Evaluations on New Drugs

Drugs 15: 93-131 (1978) ©ADIS Press 1978

Cimetidine: A Review of its Pharmacological Properties and Therapeutic Efficacy in Peptic Ulcer Disease R.N. Brogden, R.C. Heel, T.M. Speight and G.S. A very Australasian Drug Information Services, Auckland

Various sections of the manuscript reviewed by: S. Bank. Long Island Jewish Hillside Medical Center, New York, USA; K.D. Bardhan, Rotherham Area Health Authority, Rotherham Hospital, England; W.s. Blackwood. St. George's Hospital, London, England; G. Bodemar, Institution for Internal Medicine and Clinical Pharmacology, Linkoping, Sweden; WP. Dyck. Department of Medicine, Section on Gastroenterology, Scott and White Clinic, Texas, USA; K.V. Eden, University of Colorado, Denver, Colorado, USA; RR. Giffies. Ottawa Civic Hospital, Ottawa, Canada; GR Gray, Royal Alexandra Infirmary, Paisley, England; D. Hetzel, University of Adelaide, Royal Adelaide Hospital, Australia; A. Ippoliti, UCLA School of Medicine, Veterans Administration Wadsworth Hospital, Los Angeles, USA; M.J.s. Langman. University of Nottingham, City Hospital, Nottingham, England; GF. Longstreth. Kaiser Permanente Medical Center, San Diego, Califomia, USA; J.E. McGuigan, University of Florida, College of Medicine, Florida, USA; J.-R. Malagelada. Mayo Foundation, St. Mary's Hospital, Rochester, Minnesota, USA; J.J. Misiewicz. Central Middlesex Hospital, Acton Lane, London, England; D.W. Piper, Royal North Shore Hospital, St. Leonards, New South Wales, Australia; RE. Pounder. St. Thomas' Health District, St. Thomas' Hospital, London, England; R.W. Spence. Frenchay Hospital. Bristol, England; A. Walan. Institution for Internal Medicine and Clinical Pharmacology, Linkoping, Sweden.

Table o/Contents Summary ..................... .. I. Histamine Receptors and H!·Receptor Antagonists 2. Animal Pharmacodynamics 2.1 Effect on Gastric Acid Secretion 2.2 Effect on Pepsin Secretion, Gastric Motility and Gastric Emptying ............... . 2.3 Effect in Preventing Ulcers 2.4 Ulcer Healing Effect ................. . 2.5 Effect Against Drug-Induced Gastritis 2.6 Anti-Androgenic Activity 2.7 Miscellaneous Effects 2.8 Toxicology Studies ............... .

95

98 100 100 101 101 101 101 101 103 103

94

Ometidine: A Review

2.8.1 Acute Toxicity 2.8.2 Sub-Acute Chronic Toxicity 2.8.3 Dysmorphology and Reproductive Studies 3. Human Pharmacodynamics 3.1 Effect on Gastric Acid Secretion in Healthy Man 3.2 Effect on Gastric Acid Secretion in Duodenal Ulcer 3.3 Effect on Cimetidine on Serum Gastrin 3.4 Effect on Pepsin. Biliary and Pancreatic Secretory Output ................ . 3.5 Effect on Intrinsic Factor Secretion 3.6 Effect of Continuous Treatment on the Parietal Cell ........................ . 3.7 Effect on Gastric Potential Difference 3.8 Effect on Lower Oesophageal Sphincter Pressure 3.9 Effect on Gastric Emptying ................ .. 4. Pharmacokinetics 4.1 Absorption 4.2 Distribution 4.3 Elimination 4.3.1 Metabolism 4.3.2 Excretion 4.3.3 Half-Life .................... .. 4.4 Plasma Concentration and Clinical Effects 4.5 Influence of Disease on Kinetics 5. Therapeutic Trials .................. . 5.1 Treatment of Duodenal Ulcer 5.1.1 Open Trials 5.1.2 Controlled Trials 5.2 Factors Influencing Response of Duodenal Ulcer to Cimetidine 5.2.1 Dosage 5.2.2 Timing of Administration Relative to Meals 5.2.3 Basal Acid Output 5.2.4 Duration of Treatment 5.2.5 Severity of Ulceration 5.2.6 Previous Treatment with HI-Receptor Antagonist 5.3 Prevention of Ulcer Recurrence 5.4 Treatment of Gastric Ulcer 5.4.1 Open Trials 5.4.2 Controlled Trials ...................... .. 5.5 Oesophagitis 5.6 Zollinger-Ellison Syndrome 5.7 Acute Gastrointestinal Haemorrhage 6. Side-Effects 6. I General Effects 6.2 Biochemical Values 6.3 Endocrine Effects .................... . 6.4 HaematologicaI Abnormalities 6.5 Long-Term Effects ................ . 6.6 Central Nervous System Effects 7. Drug Interactions .................... . 8. Precautions 9. Dosage

9.1 Oral Administration 9.2 Parenteral Administration 9.3 Dosage in Impaired Renal Function

103 103 104 104 104 104 106 109 109 110 110 III III III III

112 113 113 113 113 113 113 113 114 114 114 116 116 117 117 117 118 118 118 119 119 119 121

121 121 122 122 123 124 124 124 124 124 125 125 125 125 126

Cimetidine: A Review

Summary

95

Synopsis: Cimetidinei is a specific competitive histamine H 2 -receptor antagonist which effectively inhibits gastric acid secretion and is advocated for the treatment of chronic peptic ulceration. haemorrhage from erosive gastritis. and the control of gastric hypersecretion and peptic ulceration in the Zollinger-Ellison syndrome. Placebo-controlled trials in outpatients have demonstrated its efficacy in promoting the healing of endoscopically diagnosed duodenal ulceration. during a period of 4 to 6 weeks. but its role in the treatment of gastric ulcer is less clear.· Preliminary evidence suggests that maintenance therapy with cimetidine reduces the rate of recurrence of duodenal ulcer. but further studies are required to clarify its role in this situation and in the treatment of oesophagitis and acute gastrointestinal haemorrhage. Cimetidine controls the peptic ulceration of Zollinger-Ellison syndrome in most patients when given continuously for up to 2 years. Side-effects have generally been trivial and have very seldom necessitated withdrawal of therapy except in the rare occurrence of gynaecomastia. The haematological abnormalities. particularly agranulocytosis. which lead to the withdrawal from clinical use of metiamide. have not been reported with cimetidine. except for I case of transient neutropenia. The safety of long-term cimetidine administration has yet to be determined. Animal Pharmacodynamics: In vitro. and in intact animals, oral or intravenous cimetidine acts as a competitive inhibitor of histamine at H 2-receptor sites. Administered orally or intravenously cimetidine inhibits basal (non-stimulated) acid secretion and that stimulated by histamine or pentagastrin, but is generally much less effective in inhibiting carbachol (carbamylcholine chloride)..stimulated acid secretion. Cimetidine has a lesser effect on the secretion of pepsin than on acid secretion. Controlled experimental studies have shown that pre-treatment with cimetidine protects rats against gastric ulceration caused by stress, pyloric ligation and treatment with aspirin, or indomethacin, and duodenal ulcers induced by carbachol-histamine. Cimetidine also protected guinea-pigs against histamine-induced ulceration. Cimetidine does not prevent gastric ulcers produced by serotonin or reserpine in rats. Oral cimetidine given for 10 or 12 consecutive days accelerated the spontaneous healing of gastric and duodenal ulcers produced by acetic acid in rats. Cimetidine possesses a weak anti-androgenic effect, and in toxicological studies reduced the rate of growth of the prostate and seminal vesicles. Human Pharmacodynamics: In healthy volunteers as well as in patients with duodenal ulcer, oral or intravenous cimetidine significantly reduces gastric acid secretion stimulated by solid, liquid or peptone meals as well as that stimulated by sham feeding or fundic distention, and by pentagastrin, histamine, caffeine or insulin infusion. The extent of inhibition is doserelated and a 50 % reduction in gastric acid secretion is obtained by doses of cimetidine giving a blood concentration of I to 2)llJlo1lL (0.25 to 0.5)1g I mI). Cimetidine reduces both hydrogen ion concentration and volume of gastric secretion. Addition of an anticholinergic to cimetidine at dosages of greater than 400mg does not significantly enhance inhibition of acid output. Oral cimetidine 300mg is more effective in inhibiting meal-stimulated acid secretion than an optimal dose of propantheline bromide. A single 300 or 400mg dose maintains reduced acid secretion throughout the night.

I

'Tagamet' (Smith Kline; SK&F).

• In the USA, cimetidine is approved for use only in short-term (up to 8 weeks) treatment of duodenal ulcer and for treatment of pathological hypersecretory conditions.

Cimetidine: A Review

96

It appears that cimetidine does not significantly increase gastrin release in most patients studied. However. there was a marked increase in serum gastrin levels in patients whose basal antral pH was above 6 after 3 months of treatment with cimetidine 1.6g daily. Serum gastrin was lowered when acid secretion returned to normal. Further study of these patients after I year's treatment with cimetidine showed significantly increased integrated gastrin response to an OXO test meal compared with pre-treatment and 3-month values. but fasting gastrin concentrations were not significantly altered. However. the three-fold increase in serum gastrin response in these patients did not result in a rebound of acid secretion on discontinuation of cimetidine. Studies which provide sequential results in individual patients during long-term cimetidine are needed to determine the likelihood of parietal cell hyperplasia consequent to increased serum gastrin concentration. Further studies are needed to define more clearly the effect of prolonged cimetidine treatment on the parietal cell. but present evidence suggests that acid output is not significantly altered after cimetidine withdrawal. Pepsin output is decreased by cimetidine. largely due to reduced volume. but to a lesser extent than acid output in the same patients. Pancreatic secretion of bicarbonate and enzymes is not influenced by cimetidine. Studies in healthy volunteers have demonstrated that cimetidine does not consistently alter gastric emptying or lower oesophageal sphincter pressure.

Pharmacokinetics: Cimetidine is readily absorbed after oral administration and bioavailability is about 70 %: In fasted subjects peak blood levels are attained 60 to 90 minutes after ingestion and are dose-related in doses of up to 400mg. Peak blood levels are delayed and lower when cimetidine is given with food. but the percentage inhibition of gastric acid secretion is similar whether the drug is given before. with or after food. Most of a dose of cimetidine is recovered in the urine within 24 hours. about half as unchanged drug. although there is a tendency for a higher proportion of a dose of less than 200mg to be recovered unchanged. Excretion is reduced and the half-life prolonged in patients with renal failure. but blood levels are readily lowered by haemodialysis. Therapeutic Trials: Placebo-controlled therapeutic tria.ls in outpatients have demonstrated the efficacy of cimetidine 0.8 to 2g daily in increasing the proportion of duodenal ulcers healed during a period of 4 to 6 weeks. Endoscopic evidence of duodenal ulcer healing has been reported in 67 to 93 % of patients treated with cimetidine and in about 25 to 40 % given placebo. The relative efficacy of cimetidine and other agents used to accelerate healing of duodenal ulcer has yet to be demonstrated in comparative studies. Preliminary evidence suggests that maintenance treatment" with cimetidine 400 to 800mg daily lowers the recurrence rate of duodenal ulcer. but its role in this regard has yet to be clarified. Studies of cimetidine in gastric ulcer" have given varying results. Whereas some studies have shown cimetidine to completely heal gastric ulcer more frequently than placebo. others could find no difference. Further suitably designed studies in adequate numbers of patients are in progress and may clarify the role of cimetidine in gastric ulcer relative to that of other agents in use. Cimetidine has yet to be shown to be of value in oesophagitis. but appears to be useful in many patients for the control of gastric hypersecretion and peptic ulceration in the ZollingerEllison syndrome. The optimum dosage. long-term safety and best method of use of

• In the USA. cimetidine is approved for use only in short-term (up to 8 weeks) treatment of duodenal ulcer and for treatment of pathological hypersecretory conditions.

Cimetidine: A Review

97

cimetidine in this latter disease has still to be determined. but the drug certainly has a role in the elderly. in those in whom the risk of surgery is high. and in preparation for surgery. Some workers advocate long-term maintenance with cimetidine as the treatment of choice in the Zollinger-Ellison syndrome. because of the appreciable mortality of total gastrectomy. especially in patients who have had previous surgery. and because of the frequent inoperability for technical reasons. or because of the presence of secondary deposits of the primary tumour. Cimetidine has been successfully used to prevent acute gastrointestinal haemorrhage in patients with fulminant hepatic. failure. and to treat acute gastrointestinal haemorrhage associated with gastritis and gastric an!1lor oesophageal erosions.· However. its role in gastrointestinal haemorrhage from chronic gastric or duodenal ulcer or from oesophageal varices has not yet been clarified· and Hl-receptor blockade should not at present be allowed to modify the established principles of clinical management of upper gastrointestinal haemorrhage.

Side-Effects: Although minor side-effects occur in about a quarter of patients treated with cimetidine. they have also been reported in a similar proportion of patients given placebo. The most frequently reported side-effects are headache. tiredness. diarrhoea. muscular pain. skin rash and dizziness. Withdrawal of treatment because of side-effects has been necessary in only 1.4 % of patients and in only some of these instances was there a likely association between cimetidine and the side-effects. Withdrawal of treatment was necessary in 1.2 % of patients receiving placebo. Long-term surveillance of a larger number of patients than have been studied to date will be necessary to determine its long-term effects and the symptoms. Haematological abnormalities. such as were reported with metiamide. have not occurred with cimetidine with the exception of a case of transient neutropenia. Breast changes. including gynaecomastia. have been reported in a few male patients. mostly with Zollinger-Ellison syndrome receiving long-term therapy. A few instances of galactorrhoea in women. associated with elevated prolactin levels. have also been reported. Dosage: The dose size and daily dosage of cimetidine vary in some countries. In benign gastric· and duodenal ulceration the usual dosage in most countries is 200mg 3 times daily with meals and 400mg at bedtime. In the USA and Canada however. tablets of cimetidine contain 300mg and the corresponding dosage is 300mg 4 times daily. with meals and at bedtime. Treatment should be continued until ulcer healing occurs or if reassessment is not possible then for 4 to 6 weeks. In Zollinger-Ellison syndrome the dosage may be increased if necessary to 1.6 to 2g daily in most countries. or to 2.4g daily in the USA and Canada. By intravenous injection the usual dose is 200mg at intervals of 4 to 6 hours in most countries. In the USA and Canada. ampoules of cimetidine contain 300mg and the recommended intravenous dose is 300mg every 6 hours. Patients with moderate or severe renal impairment should receive an initial dose of 200mg (or 300mg in the USA and Canada) every 12 hours orally or by intravenous injection. Any increase in dosage in these patients is best achieved by increasing the frequency of 200mg (or 300mg) doses .

• In the USA. cimetidine is approved for use only in short-term (up to 8 weeks) treatment of duodenal ulcer and for treatment of pathological hypersecretory conditions.

98

Cimetidine: A Review

J. Histamine Receptors and Hz-Receptor Antagonists

histamines on these actions of histamine it is considered that they are mediated via a different type of receptor which has been termed a histamine H 2-receptor by Black et al. (I972). These workers described the first antagonist binding speciflcally to H 2-receptor sites, burimamide. As burimamide had low potency when administered orally it was superseded in pharmacological and clinical evaluation by metiamide which is more active orally. Metiamide produced a marked inhibition of gastric acid secretion in vitro (Schofield et aI., 1975), in animals (Grossman and Konturek, 1974) and in man (Milton-Thompson et aI., 1974). In therapeutic trials it alleviated duodenal ulcer symptoms (Pounder et al .• 1975) and promoted ulcer healing (Multicentre Trial. 1975), but was associated with reversible granulocytopenia and was consequently withdrawn. Metiamide was superseded by cimetidine, in which the thiourea moiety of the metiamide side chain was replaced by a

Histamine is widely distributed throughout the body of humans and of animals, and has an effect on a number of different organs (table O. Characteristically, visceral muscles from gut, bronchi and arteries contract when exposed to histamine, but the effect varies between species. These actions of histamine can generally be inhibited by low concentrations of conventional antihistamines such as mepyramine, and the pharamacological receptors inhibited by mepyramine have been termed histamine HI-receptors (Ash and Schild, 1966). Histamine also stimulates gastric secretion, increases the heart rate in several animal species and inhibits uterine contractions in the rat (Vernia and McNeill, 1976), but these effects cannot be antagonised by conventional antihistamines. Because of the lack of effect of anti-

/

( CH 2CH 2NH 2

HN

~N

Histamine

r=t CH2CH2CH,CH2NHCNHCH u

, __ \ HN

~N

CH 3 MCH2SCH2CH2NHCNHCH __ U 3

S

3

HN~N

S

Metiamide

Burimamide CH 3 M __

CH2SCH2CH2NHCNHCH I 3 N-C-N

HNVN Cimetidine

Fig. 7. Structural formula of histamine and the histamine H,-receptor antagonists burimamide. metiamide and cimetidine.

Cimetidine: A Review

99

Table I. Pharmacological characterisation of cardiac and vascular histamine receptors in various animal preparations Preparation

Measured effect of histamine mediated by

H, + H2

Reference

Response is balance between H, and H2

Carrol et al. (1974)

H ,-receptors

H2-receptors

Rabbit (intact!

Pressor

Depressor

Rabbit (isolated perfused heart)

Coronary vasoconstriction

Positive inotropic Positive chronotropic

Broadley (1975)

Guinea-pig

Initial vasodilatation

Positive inotropic Positive chronotropic

Broadley (1975)

Slowing of A-V conduction

Vasodepressor positive Inotropic Positive chronotropic

Levi et al. (1975)

Positive inotropic left atrium

Positive inotropic right atrium

Positive inotropic right ventrical (predominantly H2)

Increase in cyclic AMP

Verma and McNeill (1977) Verma and McNeill (1977) Johnson and Mizoguchi (1977)

Increase in adenylate cyclase Guinea-pig (isolated lung)

Okpako (1974)

Cat (intact!

Vasodilatation hind limb vascular bed Vasodilatation Superior mesenteric vascular bed

Flynn and Owen (1975)

Cat (intact)

Depressor response

Owen (1975)

Cat (isolated intra- and extracranial arteries)

Contraction extracranial

Cat (isolated arterioles of corpus and antrum)

Antrum Vasodilatation

Dog

Vasoconstriction Cardiac depressant

Dog

Airway (large and small) constriction (predominant)

Guinea-pig

Histamine wheal (cutaneous vasodilatation)

Rat

Dilatation

Vasodilatation Increased heart rate Increased cardiac output

Edvinsson and Owman(1974) Corpus vasodilatation

Guth and Smith (1977)

Mesenteric vasodilatation

Tucker etal. (1975) M~ler et al. (1977)

Small airway constriction but H, predominant Histamine wheal but predominantly H,

Irvin and Dempsey (1977)

Blood pressure depressor response to histamine

Szelenyi and Thiemer (1977)

Cheng et al. (1977)

100

Cimetidine: A Review

Table II. The effects of cimetidine on gastric acid secretion in various animal preparations (after Brimblecombe et at. 1975b)

Preparation

Stimulant

Effect of cimetidine

Histamine 15pmol/kg/h

10 50 : rapid IV 1.37pmol/kg

Rat: lumen-perfused stomach

Gastric fistula

intraduodenal 5.5pmol/kg IV infusion 3pmol/kg/h produced 71 % inhibition Pentagastrin 60pg/kg/h

10.0 : rapid IV 1.4pmol/kg

CarbachoI30pg/kg/h

Inhibition significant at 8pmol/kg and about 50% at 128-256pmol/kg

Basal secretion

IV infusion 6pmol/kg/h: inhibition of 20% first hour and 30% second hour IV infusion 60pmol/kg/h: inhibition of 71 % first hour and 96 % second hour

Histamine 3pmol/kg/h

1050 : rapid IV 0.85pmol/kg

Pentagastrin 10pg/kg/h

10.0 : rapid IV 1.45pmol/kg

Histamine 1.3pmol/kg/h

10.0 : rapid IV 1.7pmol/kg

Cat: lumen-perfused stomach

Dog: Heidenhain pouch

IV infusion 4.7pmol/kg Oral 10pmol/kg produced 70% inhibition. 20pmol/kg produced 90% inhibition Pentagastrin 8pg/kg/h

Rapid IV 2pmol/kg produced 55% inhibition

Carbachol 6.7pg/kg/h

Rapid IV 4pmol/kg produced 59% inhibition

cyanoguanidine radical (fIg. I). Cimetidine is an effective inhibitor of gastric acid secretion and its use in peptic ulcer and allied disorders is reviewed below.

2. Animal Pharmacodynamics 2.1 Effect on Gastric Acid Secretion

In vitro (Sjostrand et al., 1977) and in intact animal preparations (Brimblecombe et al., 1975b; Kuhn et al., 1977) cimetidine administered intravenouslyand orally (Brimblecombe et al., 1975a) or rectally (Khamus et al., 1977a, b) inhibits basal and pentagastrin"Stimulated acid secretion, but is generally much less effective in inhibiting carbachol

(carbamylcholine chloride)..stimulated secretion (table 11). The lower potency against cholinergically mediated acid secretion in laboratory animals however, does not seem to obtain in man (section 3.2). Cimetidine produced a parallel displacement to the right of the histamine dose-acid secretory curve from guinea-pig isolated gastric mucosa without significantly affecting the slope or maximum response (Sjostrand et al., 1977). This rmding is suggestive of competition of cimetidine with histamine for a common receptor site (Black, 1976; Sjostrand et al., 1977). Relatively high doses were required to inhibit basal secretion in rats with gastric fistula (Kuhn et al., 1977), probably because of the relative lack of effect of cimetidine on the cholinergic components of the

Cimetidine: A Review

stimulus (Brimblecombe et al., 1975a). In pylorusligated rats, intraduodenal cimetidine 50 and 100mg/kg, like atropine 15mg/kg, reduced the volume and acid content of gastric juice (Okabe et al., I 977a), but cimetidine given intraperitoneally or intraduodenally was without significant effect on gastric contents in rats with ulcers induced by aspirin or in guinea pigs with histamine-induced ulceration (Okabe et aI., 1977b). Despite this lack of effect on gastric contents (volume, acid output, pepsin) cimetidine was effective in preventing ulcer formation (see section 2.3).

101

2.3 Effect in Preventing Ulcers Controlled experimental studies have shown that pre-treatment with cimetidine 12.5, 50 and 100mg/ kg protects against gastric stress ulcer formation and gastric ulcers induced following pylorus ligation and treatment with aspirin or indomethacin, against carbachol-histamine duodenal ulcers and those produced following histamine administration in guinea-pigs. Cimetidine did not prevent gastric ulcers produced by serotonin or reserpine in rats (table III).

2.4 Ulcer Healing Effect 2.2 Effect on Pepsin Secretion, Gastric Motility, and Gastric Emptying The effects of cimetidine 12.5 to 100mg/kg (intraduodenally and intraperitoneally) have been studied in pylorus ligated rats (Okabe et al., I 977a, b), in rats with gastric ulcers induced by aspirin, in guinea pigs with ulcers caused by histamine (Okabe et al., I 977b) and in gastric fistula dogs given 2mg/kg/h intravenously (Hirschowitz and Gibson, 1976). Although Okabe et al. (t 977a) reported a marked reduction (60%) in pepsin output 3 hours after intraduodenal administration of 100mg/kg of cimetidine, no such effect was noted by Okabe et al. (t 977b) in the same type of pylorus-ligated rats (male Donryn). Similarly, cimetidine 12.5, 50 and I OOmg/kg had no significant effect on pepsin output in pylorus ligated rats with aspirin-induced gastric ulceration, or in guinea pigs with histamine-induced ulcers (Okabe et al., 1977b). In gastric fistula dogs, cimetidine 2mg/kg/h intravenously minimally lowered pepsin secretion (Hirschwitz and Gibson, 1976). In a preliminary study (Okabe et al., I 977a), cimetidine was found to not affect gastric acid motility in rats and rabbits. Cimetidine infusion 4mg/kg/h markedly reduced gastric emptying in rhesus monkeys following a distilled water meal, but this effect was independent of intragastric acid (Dubois et al., 1977).

Oral cimetidine 100 or 200mg/kg (in 2 divided doses) given for 10 or 12 consecutive days significantly accelerated the spontaneous healing of gastric and duodenal ulcers induced by acetic acid in separate groups of about 60 rats. Oral atropine 30mg/kg (in 2 divided doses) accelerated the healing of duodenal ulcers but had no significant effect on gastric ulcers.

2.5 Effect Against Drug-Induced Gastritis Cimetidine 4mg/kg given IS minutes before each dose of test drug completely prevented acute gastric erosions caused in rats by ~ophageal administration of ketoprofen, naproxen, ibuprofen, tolectin, levodopa, colchicine, capsaicin and D-penicillamine, and significantly inhibited erosions caused by indomethacin, aspirin and phenylbutazone. Gastric erosions caused by the same drugs were also prevented by metiamide and a suspension of a commercial preparation containing simethicone, magnesium hydroxide and aluminium hydroxide gel (Mann, 1977).

2.6 Anti-Androgenic Activity Repeated dose studies in the rat and the dog (see section 2.7) have shown that cimetidine reduces the rate of growth of the prostate. In studies in the im-

Cimetidine: A Review

102

Table III. Effect of cimetidine in preventing experimentally-induced gastric or duodenal ulcers in animals (after Okabe et al.. 1977b) Animal preparation

Ulcerinducing agent

Dose cimetidine (mg/kg)

Effect of control (% inhibition?

Intact rat

Stress

12.5 (ip; po)' 50 100

37.4ip; 64.8po 76.6ip; 8f.9po 95.4ip; 96.3po

Pylorus-ligated rat

Stress

12.5(ip; id) 50 100

18.9ip;-36.5id 8.7ip; 10.8id 57.8; 82.4id

Rat

Pylorus ligation

12.5(ip;id) 50 100

25.0ip; 15.6id 12.5ip; 18.6id 3.1ip; 31.3id

Pylorus-ligated rat

Aspirin

12.5 (ip; id) 50 100

30.9ip; 39.9id 65.9ip; 4f.Oid 96.Oip; 44.Oid

Intact rat

Indomethacin

12.5 (ip; po) 50 100

44.8ip; 43.6po 69.2ip; 79.3po 52.4ip; 94.3po

Guinea-pig

Histamine

12.5 (ip; po) 50 100

82.4ip; 10.0po 6f.8ip; 8O.0po 64.7ip; 46.7po

Rat

Serotonin

50 (ip; po) 100

-9.8ip; -17.3po 6.4ip; -19.5po

50 100

-36.8ip; 3.5po -15.3ip; -22.1 po

Reserpine

Carbachol-histamine

Rat

1 2

Route of administration: ip = intraperitoneal; id Figures in italics are statistically significant.

4 (iv)

44.3

8

82.0

intraduodenal; po

mature rat no detectable oestrogenic effect was found using the assay method of Hisaw (1959), but a weak anti-androgenic effect has been demonstrated during daily dosing with testosterone, and by its antagonism of the effects of exogenous testosterone on the prostates and seminal vesicles of young castrated rats.

oral; iv

intravenous.

Although it is known that active anti-androgenic compounds block the testosterone effect during the differentiation of the genital organs in male fetuses, the phalluses of the male fetuses in reproductive studies with cimetidine showed no evidence of feminisation (Leslie and Walker, 1977).

Cimetidine: A Review

The effect of cimetidine in retarding the development of the prostate and seminal vesicles in rats is reversible. The differences between the prostate and seminal vesicle weights in 2 and 8 month-old rats treated with 9S0mg/kg cimetidine and control animals were significant at the end of 3S days dosing, but were not significant after a I 7 day period without further dosing in rats of either age group (Leslie and Walker, 1977). Mating and reproduction functions were not affected. The antiandrogenic effect was apparent only at high dose levels, much higher than those used clinically. In man, continuous cimetidine therapy for 6 weeks did not alter mean plasma testosterone concentrations (Peter et al., 1977).

2.7 Miscellaneous Effects Ouabain cardiotoxicity in the cat is lowered by concomitant cimetidine 10mg/kg, but not by higher or lower dosages (Somberg et al., 1977). Metiamide lowered ouabain toxicity, when given in dosages of 12.S and 2Smg/kg, and neither H 2-receptor antagonist influenced heart rate, arterial blood pressure or AV conduction time.

2.8 Toxicology Studies 2.8.1 Acute Toxicity In the rat and the dog, the acute oral LDso is approximately 1000 times greater than the orallD so for antagonism of maximal histamine-stimulated gastric secretion (Leslie and Walker, 1977). In the mouse, LDso values for intravenous, intraperitoneal and oral administration are ISO, 470 and 2,SOOmg/kg respectively. Corresponding values in the rat are 106, 6S0 and S,OOOmg/kg, whilst those in the hamster are 880mg/kg intraperitoneally and 4,000mg/kg orally. The oral LDso in the dog is about 2,600mg/kg (Leslie and Walker, 1977). In the mouse the LDso of oral cimetidine was lowered from 1,970-2,380 to 1,220-1,670mg/kg by pre-treatment with chlorpheniramine S or SOmg/kg, mepyramine

103

90mg/kg or propantheline 200mg/kg (Leslie and Walker, 1977). 2.8.2 Sub-Acute and Chronic Toxicity Oral Administration Doses of 9S0mg/kg cimetidine daily caused excessive salivation and a slight increase in liver weights after 30 and 90 days and 6 and 12 months of administration to rats. Perineal soiling occurred at all intervals other than at 30 days and prostates and seminal vesicles were lighter than in controls in rats given cimetidine 378 or 9S0mg/kg daily for 6 or 12 months. An oral dose of ISOmg/kg daily resulted in increased liver weight in males after 6 months and prostates slightly lighter than in controls after 12 months' administration. Examination of the tissues revealed no histopathological abnormalities attributable to drug treatment. Although the highest dose employed (9S0mg/kg daily) was sufficient to inhibit gastric secretion continuously, there were no significant differences in parietal cell counts between controls and treated rats at 6 and 12 months. In dogs, transient tachycardia occurred after dosing in those treated with 336 or S04mg/kg for 3, 6 and 12 months whilst at these dosages and at dosages of 41, 112 and 114mg/kg daily there was a dose-related reduction in prostate size. Histological examination of 2 dogs (receiving S04mg/kg daily) which had to be killed at 4 and 33 weeks, showed centrilobular degeneration in the liver and tubular necrosis in the kidneys. Occasional but not progressive elevations of serum transaminases and alkaline phosphatase were seen at S04 and 336mg/kg dose levels and minor degenerative changes in the centrilobular areas of the liver were seen at the highest dosage level but not at lower doses. Liver changes observed after 6 months in the highest dose group were not present at 12 months. Intravenous injection of 7Smg/kg daily for 14 days raised serum cholesterol, but intravenous infusion of 126mg/kg for 10 days caused no drug-related effects in rats. Vomiting and weight loss occurred in 2 of 6 dogs given a 30 minute intravenous infusion of 84mg/kg for 14 days and moderate tachycardia was

104

Ometidine: A Review

pentagastrin infusion (Aadland et al., 1976; 1977a, b; Burland et aI., I 975a), histamine (Burland et al., 1975a), infusion of insulin 0.03pg/kg/h (Carter et al., 1976) or caffeine (Cano et al., 1976)[see table IV]. 2.8.3 Dysmorphology and Reproductive Studies Oral doses of up to 950mg/kg of cimetidine per The reduction results from a decrease in acid output day have been given to the rat, rabbit and mouse dur- and volume of gastric juice. A method of measuring ing pregnancy. In the treated rats a few more acid output without using bicarbonate infusion, but embryos were lost between ovulation and implanta- employing a liquid meal, was employed by Moberg et tion than in controls but eventual litter size did not al. (I 977) whilst Longstreth et al. (1977) used a new differ. 4 unexplained deaths occurred in pregnant rab- advanced and more physiological method bits at the two highest dose levels and embryo losses (Malagelada et al., 1976) which allows measurement after implantation, leading to reduced litter size, oc- of acid output without altering intragastric pH, and in curred at 328 and 950mg/kg dose levels. Pregnant response to an ordinary solid meal. Conventional mice given 950mg/kg grew less quickly than con- methods were used by other investigators. Pounder et trols. No evidence of increased deformities or im- al. (1976a) reported that acid concentration stimUlpaired fetal development was seen in any of the ated by food, was reduced by 57 % when cimetidine species studied. 200mg was given with the meal whilst there was a Fertility and mating performance of male rats 67 % reduction when the drug was given after the were not impaired by administration of cimetidine at meal. dosages of up to 950mg/kg for at least 70 days A dose-dependent inhibition of pentagastrindespite dose-related reductions in prostate and gonad stimulated gastric acid secretion was demonstrated by weights. Subsequent studies demonstrated that the Aadland et al. (1976, I 977a, b) when the dosage of effect of cimetidine 950mg/kg in reducing the size of intravenous cimetidine was increased from 0.3 to prostate and seminal vesicles is reversible (Leslie and 2.4mg/kg/h. Increasing the dosage of pentagastrin Walker, 1977). In females dosed with up to from 0.03 to 7.5pg/kg/h reduced acid inhibition by 950mg/kg cimetidine for 14 days prior to mating cimetidine from 74 to 57 %. A blood concentration of with undosed males and then during pregnancy and 1 to 2pmoIlL (0.25 to 0.5pg/mO is usually required lactation, there were no adverse effects on oestrous for a 50 % reduction in stimulated gastric acid secrecycles, mating, fertility, maternal weight gain or tion (Burland et al., I 975a), but in some studies perinatal behaviour, nor in litter size, viability or fetal (Bodemar et al., 1977) a concentration of Img/ml development. In some litters born to dams given high was required. dosages, pinna unfolding was delayed (Leslie and A 70 to 72 % reduction in 24-hour gastric acidity Walker, 1977). in subjects studied under physiological conditions was achieved with cimetidine 0.8 to Ig daily in four divided doses. Timing of the dose relative to meals did not influence the decrease in acidity (Pounder et al., 1976b). 3. Human Pharmacodynamics associated with intravenous injection of 41 mg/kg daily for 14 days.

3.1 Effect on Gastric Acid Secretion in Healthy Man Cimetidine given orally or by intravenous infusion effectively lowers gastric acid secretion stimulated by food (Moberg et al., 1977; Pounder et al., 1976a),

3.2 Effect on Gastric Acid Secretion in Duodenal Ulcer Cimetidine administered orally or by intravenous infusion, significantly lowers gastric acid secretion in

Cimetidine: A Review

105

Table IV. Inhibition of stimulated gastric acid secretion by cimetidine in healthy volunteers Method of stimulation

Author

No. of subjects

Cimetidine dosage

Reduction in acid secretion

Meal

Moberg et a!. (1977)

6

l00mg/hIV infusion

Statistically significant

Pounder et a!. (1976a)

6

200mgoral

57% cim with meal; 67% cim before meal

Aadland et al. (1976; 1977)

3

0.3-2.4mg/kg/h IV

50% with 0.3mg 90% with 2.4mg

Burland et al. (1975a)

3

l00mg/hIV infusion 200mg intraduodenal

53-91 % (75% av)

Pentagastrin

Histamine

Burland et a!. (1975a)

4

l00mg/hIV infusion 200mg intraduodenal

75-95%

53-91% 75-95%

Vagally-induced (insulin infusion)

Carter et a!. (1976)

6

l00mg/h IV infusion

75% mean

Caffeine

Cano et a!. (1976)

10'

300mgoral

Secretion lower than basal

5 subjects were healthy volunteers. 5 had inactive duodenal ulcer.

patients with duodenal ulcer. The reduction in total acid output results from a reduction in both acidity and volume. but the effect on acidity generally exceeds that on volume (Longstreth et al .• 1976b; 1977). Inhibition of meal-stimulated acid secretion is related to dose (Bodemar et al., 1977; Richardson and Fortran. 1975) and to blood levels of cimetidine (Bodemar et aI.. 1977; Henn et al., 1975; Longstreth et al .• 1976a; Pounder et al .• 1977). A 300mg oral dose lowers meal-stimulated 3-hour acid output by about 67 % and completely inhibits basal secretion in duodenal ulcer patients (Barbezat and Bank. 1977; Henn et al .• 1975). Oral or intravenous cimetidine also inhibits acid secretion stimulated by sham feeding and fundic distention (Schoon and Olbe. 1977). by

peptone meal (Henn et al .• 1975). pentagastrin infusion (Fielding et aI.. 1976). solid meal (Longstreth et al.. 1977; Richardson and Fortran. 1975). by histamine (Spence et al .• I 977a) and caffeine (Cano et al .• 1976). In a study (Blackwood and Northfield. 1977) in which cimetidine was.given 4 hours after the evening meal. poldine 8mg increased the inhibition of nocturnal acid secretion of cimetidine 200mg from 53.6 to 94.8 %. but did not increase the effect of a 400mg and 800mg dose (fig. 2). Whereas cimetidine 400 and 800mg inhibited both volume and acid output. poldine reduced acid secretion largely by reducing volume output. However. poldine 4mg increased the inhibition of nocturnal acid secretion of a 200 and

106

Ometidine: A Review

SQ.

... :::l

0

:g ~ 100

'0 § 80

~60 .5

_ _ Cimetidine -----"'" Cimetidine plus poldine

*40 c: 3l

E 20

o

200mg 400mg Cimetidine dosage

SOOmg

Fig. 2. Mean percentage inhibition of nocturnal acid output by cimetidine alone and in combination with poldine Bmg in 6 patients with duodenal ulcer {after Blackwood and Northfield,

1977}.

400mg dose of cimetidine in 6 patients who received cimetidine immediately after the evening meal (Saunders et aI., 1977). Cimetidine 300mg is more effective in inhibiting peptone meal-stimulated acid secretion than an 'optimal effective dose' of propantheline bromide (Henn et aI., 1975). However, in a comparison (Deering and Malagelada, 1977) of cimetidine 400mg (given with a meal) and 30ml doses of a commercial magnesiumaluminium hydroxide preparation (given 1 and 3 hours after the meal) the rate of 4-hour postprandial acid delivery into the duodenum of six patients was not significantly different after cimetidine or antacid therapy. Although a dose of 300mg at night reduces acid secretion throughout the night, a dose of 400mg at night seems to be necessary to maintain achlorhydria for 8 hours in a high proportion of patients studied (Longstreth et aI., I 976a). In a study of 24-hour gastric acidity (Pounder et aI., 1975b) a dosage regimen of 800mg daily (200mg four times daily) reduced mean hourly intragastric

acidity by 55 % whilst double the dosage of cimetidine produced a 67 % reduction. The difference between the dosages in inhibition of intragastric acidity was largely accounted for by the decrease in acidity between 2am and 8am. Longstreth et aI. (I 976a) noted that individual responses were variable and unrelated to the spontaneous rate of acid secretion, but there was a good correlation between blood levels and the extent of inhibition of gastric acid secretion. Anacidity was reported by Longstreth et aI. (I 976a) in 6 of 8 patients given a 400mg oral dose of cimetidine 6 hours after the evening meal. Hollander et aI. (I976), who administered cimetidine 4 hours after the evening meal, and Longstreth et aI. (I 976a} recorded significantly reduced nocturnal acid secretion for 8 hours after a 300mg dose of cimetidine (table V). The effect of a 200mg dose was significant for up to 7 hours, but a 1OOmg dose was without effect. Although cimetidine 1.6g daily reduced mean 24hour intragastric acidity by 67 % in patients receiving normal standardised meals (Pounder et aI., 1975b), intragastric pH remained below 2 for much of the 24hour period of treatment. In this study, as in that of Saunders et aI. (I 977}, cimetidine was given immediately after the evening meal which probably accounts for the lower degree of inhibition of gastric secretion in these studies than in those of Hollander et aI. (I 976) and Longstreth et aI. (I 976a). Nevertheless, the pH over a given period was similar to that in 4 patients who had undergone clinically successful vagotomy and suggests that such an intragastric pH level is compatible with successful therapy for duodenal ulcer.

3.3 Effect of Cimetidine on Serum Gastrin There is a theoretical possibility that the increase in intragastric pH produced by treatment with cimetidine (section 3.2) may increase gastrin release. If cimetidine therapy were prolonged and gastrin release continuously increased there might be hyperplasia of the parietal cell mass. This would in turn result in increased acid secretion and rebound secre-

Cimetidine: A Review

107

Table V. Effect of various doses of cimetidine (given 4 hours after the last meal of the day) on nocturnal acid secretion in 7 patients with duodenal ulcer (after Hollander et al., 1976) Hours after cimetidine

Placebo

Hydrogen ion concentration Cimetidine 100mg

2

3 4 5 6 7

8 9 10

78 71 88 59 58 54 46 56 53

± 12 ± 9 ± 15 ± 11 ± 10 ± 7 ± 11 ± 9 ± 11

43 57 34 31 31 35 36 40 41

± ± ± ± ± ± ± ± ±

Cimetidine 300mg

Cimetidine 200mg

13 15 7 5 6 8 7 4 8

38 29 15 20 24 23 46 53 53

± ± ± ± ±

22 20 15 12

10' 14

63 10'

9

92 ± 8

15 17 39 23

± 5 ± 5 ± 9

± ± ± ± ± ± ± ± ±

62 82 103

72 42 43 53 10

5

Differences statistically significantly different from placebo: 1 p plac

Cim > plac (day) Cim > plac (night) for first 3 weeks

86% cim 42% plac

Blackwood et al. (1976)

23

400mg tid pc 400mg n

6 weeks

82% cim 25% plac

Bodemar and Walan (1976)

443,8

200mg 200mg 300mg 300mg

tid cc n tid cc n

6 weeks

86% cim 93% cim 36% plac

Domschke et al. (1976)

125 ,-

200mg tid pc 200mg n

6 weeks

Healing (100%) significantly faster with cim

Gray et al. (1977)

40'0

200mg tid pc 400mg n

4 weeks

85% cim 25% plac

Cim >plac

Cim > plac (day) Cim> plac (night)

Hetzel et al. (1977a)

67"

300mg tid ac 300mg n

6 weeks

82% cim 39% plac

Cim > plac

Cim > plac (day) Cim > plac (night) for 1/2 of observed period

idem ( 1977b)

29 7

300mgqid

6 weeks

80% cim 36% plac

Multicentre Trial (1977a)

89

200mg tid pc 400mg n 400mgtid pc 800mg n

4 weeks

67% cim

Cim )plac

Cim> plac (day) less difference in effect on night pain

Semb et al. (1977)

40

300mg tid pc 300mg n

78% cim 29% plac 85% cim 60% plac

Relief of pain significantly more rapid with cimetidine

Abbreviations: tid = three times daily; pc = after meals; ac = before meals; cc = with meals; n = at night; qid times daily. 2 Complete healing in each group expressed as percentage of patients. 3 8 patients had prepyloric ulcers. 4 Cimetidine significantly superior to placebo (i.e. lower antacid use and greater number of pain-free days). 5 Hospital inpatients. 6 Pyloric ulcers in 12 patients. 7 Pyloric ulcers in 4 patients. 8 Results also reported by Bodemar et al. (1977). 9 Results also reported by Domschke et al. (1977). 10 Results also reported by Gillespie et al. (1977).

=

four

116

Ometidine: A Review

Table IX. Results of duodenal ulcer therapy with cimetidine for periods of 4 to 6 weeks according to dosage

Dosage

200mg 200mg 400mg 300mg 400mg 400mg 800mg

tid tid n tid tid tid n

and n and and n and n and

No. of patients'

Average percentage of patients with healed ulcers

15

86% 76%

53 55

20 32

88% 82% 78%

drank are self-selected groups and there were relatively few patients, the real influence on ulcer healing of these factors could not be conclusively determined. A recently completed double-blind study (Ippoliti, personal communication) which compared intensive antacid therapy with cimetidine 800 and 1200mg daily in 94 outpatients, found no statistical significance in the percentage of duodenal ulcers healed by four weeks' treatment with cimetidine (62 %) or antacid therapy (52 %). Diarrhoea occurred in about one-quarter of antacid-treated patients, whilst no sideeffects occurred in those treated with cimetidine.

Number of patients treated with the regimen shown.

5.2 Factors Influencing Response of Duodenal Ulcer to Cimetidine Therapy In a preliminary report of a well-conducted multicentre trial in the United Kingdom (Multicentre Trial, 1977a) in which groups were well matched with regard to age, sex, duration of ulcer symptoms and duration of current relapse, smoking history and ulcer type, cimetidine I or 2g daily was significantly superior to placebo. The rate of complete endoscopic ulcer healing was 29 % in the placebo group compared with 67 % and 78 % in those treated with Ig and 2g of cimetidine respectively. Thus, doubling the dose to 2g daily conferred little extra benefit in this study (see also section 5.2. I). A similar pattern of response was observed with regard to duodenitis, which healed or imprOVed in 68 % receiving cimetidine Ig daily, in 74 % on 2g daily, and in 22 % of those given placebo. Patients whose ulcers healed showed an improvement in their duodenitis three times more often than those whose ulceration persisted. The preliminary results have been confirmed on completion of the trial (Bardham, personal communication). The proportion of ulcers healed was 61.4 and 70.3 % in the cimetidine I and 2g groups respectively and 28.3 % in the placebo group. In a recent trial conducted in Australia (Hetzel, personal communication), ulcer healing did not appear to be clearly influenced by smoking or drinking of alcoholic beverages. However, as those who smoke or

On the basis of present data, the efficacy of cimetidine in accelerating the healing rate of duodenal ulcer does not appear to be influenced by timing of administration in relation to meals (section 5.2.2), or by severity or duration of ulceration (section 5.2.4 and 5.2.5). There is no clear evidence that response rate is influenced by pre-treatment basal acid output or by dosage.

5.2.1 Dosage To date, the studies which have compared different regimens of cimetidine, have not contained sufficient numbers of patients to detect a significant difference between groups in which a similar result is expected. In the study which involved the greatest number of patients (Multicentre Trial, I 977a) there was a tendency, which was not statistically significant, for a higher response rate with a dose of 2g daily than with Ig daily, but pooled results of the various regimens used in published reports (table IX) show no trend for results with 0.8g to Ig daily to be less satisfactory than those with higher doses. However, there appears to be a greater likelihood of abnormal biochemical values with higher dosage regimens (Blackwood et a\., 1976; Multicentre Trial, I 977), although a trend towards greater symptomatic

Cimetidine: A Review

response was reported by Bank et al. (I 976) with a dose of 1.6g daily than with 1.2g daily. There is pharmacological evidence (Blackwood and Northfield, 1977; Pounder et al., 1975b) [see section 3.2] that a dose of 300 to 400mg of cimetidine at night is the optimum dosage for suppression of nocturnal gastric acid secretion. The suppression of meal-stimulated acid secretion is related to dosage (see section 3.2) in duodenal ulcer patients, but it is not known if suppression of acid secretion is the factor responsible for the healing effect. If inhibition of acid output is the principal objective, treatment is directed at a reduction in basal or nocturnal secretion, or that in response to gastric secretory stimulants, or a decrease in acid concentration (Wormsley and Saunders, 1977). Further study of those patients whose ulcers fail to heal with cimetidine therapy and longer followup of those whose ulcers have healed may provide the information needed to determine optimum dosage.

5.2.2 Timing of Administration Relative to Meals In studies of cimetidine therapy of duodenal ulcer in outpatients (table VIII), the drug has been given immediately before (Hetzel et al., 1977a), with and after meals (Bodemar and Walan, 1976; Blackwood et al., 1976; Gray et al., 1977; Multicentre Trial, I 977a; Semb et al., 1977). The rationale for the chosen timing of administration are not discussed in the studies by the investigators, but on the basis of the clinical and endoscopic results there appears to be little difference in efficacy irrespective of timing of administration relative to meals during the day.

5.2.3 Basal Acid Output Preliminary data on the influence of pre-treatment basal acid output on the efficacy of cimetidine in healing duodenal ulcers are at variance, and further studies, particularly comparing larger numbers of those patients whose ulcers fail to heal with cimetidine with those in whom treatment was associated with healing, are required to determine what influence pre-treatment basal acid output has on the outcome of treatment. The pre-treatment basal acid output in patients whose ulcers did not heal was sig-

117

nificantly higher than in those whose ulcers healed in the study of Hetzel et al. (I 977a), and this has been confrrmed in an extension of this study (Hetzel, personal communication). No correlation between basal acid output and ulcer healing was found by Ippoliti (personal communication), but peak acid output in cimetidine-treated patients with healed ulcers was significantly higher than in those without healing. In smaller numbers of patients, Bank et al. (I976) reported that neither basal acid output (or pentagastrin stimulated acid output) before treatment nor extent of acid reduction by the H 2-receptor antagonist appeared to influence ulcer healing.

5.2.4 Duration of Treatment Whilst the healing rate of gastric ulcer can be assessed radiologically, radiology cannot reliably be applied to duodenal ulcer to determine healing. Duodenoscopic techniques offer a safe and acceptable procedure for direct examination of the duodenal bulb, but this technique is considered by many not to permit accurate measurement of the size of duodenal ulcers, and studies of the effect of drugs on the healing of duodenal ulcer can simply record whether or not the ulcer has healed. Thus it is not surprising that two studies (Blackwood et al., 1976; Hetzel et al., 1977a), in which endoscopy has been performed 2 weeks after beginning treatment, have reported that there was no significant difference in healing rate between placebo and cimetidine groups at 2 weeks. At 6 weeks both studies reported an 82 to 85 % healing rate with cimetidine compared with a 25 % healing rate with placebo. These fmdings may indicate that a period of treatment longer than 4 to 6 weeks may be of benefit in selected patients, but suitably designed controlled studies are required to determine this. Gray et al. (1977) reported complete healing of ulcers after 4 weeks cimetidine in all 13 patients with persistent ulceration after 4 weeks' placebo, but there waS no placebo group retained to determine the spontaneous healing rate over an 8-week period. It has been suggested, following a report of 3 cases of perforation of chronic peptic ulcer after abrupt cimetidine withdrawal (Wallace et al., 1977), that

118

Qmetidine: A Review

cimetidine 400mg at night should be continued for 3 months (or until healing is confirmed endoscopically)* after the initial course of cimetidine 1 to 1.2g daily.

5.2.5 Severity of Ulceration There are no published data in sufficient numbers of patients to permit any valid conclusions as to the influence of the duration or severity of duodenal ulceration on the efficacy of cimetidine. Preliminary studies do not suggest that ulceration which would have merited elective surgery (Gray et al., 1976; Gillespie et al., 1977) or that has been present for long periods (Bank et al., 1976), or that large ulcers (Bank et al., 1976) or multiple ulcers (Multicentre Trial, I 977a) are less likely to heal during cimetidine therapy. In fact, ulcer size, number and history does not appear to influence spontaneous healing either (Bank et al., 1976; Multicentre Trial, I 977a).

5.2.6 Previous Treatment with a H2-Receptor Antagonist Results of a study in patients with severe duodenal ulcer (Gillespie et al., 1977) suggested that some patients who experience endoscopic relapse after successful therapy with cimetidine may not show healing of their ulcer during a repeated 4 weeks of therapy with cimetidine. These investigators reported endoscopic ulcer healing in only 6 of II patients with relapse after an initial successful course of therapy with cimetidine several weeks earlier. This finding has not been confirmed by other investigators who have likewise studied only small numbers of patients (Venables, 1977; Bardhan, 1977). Experience with metiamide in a small number of patients (Saunders and Wormsley, 1977) suggests that subsequent courses of therapy may be less effective than the first course. However, Bodemar and Walan (personal

• In the USA, cimetidine is approved for use only in shortterm (up to 8 weeks) treatment of duodenal ulcer and for treatment of pathological hypersecretory conditions.

communication} found that cimetidine seemed to be as effective during treatment of recurrences as during the first course. Further study is required to clarify whether or not the response to a further full course of cimetidine treatment is likely to be as successful as the first treatment.

5.3 Prevention of Ulcer Recurrence* Preliminary published data, completed studies yet to be published (Bodemar and Walan, personal communication; Hetzel, personal communication) and studies still in progress (Mekel, personal communication), suggest that the recurrence rate of duodenal ulcer in patients in remission can be reduced by maintenance therapy with cimetidine 400mg (Bardhan et al., 1977; Gray et al., 1976) or 800mg daily (Bodemar and Walan, personal communication; Bardhan et al., 1977; Northfield and Blackwood, 1977; Northfield et al., 1977; Hetzel, personal communication). 68 patients with an endoscopically-healed peptic ulcer (42 duodenal, 17 prepyloric and 9 gastric) not more than 6 months old were treated prophylactically with a placebo (36) or cimetidine 400mg twice daily (32) for I year (Bodemar and Walan, personal communication). 65 % of the patients had received cimetidine 1000mg a day to heel active peptic ulcers before entering the double-blind trial. Patients who relapsed were given 1000mg of cimetidine daily until endoscopy showed complete healing, and were then re-assigned to their original double-blind medication or were submitted to surgery. 6 of 32 (J 9 %) patients on cimetidine and 30 of 36 (83 %) of patients on a placebo had endoscopically proven recurrent ulcer after a mean time of 7 and 4 months, respectively. I patient receiving cimetidine had 2 recurrences compared with 12 patients in the placebo group. 15 patients on a placebo and one on cimetidine were operated on during the trial because of recurrent ulcer symptoms. A recurrence rate at 12 weeks, on endoscopic assessment, of 4 out of 14 patients given cunetidine

119

Cimetidine: A Review

800mg at night and of I 3 of 14 given placebo was reported in another study. After 6 months, 2 of 8 on cimetidine and all 8 on placebo had relapsed (Northfield and Blackwood, 1977). Results of a multicentre trial (Bardhan et aI., 1977) showed a recurrence rate of 4.6 % (6 of 131) after a mean period of 3.6 months' therapy with cimetidine 800mg (400mg twice daily). A 7.9 % recurrence rate over almost the same period accompanied the use of cimetidine 400mg at night, whilst 42.1 % of placebo-treated patients relapsed a mean of 2.9 months after beginning the trial. However, in this report ulcer recurrence was not defined. It is still not known for certain if ulcers will recur rapidly after stopping long-term maintenance therapy, but there is some evidence that recurrence of duodenal ulcer after a single successful course of cimetidine is not more frequent than that after spontaneous healing (placebo therapy) [Bardhan et aI., 1977; Hetzel, personal communication]. Of 32 patients with healed peptic ulcers who received cimetidine 400mg twice daily prophylactically for I year, none had any complications in the 6-month follow-up period following completion of the trial (Bodemar and Walan, personal communication). The optimum dosage and duration of cimetidine treatment in the prevention of recurrence of duodenal ulcer has yet to be determined.

5.4 Treatment of Gastric Ulcer* Cimetidine has been shown to be effective in the initial healing of chronic duodenal ulcers (section 5.1.2), but its value in the healing of benign gastric ulcers is less clear. On the basis of complete healing, assessed endoscopically or by radiology, a statistically significant difference between cimetidine 800 to

• In the USA. cimetidine is approved for use only in shortterm (up to 8 weeks) treatment of duodenal ulcer and for treatment of pathological hypersecretory conditions.

1200mg daily and placebo has been demonstrated during 4 to 6 weeks treatment in less than half of the studies available to date (table X).

5.4.1 Open Trials An open study by Pounder et aI. (I 97 6c) in 10 patients with benign gastric ulcer in which all ulcers were healed at the end of 6 weeks treatment with cimetidine 0.8 or 1.6g daily, suggested that the drug may be useful in gastric as well as duodenal ulcer and indicated the need for controlled studies.

5.4.2 Controlled Trials Published experience with cimetidine in controlled trials in gastric ulcer is much less than that in duodenal ulcer. Although some reports are promising (e.g. Frost et aI., 1977; Multicentre Trial, 1977b) others are equivocal (table X) and further studies in larger numbers of patients with gastric ulcer are required to determine the efficacy of cimetidine in this disease. In a recent report (Frost et aI., 1977) of a multicentre trial conducted in Denmark, cimetidine Ig daily completely healed a significantly higher proportion (78 %) of benign gastric ulcers than placebo (27 %). The mean number of pain-free days was higher with cimetidine than with placebo, but the difference was not statistically significant. The ulcer history in the 22 patients given placebo was significantly longer than in the 23 patients treated with cimetidine and may have contributed to the low healing rate in the placebo group. A relatively low percentage of healed ulcers was also reported in patients given placebo in the multicentre trial conducted in France (Multicentre Trial, I 977b), in which cimetidine I g daily was significantly superior to placebo over a 4 week period. A somewhat higher percentage of completely healed ulcers has been reported in the placebo groups of those studies in which no significant difference between cimetidine and placebo could be demonstrated on the basis of complete ulcer healing (e.g. Ciclitira et aI., 1977; Machell et aI., 1977; Landecker et aI., 1977; Dyck, personal communication). A significant

Cimetidine: A Review

120

Table X. Results of studies comparing cimetidine with placebo and with carbenoxolone in outpatients with gastric ulcer Author

No. of pats.

Dosage

Duration

Healing rate'

Clinical results

Ciclitira et al. (1977)

25

200mg tid cc 400mg n

4 wks

12/15 (80%) cim 5/10 (50%) plac

Some evidence of more rapid relief of symptoms with cimetidine

Frost et al. (1977)

45

200mg tid pc 400mgn

6 wks

18/23 (78%)3 cim 6/22 (27%) plac

Fewer days of pain in cimetidine group but difference not significant

landecker et al. (Piper, personal communication)

48

300mg qid

5 wks

16/25 (64%) cim 11/23 (48%) plac 7/12 (58%) cim 6/12 (50%) plac 9/13 (69%) cim 5/11 (45%) plac

Symptoms improved in all patients and in most disappeared irrespective of treatment

More rapid relief of pain with cimetidine

24 inpts.

24 outpts.

Multicentre Trial (1977b)

53

200mg tid pc 400mgn

4 wks

18/26 (69%)3 cim 10/27 (37%) plac

Hunt et al. (1977)

24

cimetidine 200mg qid carbenoxolone l00mg tid 1 week, then 50mg tid

6 wks

10/12 (83%) cim 4/11 2 (28%) carb

1 Complete healing by endoscopic assessment expressed as number of patients. 2 Examination possible in only 11 of 12 patients treated. 3 Cimetidine statistically significantly superior to placebo.

difference between cimetidine and placebo, in the study ·of Landecker et aI., (I 977) was evident when results were assessed on the basis of the proportion of ulcers which decreased in size by 90 % or more over a 5-week period (radiological assessment). No signifi-

cant difference between the drugs was detected in the 24 inpatients studied, but cimetidine was superior to placebo in the 24 outpatients. The failure of Dyck et aI. (see Dyck, 1977) to demonstrate a statistically significant difference between cimetidine and placebo in

121

Cimetidine: A Review

60 outpatients may possibly have been due in part to the relatively liberal intake of a potent antacid by both cimetidine and placebo groups. The only study in peptic ulceration which compared cimetidine with an established treatment (Hunt et al., 1977) involved too few patients in the interim report to provide conclusive results~ These findings suggest that cimetidine may be at least as effective as usual doses of carbenoxolone in benign gastric ulcer. However, further studies comparing cimetidine and carbenoxolone are necessary as it cannot be assumed that both drugs are equally effective in the same subgroups of patients with gastric ulcer (Frost et· al., 1977). Because of the theoretical danger that cimetidine may mask the symptoms of malignant gastric ulceration, the possibility of malignancy should be excluded by both endoscopy and target biopsy, before beginning treatment.

5.5 Oesophagitis* Controlled double-blind therapeutic trials of cimetidine in oesophagitis are lacking. Results of an open study (McCluskie et aI., 1977) in 30 patients with oesophagitis confirmed by oesophagoscopy (26) or by radiological examination (4) suggest that cimetidine may be useful in the treatment of oesophagitis but do not provide evidence of efficacy. Repeat oesophagoscopy at 4 weeks in 25 patients revealed healing in 6 (24 %) and an improvementin U (44%).11 patients (43%) became painfree, and a similar proportion experienced relief from dysphagia and odynophagia. A review of 10 patients 3 months after the end of cimetidine treatment revealed that 5 remained well.

• In the USA. cimetidine is approved for use only in shortterm (up to 8 weeks) treatment of duodenal ulcer and for treatment of pathological hypersecretory conditions.

5.6 Zollinger-Ellison Syndrome Results of published studies with cimetidine in small numbers of patients with the Zollinger-Ellison syndrome (Bonfils et aI., I 977a,b; Burland and Parr, 1977; Cremer, 1977; McCarthy et al., 1977; Stage et al., 1977), indicate that at dosages of I to 2g daily there is relief of symptoms in many cases. Generally, diarrhoea and vomiting have been controlled and peptic ulceration has healed. Although continued administration for varying periods of 3 to 15 months has controlled symptoms in some cases (Cremer, 1977; McCarthy et al., 1977; Orchard and Peternell, 1977; Stage et aI., 1977), relief of symptoms has been transient or absent in others (Bonfils et al., J 977a,b). Some such cases responded to increased dosage (Burland and Parr, 1977). Further studies of the effects of long-term treatment are necessary to determine the safety of the continued treatment necessary in the Zollinger-Ellison syndrome, optimum dosage, and the best way to use the drug in this disease. The place of cimetidine treatment in the management of this syndrome is not clear, and although it does not influence the underlying disease, it may become a substitute for gastrectomy in symptomatic management. In the elderly and in those who have undergone previous gastric surgery, in whom the associated mortality from surgery is high (Larkworthy, 1977) it appears to have a valuable role.

5.7 Acute Gastrointestinal Haemorrhage* Cimetidine has been successfully used in a controlled, but unblinded, study (MacDougall et al., 1977a,b) to prevent acute gastrointestinal haemorrhage in patients with fulminant hepatic failure, and in uncontrolled studies to treat acute gastrointestinal haemorrhage associated with gastritis (Dunn et al., 1977) and gastric and/or oesophageal erosions (Burland and Parr, 1977; MacDougall et al., 1977b). Gastrointestinal haemorrhage (quantification of haemorrhage not dermed) developed in 13 of 24 placebo-treated patients with severe liver disease com-

122

umetidine: A Review

pared with in I of 26 treated with 150mg of intravenous cimetidine or metiamide repeated as necessary to maintain intragastric pH above 5 (MacDougall et al., I 977a). This difference was highly statistically significant (p