to effects on pregnancy, embryonal/ fetal development, parturition and/ or postnatal development. The potential risk for humans is unknown. The safety of DICETEL during pregnancy has not been established. Consequently, in the pregnant patient, this drug should only be administered if, in the judgement of the physician, its use is essential to the welfare of the patient. Furthermore, the presence of bromine should be taken into account. Theoretically, administration of pinaverium bromide at the end of the pregnancy can affect the new-born neurologically (hypotony, sedation). No such cases however have been reported with DICETEL.
Use during lactation: There is insufficient information on the excretion of DICETEL in human or animal breast milk. Physico-chemical and available pharmacodynamic/ toxicological data on DICETEL point to excretions in breast milk and a risk to the suckling infant cannot be excluded. DICETEL should not be used during breast-feeding.
Minor adverse events were reported and listed as mild and moderate. They were mainly minor digestive disorders that may be related to the disease, such as epigastric pain and/or fullness (0.8%), nausea (0.5%), constipation (0.4%), heartburn (0.3%), distension (0.3%), diarrhoea (0.2%). 8 For other systems: headache (0.3%), dryness of the mouth (0.3%), drowsiness (0.2%), vertigo (0.2%) and skin allergy (0.2%). There have been spontaneous reports of systemic hypersensitivity reactions involving the subcutaneous tissue and other organ systems of the body such as angioedema and anaphylactic shock.
In man, apart from diarrhoea and/or flatulence, DICETEL(r) (pinaverium bromide) induced no undesirable effects in daily dosages of up to 1,200 mg. 41,42 No cases of overdosage of DICETEL have been reported to date. No specific antidote is known. However, if overdosage occurs, gastric lavage is recommended and symptomatic treatment initiated if deemed necessary.
The usual adult dosage is 50 mg three times a day (total daily dose of 150 mg). The dosage may be increased up to a maximum of 100 mg taken three times a day (maximum total daily dose of 300 mg). It is recommended that the tablet be taken with a glass of water during meals or snacks. The tablet should not be swallowed when in the lying position or just before bedtime. The duration of treatment depends on the disorders for which DICETEL is given.
(pinaverium bromide) is available as:
50 mg Film-coated Tablets
: Each orange-coloured, circular-shaped, film-coated tablet with a slightly convex surface contains 50 mg of pinaverium bromide as active ingredient. The tablet is
engraved with "S" on one side and "50" on the reverse side. Available in blister packs, in boxes of 100 tablets.
100 mg Film-coated Tablets
: Each orange-coloured, circular-shaped, film coated tablet with a slightly convex surface contains 100 mg of pinaverium bromide as active ingredient. The tablet is engraved with "S" on one side and "100" on the reverse side. Available in blister packs, in boxes of 100 tablets.
Proper name
: pinaverium bromide
Chemical name
: 4-(6-bromoveratryl)-4-[2-[2-(6,6-dimethyl-2-norpinyl)ethoxy]ethyl]- morpholinium bromide.
Structural formula: Molecular formula: C26H41Br2NO4 Molecular weight: 591.42 Description: Pinaverium bromide is a white, fine, crystalline powder, slightly soluble in distilled water, practically insoluble in ether, but very soluble in 96% alcohol. The melting range determined by means of Mettler FP apparatus is 152deg to 158degC.
In addition to pinaverium bromide,
contains the following excipients:
in the core
: microcrystalline cellulose, modified corn starch, modified lactose, hydrophobic anhydrous silica, talc and magnesium stearate;
in the film coating: basic butylated methacrylate copolymer, sodium laurylsulphate, stearic acid, talc, Sepisperse(r) Dry 3203 (hydroxypropyl methylcellulose, microcrystalline cellulose, anatase titanium dioxide, sunset yellow (aluminium lake)).
The stability of DICETEL film-coated tablets has been demonstrated in blister packaging alone and in blister packs inserted in the dispensing box. DICETEL should be stored at room temperature (15degC to 30degC) in its dispensing box to protect from light.
This information provides a summary on DICETEL and explains how to use it. For more information or advice, please ask your doctor or pharmacist.
DICETEL is the brand name for the medication, pinaverium bromide. It is available as a round, orange film-coated tablet containing either 50 mg or 100 mg of pinaverium bromide. In addition, the tablets also contain the following nonmedicinal ingredients: microcrystalline cellulose, modified corn starch, modified lactose, hydrophobic anhydrous silica, talc, magnesium stearate, basic butylated methacrylate copolymer, sodium laurylsulphate, stearic acid, talc, Sepisperse(r) Dry 3203 (hydroxypropyl methylcellulose, microcrystalline cellulose, anatase titanium dioxide, sunset yellow (aluminium lake)). If you are allergic to any of these substances ask your doctor or pharmacist whether these ingredients may pose a problem.
DICETEL works by relaxing the muscles in the walls of the gut (also called the intestine). DICETEL treats and relieves the symptoms associated with irritable bowel syndrome (IBS) such as abdominal pain, bowel disturbances (constipation and/or diarrhea) and intestinal discomfort (bloating).
If you are pregnant or breast-feeding. DICETEL should not be used during breastfeeding. If you have any allergies or have had a reaction to any of the ingredients in DICETEL (see What is DICETEL? ). If you are lactose intolerant, talk to your doctor, as this product contains lactose. If you have been told by your doctor that you have a rare condition of intolerance to some sugars or difficulty absorbing some sugars (galactose intolerance, Lapp lactase deficiency or glucose/ galactose malabsorption), do not take this medicinal product before talking to your doctor. If you have other medical conditions.
Take only as directed by your doctor. The dose-range for adults is DICETEL 50 - 100 mg three times a day. It is strongly recommended that the tablet be taken with a glass of water during meals or snacks. The tablet must be swallowed without being chewed or sucked. The tablet should not be swallowed when in the lying position or just before bedtime.
If you miss the usual time for taking a DICETEL tablet, take it as soon as possible. If however, it is near the time of your next dose, skip the missed pill and return to your usual dosing schedule. Do not take double the dose.
Never change the amount of DICETEL you are taking unless instructed to do so by your doctor. If you have taken more DICETEL tablets than the recommended dose, tell a doctor immediately. Show the doctor your pack of tablets.
Most people tolerate DICETEL well. Like any other medicine, however, DICETEL may cause side effects in some people. These tend to be mild when they occur. Some people may feel stomach pain and/or fullness, nausea, constipation, heartburn, bloating or diarrhea. Since these side effects are similar to the symptoms of IBS, it may be hard to tell the difference. Other side effects include headache, dryness of the mouth, drowsiness, dizziness, skin allergy and allergic reactions. If you get these or any other problems while you are taking DICETEL, consult your doctor or pharmacist.
Keep DICETEL in its original blister pack in the dispensing box provided by the pharmacist in order to protect it from light. Store at room temperature (15degC to 30degC). Keep away from children. Don't take your tablets if they are past their expiry date.
In vitro and in vivo animal studies have shown that DICETEL(r) (pinaverium bromide) has a spasmolytic effect in the gastrointestinal tract, as supported by a clearly demonstrated Ca++ antagonistic mechanism of action. It acts on the calcium influx by blocking the voltage- dependent calcium channel. Its selectivity of action has been established with validated models. 6,7,10,13,19,34 Animal studies demonstrated that pinaverium bromide possesses potent spasmolytic properties on intestinal smooth muscle and very weak anticholinergic effects observed at high dosage. There is no noticeable cardiovascular effect. 12 Radiolabelled pinaverium bromide was poorly absorbed (5 to 10%) after oral administration (a solution of 2.46 mg/kg, corresponding to 50 FCi/kg) to rats. The radioactivity was rapidly taken up by the liver and excreted in the bile. There was no noticeable enterohepatic cycle and only 5% of the biliary radioactivity was reabsorbed after oral dosing.5
,28,29
Several studies have shown that pinaverium bromide induces the following effects: oesophageal, gastric and duodenal relaxation; acceleration of gastric emptying; colonic and intestinal relaxation; inhibition of motor colonic response to a meal; reduction or inhibition of colonic response to stimulation by neostigmine; reduction of gall bladder contractions, of Oddi's sphincter phasic contractions, of endocholedochal pressure and of retention index during
scintigraphy.
4,9,15,20,24,31,36,37,40,46,47
Other more recent studies (doses up to 1.2g) showed that pinaverium bromide did not affect the cardiovascular system nor have any anticholinergic side effects. 4,9,23,27,39 In particular, two clinical studies carried out with the injectable formulation (total dose of 2 or 4 mg corresponding to a 50 mg oral dose) demonstrated that pinaverium bromide did not influence sinoatrial, atrioventricular, intraventricular conduction, or atrial excitability. It also exhibited no antiarrhythmic properties. 25,26 Administered to patients with glaucoma in a placebo-controlled study, pinaverium bromide did not interfere with the ocular parameters of glaucoma patients: acuity and visual field, ocular tonus measure at aplanation and especially intraocular pressure. 39 Various investigators studied total or segmental intestinal transit time by different techniques in healthy volunteers or in patients. Pinaverium bromide does not increase transit time; it either has no effect or decreases transit time, especially in constipated patients. 4
,9,23
Recent clinical data have confirmed the effects of pinaverium bromide on the lower gastrointestinal tract. A four-centre, double-blind, double-dummy, crossover, randomized study grouped 86 out- patients of both sexes, suffering from irritable bowel syndrome. Patients received either three DICETEL tablets or capsules daily for 19 days. The major symptoms of irritable bowel syndrome were studied separately: pain, bowel disturbances and distension. Pinaverium bromide tablets were shown to be equivalent to the capsules; the tablet was however better tolerated. 16,35 In addition, the long-term safety and tolerance of the tablet at a dose of 3 tablets/day for a duration of 3 to 9 months was demonstrated. 17 Three other studies have confirmed the action of pinaverium bromide in irritable bowel syndrome. 20
,24,37
The pharmacokinetic profile of orally administered pinaverium bromide is a very important feature in explaining its selectivity of action on the gastrointestinal tract. Following administration of an oral solution to animals (2.46 mg/kg) and humans (50 mg) pinaverium bromide was poorly absorbed (5 to 10%) due to its highly polar quaternary ammonium group and its high molecular weight.44,45 In vitro studies have shown that pinaverium bromide is highly bound to both animal and human plasma proteins (97%).28 The selective distribution in the digestive tract, low absorption, low enterohepatic cycle and almost exclusive elimination in the feces are the main kinetic characteristics of pinaverium bromide following oral administration. A kinetic single dose study was performed in 24 healthy volunteers receiving 4 mg intravenously or 100 mg (2 x 50 mg tablets) orally of non-radiolabelled pinaverium bromide. Maximum peak plasma levels were reached within one hour after oral dosing. The absolute bioavailability was very low after oral administration (less than 1%). The mean half-life of elimination is close to 1.5 hours for both routes of administration. 14
Biotransformation
The metabolic pathway is characterized by demethylation of one of the methoxy groups, hydroxylation of the norpinanyl ring and elimination of the benzyl group with subsequent opening of the morpholine ring. 11
Interference With Other Drugs
Various studies were carried out to investigate the possible interaction with drugs usually prescribed for long-term use; digitalis, digoxin, oral antidiabetics, insulin, oral anticoagulants and heparin.18,49 No drug interactions nor interference with laboratory tests for drug level detection were observed.
The results of acute toxicity studies performed in various species using different routes of administration are as follows: 22
P.O. 1531 mg/kg (20 animals/dose) I.P. 41 mg/kg (20 animals/dose) S.C. 436 mg/kg ( 5 animals/dose) I.V. 62 mg/kg (20 animals/dose)
P.O. 1145 mg/kg (20 animals/dose) I.P. 36 mg/kg (20 animals/dose)
P.O. 154 mg/kg ( 6 animals/dose) Safety studies were conducted in conscious Beagle dogs to whom a single oral dose of 50 mg/kg pinaverium bromide was administered. No changes were observed in the body temperature or in the cardiovascular parameters.
Wistar rats were treated daily for two months with 25 to 50 mg/kg/day of pinaverium bromide administered by an intragastric catheter. No clinical, biological or histological signs of intolerance were observed and no deaths occurred. A three-month tolerance study was conducted in the Sprague-Dawley rat using doses of 250, 500 and 1000 mg/kg/day of pinaverium bromide administered in the diet. At doses of 500 and 1000 mg/kg/day, anorexia, weight loss and liquid feces were observed. No other signs of clinical, biological or histological toxicity were detected and no deaths occurred. Similarly, a fifty-two week oral toxicity study conducted with pinaverium bromide in the Sprague-Dawley rat demonstrated that, under the experimental conditions, the minimal toxic dose in the rat was in the range of 100 - 300 mg/kg/day when administered in the diet. An oral chronic study in the dog indicated that administration of pinaverium bromide at doses of 10 and 25 mg/kg/day for 6 months did not cause any toxic signs. At doses of 25 and
50 mg/kg/day for 13 months, pinaverium bromide caused a decreased weight gain in the treated animals relative to the controls; however, no significant haematological modifications were observed.
Teratology Studies
Teratology Study in the Rat
During a teratology study, 4 groups of 20 Wistar albino rats received 10, 25 or 50 mg/kg/day of pinaverium bromide by means of a gastric catheter. Drug administration was performed 6 days a week, from the day of conception to the 18th day of gestation. 3 Results indicated that for the high dose group (50 mg/kg/day) the number of fertilized females was slightly lower and the numbers of sterile females and resorptions were higher when compared to placebo. The lower doses groups (10 and 25 mg/kg/day) did not differ significantly from placebo. None of the fetuses or young of treated females from any dose group exhibited anatomical anomalies. Up to 30 days post-birth, neither development nor behaviour modifications were observed in the offspring. Pinaverium bromide was not considered teratogenic in the rat under the experimental conditions of the study.
Teratology Study in the Rabbit
Doses of 2.5, 5 and 10 mg/kg/day of pinaverium bromide were administered 6 days per week, from day 6 to day 18 of gestation to 4 groups of 10 Russian albino rabbits. 3 None of the fetuses from the mothers treated with pinaverium bromide showed any visceral or skeletal abnormalities. The number of resorptions, the mean number of fetuses, and the percentage of abortions were not significantly different at any of the dose levels administered. Under these experimental conditions, pinaverium bromide did not demonstrate a teratogenic effect in the rabbit.
Pinaverium bromide has no mutagenic potential as illustrated by the negative results obtained in tests for chromosomal mutation (i.e., micronucleus test in mice for pinaverium bromide administered by various routes) and for chromosomal aberrations on human lymphocytes-genic mutation (i.e., two Ames tests, mouse lymphoma assay). 1
,2,21,30,38,43
These results were also confirmed in the cell transformation test on embryonic lung cells of Syrian hamsters (SHE cells). 33
ALLEN J.A., et al
Pinaverium bromide metaphase chromosome analysis of human lymphocyte cultures in-vitro.
Unpublished document, January 20, 1986
ALLEN J.A., PROUDLOCK R.J.
Micronucleus test on pinaverium bromide
Unpublished document, January 27, 1986
BALEA T. (Paris)
Expertises teratologiques. Data in files.
BARBARA L., CORINALDESI R., BALDI F., RAITI C., LONGANESI A., REA E., CORNIA G.L., CIAMPINI M., STANGHELLINI V.
Effects of pinaverium bromide on intestinal transit time and sigmoid contractile activity in
patients with chronic idiopathic constipation. Farmacie Terapia, 1984, 1 (1), 43-46
BARONNET R., FOUSSARD-BLANPIN O., BRETAUDEAU J., HUBERT F.
Synthese et etude pharmacodynamique comparee d'ammoniums quaternaires derives du dimethyl-6,6 norpinane: leur action spasmolytique.
Eur. J. Med. Chem. - Chimica Therapeutica, 1974, 9, 182-187
BAUMGARTNER A., DRACK E., HALTER F., SCHEURER U.
Effects of pinaverium bromide and verapamil on the motility of the isolated rat colon. Br. J. Pharmacol., 1985, 86, 89-94
BEECH D.J., MCKENZIE I., BOLTON T.B., CHRISTEN M.O.
Effects of pinaverium on voltage-activated calcium channel currents of single smooth muscle cells isolated from the longitudinal muscle of the rabbit jejunum.
Br. J. Pharmacol., 1990, 99, 374-378
BEL (Lyon), BOCKEL (Strasbourg), CLAUDE (Limoges), CAULIN (Paris), COLIN (Rouen),
DELMONT (Nice), EMERIT (Paris), GAUCHER (Nancy), GUILLEVIN (Bobigny), LAFON
(Aix-en Provence), LE QUINTREC (Paris), LORRIAUX (Amiens), MARTI (Calais), MICHEL (Montpellier), PARIS (Lille), QUINTON (Bordeaux), TOURNUT (Clermont- Ferrand), VICARI (Nancy), ZEITOUN (Reims).
Multicentre study of the clinical safety of DICETEL tablets.
Unpublished document, 1984-1985
BERTRAND J., METMAN E.H., DANQUECHIN DORVAL E., ITTI R.
Effets du bromure de pinaverium sur l'evacuation gastrique et le transit digestif de l'homme etudies par granules radio-opaques.
Therapie, 1981, 36, 555-560.
BOLTON T.B., MCKENZIE I., BEECH D.J.
Antagonism of inward calcium current by pinaverium in isolated single smooth muscle cells from the rabbit jejunum.
Published in: Calcium Antagonism in Gastrointestinal Motility
CHRISTEN M.O., GODFRAIND T., MCCALLUM R.W. (Eds) ELSEVIER, Paris, p 109-115, 1989.
BORCHERS F., ACHTERT G.
Metabolism of pinaverium bromide (DICETEL) in rat, dog and man. Anal. Chem. Symp. series, 1981, 7, 39-56.
BRETAUDEAU J., FOUSSARD-BLANPIN O., BARONNET R., DESPRAIRIES R.
Etude pharmacodynamique des proprietes spasmolytiques du bromure de pinaverium. Therapie, 1975, 30, 919-930
CHRISTEN M.O.
Action of pinaverium bromide, a calcium antagonist, on gastrointestinal motility disorders. Gen. Pharmacol., 1990, 21, 821-825.
CHRISTEN M.O., PAILLET M., ACHTERT G.
Open, randomized, single dose, crossover study of oral and intravenous dose of pinaverium bromide (DICETEL) investigating absolute bioavailability and pharmacokinetics in healthy male volunteers.
Unpublished report, Suresnes, 1990 (France)
DISOMMA C., REBOA G., PATRONE M.G., MORTOLA G.P., SALA G., CIAMPINI M.
Effects of pinaverium bromide on Oddi's sphincter. Clin. Ther. (Princeton), 1986, 9, (1), 119-122
DORF G., LAFON L., QUINTON A., RAMPAL P.
Comparative study of the efficacy of DICETEL tablets versus DICETEL capsules.
Unpublished document, 1985-1986
DORF G., GUILLEVIN L., LAFON J., PARIS J.C., QUINTON A., VICARI F.
Long term clinical trial of DICETEL tablets.
Unpublished document, 1985-1986
DEVRED C., GODEAU P., GUEROT C., LIBREZ P., MOUGEOT G., ORSETTI A., SEGRESTAA J.M.
Investigation of drug interactions with pinaverium bromide. Curr. Med. Res. Opin., 1986, 10 (1), 1-9
DROOGMANS G., HEMPENS B., CASTEELS R.
Effects of pinaverium bromide on electrical and mechanical activity of smooth muscle cells. Naunyn-Schmiedeberg's Arch. Pharmacol., 1983, 323, 72-77
FIORAMONTI J., FREXINOS J., STAUMONT G., BUENO L.
Inhibition of the colonic motor response to eating by pinaverium bromide in irritable bowel syndrome patients.
Fundam. Clin. Pharmacol., 1988, 2, 19-27
FOURNIER P.E.
Study of the mutagenicity of pinaverium bromide by the mutatest.
Unpublished document, January 4, 1979
FOUSSARD-BLANPIN O. (Tours)
Expertises toxicologiques, Data in files.
FROGUEL E., CHAUSSADE S., ROCHE H., FALLET M., COUTURIER D., GUERRE J.
Effect on an intestinal smooth muscle calcium channel blocker (pinaverium bromide) on colonic
transit time in humans.
J. Gastrointestinal Motility., 1990, 2 (3), 176-179
GALEONE M., STOCK F., MOISE G., CACIOLI D., TOTI G.L., MEGEVANT J.
Pinaverium bromide versus otilonium bromide in patients with irritable bowel syndrome. Curr. Ther. Res., 1986, 39, (4), 613-624.
GUEROT C.
Cardiac electrophysiological studies of pinaverium bromide in man.
Unpublished document, 1984
GUEROT C.
Electrophysiological study of i.v. DICETEL (4 mg) (double-blind trial versus placebo).
Unpublished document, 1987.
GUEROT C., KHEMACHE A., SEBBAH J., NOEL B.
Electrophysiological study of intravenous pinaverium bromide in cardiology. Curr. Med. Res. Opin., 1988, 11, (2), 73-79.
JACQUOT C., RAPIN J., LAMBREY B., BARONNET R., PICHAT L.
C pinaverium bromide synthesis and pharmacokinetics study in the rat.
Eur. J. Med. Chem. - Chimica Therapeutica, Jan. - Feb., 1978, 13, #1, p.p. 61-66
JACQUOT C., TROUVIN J.H., CHRISTEN M.O.
Selectivity of gastrointestinal calcium-antagonists: pharmacokinetic aspect.
Published in: Calcium Antagonism in Gastrointestinal Motility
CHRISTEN M.O., GODFRIAND T., MCCALLUM R.W. (Eds) ELSEVIER, Paris, p.p. 141- 151, 1989.
JONES E., et al
Ames metabolic activation test to assess the potential mutagenic effect of pinaverium bromide.
Unpublished document, February 21, 1986
LAMAZZA A., TOFI A., BOLOGNESE A., FONTANA B., DEMASI E., FRONTESPEZI S.
Effects of pinaverium bromide in the premedication of endoscopic retrograde cholangio- pancreatography and on motor activity of the sphincter of Oddi.
Curr. Med. Res. Opin., 1986, 10, 280-284.
LEVY C., CHARBONNIER A., CACHIN M.
Bromure de pinaverium et colopathie fonctionnelle - etude a double insu. Sem. Hop. Paris Therapeutique, 1977, 53 (7-8), 372-374.
MILTENBURGER H.G.
Cell transformation assay with Syrian hamster embryo (SHE) cells.
Unpublished document, June 3, 1986
MIRONNEAU J., LALANNE C., MIRONNEAU C., SAVINEAU J.P., LAVIE J.L.
Comparison of pinaverium bromide, manganese chloride and D600 effects on electrical and mechanical activities in rat uterine smooth muscle.
Eur. J. Pharmacol., 1984, 98, 99-107
NOEL B.
Double-blind comparative study of DICETEL tablet and DICETEL capsule. Multicentre study. Synthesis.
Unpublished document, March 1986
PARIS J., SIMON V., ITOUA-NGAPORO A.F.
Evaluation de l'activite spasmolytique du bromure de pinaverium sur la musculature gastro- intestinale et le sphincter d'Oddi, chez l'homme.
Rev. Fr. Gastro-Enterol., 1977, (126), 41-47
PASSARETTI S., SORGHI M., COLOMBO E., MAZZOTTI G., TITTOBELLO A., GUSLANDI M.
Motor effects of locally administered pinaverium bromide in the sigmoid tract of patients with irritable bowel syndrome.
In. J. Clin. Pharmacol. Ther. Toxicol., 1989, 27, (1), 47-50.
RICHOLD M., et al
An assessment of the mutagenic potential of pinaverium bromide in mammalian cells in vitro using the mouse lymphoma TK locus assay.
Unpublished document, March 13, 1986
ROUX J.J., SALMON D., RENY A.
Emploi d'un antispasmodique musculotrope chez la glaucomateux. Gaz. Med. France, 1980, 87, (9), 1033-1036.
SCAFFIDI A., COSTA R., FRONTESPEZI S.
Effectiveness of pinaverium bromide in the treatment of primitive biliary dyskinesia: 9 9 mTc-P- IDA scintigraphic evaluation.
Int. J. Clin. Pharmacol. Ther. Toxicol., 1987, 25 (9), 522-526.
SCHNELLE K., HOPPE H.J.
Report of study 78/336 A. Investigation of maximum tolerance to a single dose of LAT 1717 with healthy test persons.
Unpublished document, February 1979.
SCHNELLE K., HOPPE H.J.
Report of study 78/336 B. Investigation of the clinical tolerance with repeated doses.
Unpublished document, February 1979.
SIOU G.
Detection of any possible mutagenic action of pinaverium bromide (BAL 71178) using the Howell-Jolly body technique (micronucleus test).
Unpublished document, March 5, 1979
SMITH R.L.
Study on the oral bioavailability of 14C-pinaverium bromide (DICETEL).
Unpublished report, London (United Kingdom), 1978
SMITH R.L.
Study on the pharmacokinetics of 14C-labelled pinaverium (DICETEL). Results of an intravenous study in four volunteers.
Unpublished report, London (United Kingdom), 1979
SOIFER L., VARELA E., OLMOS J.
Manometric effects of pinaverium bromide in irritable bowel syndrome. To be published.
SPIVACH A., BRIGANTI F.P., CIAMPINI M.
Effects of pinaverium bromide on gallbladder contraction and intestinal passage rate; a controlled study.
Acta Therapeutica, 1983, 9, (4), 391-397.
SZEKERES L., PAPP J.G.
Relative selectivity of pinaverium bromide as a calcium antagonist for colonic smooth muscle.
Published in: Calcium Antagonism in Gastrointestinal Motility
CHRISTEN M.O., GODFRAIND T., MCCALLUM R.W., (Eds), ELSEVIER, Paris, p.p. 161- 167, 1989.
WEITZEL O., SEIDEL G., ENGELBERT S., BERKSOY M., BERHARDT G., BODE R.
Investigation of possible interaction between pinaverium bromide and digoxin.
Curr. Med. Res. Opin., 1983, 8, (8), 600-602.
WUYTACK F., DE SCHUTTER G., CASTEELS R.
Action of pinaverium bromide on calmodulin-regulated functions. Eur. J. Pharmacol. 1985, 114, 85-88.
(r) Registered Trademark used under licence by Solvay Pharma Inc.