Antihistamines

E. Bleumink

15

antihistamines

H2-Receptor blocking agents INTRODUCTION As early as 1966, Ash and Schild (IR), using a number of histamine analogues and several histamine-sensitive in vivo and in vitro preparations, succeeded in defining 2 distinct classes of histamine receptors (H~ and H2); certain of the agonists which they studied were more active at the former sites, others at the latter. The identification of these receptors in different organs is still far from complete. Some of the receptors thus far characterized are listed in Table 1. Table 1.

Effects mediated by HI-receptors are antagonized by conventional antihistamines. Those due to H2-receptor stimulation are antagonized by a new class of H2-receptorspecific antihistamines. In 1972 Black et al. (2 R) introduced a series of antagonists that specifically blocked the H2-receptors but not the H~-receptors. The formulae of some H2-blocking agents are presented in Table 2. Numerous studies have been carried out with burimamide and metiamide and much information on these compounds can be found in the proceedings of an international

Effects mediated by histamine receptors

H~

H~

Excitation o f - myometrium - bronchial muscle intestinal muscle

Excitation of

heart ratc gastric acid secretion

Inhibition o f -

myometrium histamine release feedback inhibition (from leukocytes).

-

Table 2.

H~ antagonists

Compound

Structure --~--~--CH2 -CH~ -CH~ -CH~ -NH-~-CH~

Burimamide

H N ~ N

S

~---~--CH~-S Metiamide

H N ~ N

CHz-CH2-NH-~-NH-CH 3 S

f " ~ - ~ - - C H 2 - S-CHz -CH~ - N H - ~ - NH-CH3 Cimetidine

H N ~

N

NCH

Antihistamines

symposium on H2 -receptors held in 1973 (3R). Unlike the older antihistamines, histamine H2-receptor antagonists are potent inhibitors of gastric acid secretion (4 n). Burimamide, the first H2-antagonist to be used in man, is effective intravenously, but less so orally. Metiamide is active by mouth. It decreases nocturnal and meal-stimulated acid secretion in patients with duodenal ulcer; it abolishes gastric secretory activity in patients with gastric ulcer. It decreases pepsin secretion and it inhibits acid secretion more completely than the highest tolerated doses of an anticholinergic (for literature review, see 5R). In addition metiamide has been found to control acid hypersecretion in patients with the Zollinger-Ellison syndrome (6 c). Cimetidine, the latest H2 -antagonist, is rapidly absorbed after oral administration and inhibits the same wide spectrum of secretory stimulants as metiamide. Unfortunately, metiamide has been shown to lead to (reversible) agranulocytosis in some patients. Attention has therefore shifted to cimetidine. METIAMIDE In a double-blind trial(7 C) 68 patients with endoscopically confirmed duodenal ulceration received metiamide (36 patients) or placebo (32 patients) for 4 weeks in doses of 1 0 0 0 - 1 3 0 0 m g per day. The side effects noted are shown in Tqble 3. No abnormalities in haematological indices in any patient in the trial were detected. Plasma enzyme levels, however, increased during treatment, both in the patients and the placebo group. Three patients receiving placebo and 9 patients receiving metiamide had abnormal serum-transaminase values (SGOT, SGPT) during treatment. Plasma creatinine concentrations increased in 26 patients receiving metiamide and in 12 receiving placebo. The highest concentration recorded for a patient receiving metiamide was 1.8 rag/100 ml (upper limit of normality for the laboratory being 1.3 to 1.4 rag/ 100 ml) after 2 weeks treatment. In this patient and in 4 others (2 of whom received the drug) the concentrations returned to normal before treatment was completed. Changes of plasma creatinine and serum enzymes were also noted in a study of 14 patients receiving 8 0 0 - 1 2 0 0 mg/day for 28 days (8c). One patient with a recurrent ulcer was withdrawn because of persistent vomiting and failure to respond. Plasma cre-

141

atinine rose from a mean of 0.96 to 1.19 mg/100 ml; the rise was more rapid in patients given the higher dose. It was not accompanied by any change in plasma urea. There was a significant rise in SGOT and LDH. No subjective side effects were noted during metiamide therapy. In a study by Thjodleifsson and Wormsley (9 c ) 39 individuals received metiamide for 4 - 2 4 weeks. Most of the patients started with 800 mg daily rising to a maximum of 1200 mg. Two patients complained of an increase in the frequency of headache during treatment, so that metiamide had to be discontinued. Two patients complained of transient disturbance of sleep during thc first 2-3 nights of treatment and again the course of treatment had been completed. Two further patients complained of episodic diarrhoea which was transient in one individual and relieved in the other by reducing the dose to 400 mg daily. No abnormal haematological and renal function tests were recorded during treatment. A transient rise in SGPT was noted in 8 patients, 4 of whom also had increases of SGOT. All values returned to pre-treatment levels, although treatment was continued. Metiamide was given to 163 patients for the control of hypersecretion of gastric acid in daily doses of 8 0 0 - 1 2 0 0 mg for 4 weeks or more (10c). The side effects recorded in this study were mostly mild and transient, but there were also 2 cases of acute neu-

Table 3.

Side effects with metiamMe in patients with duodenal ulceration

Headache

Sweating Itching(without rash) Sore throat Aene Constipation Vomiting Nausea Drowsiness Diarrhoea

Patient group (n = 36)

Placebo group (n = 32)

1 (patient withdrew from treatment) 1 1 2 1 1 1 0 0 0

2

0 0 0 0 1 1 2 2 1

142 t r o p e n i a w h i c h m a y have b e e n caused b y the drug. The 2 patients concerned a woman of 49 (case 1) and a man of 63 (case 2). They were admitted to the trial with recurrent duodenal ulcers. Case 1 had received dicyclomine (Merbentyl) and isopropamide iodide/trifluoperazine (Stelabid), and case 2 had received an aluminium compound (Actal) for some weeks before the trial, but these drugs were withdrawn a few days before metiamide was started. Blood cell counts were performed regularly throughout the course of treatment and data for these 2 patients are shown in Table 4. In both cases the onset of neutropenia was accompanied by a sore throat, general malaise, and fever. As soon as a severe neutropenia was confirmed, the patients were admitted to hospital and treatment was stopped. Within 7-10 days of stopping metianride, the neutropenia had been completely reversed and both patients made an uneventful recovery. The bone marrow in case 1 taken on day 35, 4 days after stopping metiamide, showed active normoblastic erythropoiesis. Myelopoiesis was relatively depressed, M/E being lower than normal, and there was an absence of metamyelocytes and segmented neutrophils. Eosinophils and theirprecursors were increased. Lymphocytes and plasma cells were prominent but not increased. Megakaryocytes were normal. Stainable iron was normal. The appearances were consistent with those seen in some forms of agranulocytosis, the left shift in myelopoiesis indicating early recovery from the disease process, or reflecting hyperutilization of cells with a relative depletion of the myeloid storage compartment. The biopsy in case 2 taken on day 103, again 4 days after stopping metiamide, showed megakaryocytes in normal numbers, and the erythrocyte series was active and normal in appearance. The myeloid series was plentiful but there was marked reduction in metamyelocytes and segmented neutrophils. No abnormal cells were seen. The picture was compatible with the recovery phase following agranulocytosis. A fall in white b l o o d cell c o u n t was also r e c o r d e d by Blair and his c o w o r k e r s ( 6 c ) in 1 out o f 3 p a t i e n t s w i t h Zollinger-Ellison s y n d r o m e t r e a t e d w i t h t h e same drug ( 8 0 0 - 1 2 0 0 mg/day). Burland (11 c ) rep o r t e d the d e v e l o p m e n t o f a g r a n u l o c y t o s i s in 4 m o r e p a t i e n t s during t r e a t m e n t for severe and c o m p l i c a t e d p e p t i c ulcer. Three of these patients recovered once metiamide was w i t h d r a w n , b u t o n e died. Bone m a r r o w d e p r e s s i o n - f o u n d in a relatively high p e r c e n t a g e o f individuals (_+ 1%) - treated w i t h m e t i a m i d e for relatively s h o r t p e r i o d s is t o o serious a side e f f e c t to allow t h e drug to be m a d e available for r o u t i n e t r e a t m e n t o f p e p t i c ulcers. The m a n u f a c -

E. Bleumink

turers p r o m p t l y warned clinicians c u r r e n t l y treating p a t i e n t s with m e t i a m i d e to withdraw it f r o m their p a t i e n t s at the earliest o p p o r t u n i t y ( l lC). The b o n e m a r r o w depression is t h o u g h t to be due to t h e t h i o u r e a residue p r e s e n t in the m e t i a m i d e molecule r a t h e r t h a n to H 2 - r e c e p t o r b l o c k a d e in itself (1 1c). A t t e n t i o n has t h e r e f o r e shifted to c i m e t i d i n e in w h i c h the t h i o u r e a has been replaced by a cyanoguanidine group (Table 2). CIMETIDINE The latest H2-antagonist seems to be more p r o m i s i n g t h a n b u r i m a m i d e and metiamide. Pre-clinical investigations s h o w e d the absence o f h a e m a t o l o g i c a l changes in 66 dogs t r e a t e d with cimetidine in d o s e s o f up to 504 m g / k g / d a y for 3-9 m o n t h s ( 12 R). This c o n t r a s t s with a g r a n u l o c y t o s i s in 5 o u t o f 68 dogs t r e a t e d w i t h doses o f u p to 244 m g / k g / d a y o f m e t i a m i d e for 1-12 months. In a small o p e n trial 79 p a t i e n t s with active d u o d e n a l ulceration were t r e a t e d with a 6-week course o f c i m e t i d i n e in doses o f 1.6 g daily (13 C). No statistically significant change in t h e h a e m o g l o b i n , w h i t e b l o o d cell c o u n t or s e r u m e n z y m e s (SGOT, alkaline p h o s p h a t a s e etc.) was associated with treatm e n t . Plasma creatinine s h o w e d a significant increase during use but the m e a n level remained w i t h i n t h e n o r m a l range. In one pat i e n t t h e drug was s t o p p e d 2 d a y s b e f o r e the end o f t h e 6-week course because a maculopapular rash had d e v e l o p e d over the forehead. Of i n t e r e s t in this c o n n e c t i o n is the case h i s t o r y o f a p a t i e n t r e p o r t e d b y Burland et al. (1 lC), since in this p a t i e n t w i t h metiam i d e - i n d u c e d a g r a n u l o c y t o s i s t h e b o n e marr o w d e p r e s s i o n was reversed during treatment with cimetidine. A man aged 45 years had a 7-year history of duodenal ulceration; he had undergone vagotomy and pyloroplasty on a bulbar duodenal ulcer which was under-sewn at operation. He had copious gastric aspirates post-operatively and a further bleed from an anastomotic ulcer for which he had a partial gastrectomy on August 20. There was a carcinoid-like malignant tumour under the duodenal mucosa in the excised specimen. Serum-gastrin was measured on September 2, 3, and 4 and was found to be 1800, 229, and 336 pg/ml respectively. Postoperatively the patient continued to have copious aspirates of between 2 and 4 l/day and further bleeding. Metiamide (100mg) was infused in-

Antihistamines

143 10,000/ram 3. On October 30 he developed a staphylococcal infection of the abdominal wound, the nose, and one eye. His total white blood cells were 2600/mm 3, and no neutrophils were identified in the peripheral film; llb was 11.6 g/dl. On his admission to hospital on November 3 his total white blood cells wcrc 700/ram 3 with 15~ neu-

travenously on September 5 and within 2 hours the aspirates had ceased. He was treated with metiamide by mouth, his general condition rapidly improved, and he was discharged home to continue taking metiamide 200 mg twice daily and 400 mg at night. At the time of dischaxge his Hb was 12 4g/dl, and total white blood cells were Table 4.

Blood changes during and after metiamide treatment

Case 1 Day Day

0 1

Day 7 Day 14 Day 16 Day 21 Day 27 Day 31 Day 32 Day 35 Day 37 Day 40 Day Day Day Day

43 46 53 60

Metiamide (300 mg four times daily by mouth) . . . . . . .... Mild sore throat . . . . . . Sore throat, fever Metiamide stopped . . . . . . Bone-marrow biopsy Recovered clinically . . . . . . . . . . . . . . . . . . . .

. . . .

6.6 4.7 4.7

74 85 74

19 11 20

2 2

1 2

2.7

1

47

7

-

1.5 2.0 2.7

1

80

3

1 1

84

2

3 3

3.8 5.6 6.4 8.0 8.0

24 41 46

62 52 46

61

30

4.9 5.0 5.9 5.8 5.2 5.4 5.8

45 54 58 61 60 66 70

51 44 38 38 38 33 20

1 0 1 0 1 0

0 0 0 0 0

4 1 4 0 2 0 10

15.6 15.2 15.6 15.3 15.2 15.3 15.5

28.8 28.2 27.8 27.8 27.7 27.5 28.2

1.5 0.7 1.9 1.2 3.1 2.3 3.7

0 10 6 12 20 14 32

95 90 94 74 80 80 59

0 0 0 0 0 2 0

0 0 0 4 0 0 0

3 0 0 6 0 0 0

13.7 11.5 13.3 14.4

27.0 26.6 26.6 26.8

5.6 7.6 9.5

34 20 50

43 25 47

1 0 0

0 0 0

1 8 3

14.1

28.2

4 2 2

13.2 13.8 11.7

30.3 30.0 29.7

45

11.3

29.9

4 10

11.6 10.7 11.3

28.6 29.0

87

11.6 12.1 12.2 12.8 13.0

Case 2 Day

1

Day 7 Day 14 Day 21 Day 28 Day 42 Day 70 Day 98 Day Day Day Day Day Day Day

99 100 101 103 104 105 106

Day 107 Day 112

Metiamide (200 mg four times daily by mouth) . . . . . . . . . . . . . . . . . . . . . . . . ,, ,, ,, . . . . . . Sore throat, malaise, fever Metiamide stopped . . . . . . Bone-marrow biopsy . . . . . . Recovered clinically . . . . . . . . . . . .

WBC = White blood cell count MCH --- Mean corpuscular haemoglobin

-

144

E. Bleumink

trophils. The platelet count was normal. Metiamide was withdrawn. He had a melaena stool and Iris haemoglobin fell to 8 6 g/dl. Cimetidine was infused intravenously, 1 g per 24 hr. Bleeding stopped. On November 6 his total white blood cells were 3400/mm 3 with 47% neutrophils. He mainrained his recovery and his white cell count continued to improve. Treatment with cimetidine 200 mg four times a day was continued by mouth and he was discharged. He had no further dyspepsia and on November 20 his total white blood cells were ll,000/mm ~ with 60% neutrophils. A bone marrow aspirate had been obtained on

November 11 by which time he was already established on treatment with cimetidhae. This showed evidence of recovering agranulocytosis. C i m e t i d i n e would a p p e a r to be a p o t e n tially useful drug. It n e e d s f u r t h e r careful and e x t e n s i v e e v a l u a t i o n w i t h p a r t i c u l a r att e n t i o n t o t h e d e t e c t i o n of b o n e m a r r o w depression, changes in c r e a t i n i n e levels and s e r u m e n z y m e s . L o n g - t e r m safety m u s t of course also be established.

H 1-Receptor blocking agents NEW C O M P O U N D S Several n e w a n t i h i s t a m i n e s f o r t h e treatm e n t o f rhinitis a n d skin disorders (eczema, c h r o n i c urticaria) have b e e n i n t r o d u c e d . For t h r e e of t h e m d a t a are available o n t h e incidence of side effects. T h e t h r e e are: Primalan [ ( M e q u i t a z i n e = ( q u i n u c l i d i n y l - 3 methyl)- 10-phenothiazine)], Eu tarpan ( W A 1 7 2 H F = C l o b e n z e p a n , see Figure 1), a n d H C 2 0 - 5 1 1 . The side e f f e c t s n o t e d for p r i m a l a n ( 1 4 C, 1 5 c ) , e u t a r p a n ( 1 6 c , 17 c ) a n d HC 2 0 - 5 1 1 (18 c ) have all b e e n mild and transient. A l t h o u g h f u r t h e r i n f o r m a t i o n will bec o m e available d u r i n g t h e c u r r e n t year, t h e r e are n o i n d i c a t i o n s so far t h a t t h e p a t t e r n of side effects is very d i f f e r e n t to t h a t o b s e r v e d w i t h the a n t i h i s t a m i n e s of longer standing. ANTAZOLINE AND IMMUNE HAEMOLYTIC ANAEMIA A case of a n t a z o l i n e - i n d u c e d t h r o m b o c y t o p e n i a has b e e n described. T h e t h r o m b o c y t o p e n i a was associated with h a e m o l y t i c a n a e m i a , h a e m o g l o b i n u r e a and acute renal failure(23c). The symptom occurred on t h r e e occasions w h e n t h e drug was given to c o n t r o l allergic m a n i f e s t a t i o n s . In t h e pat i e n t ' s s e r u m a n t i b o d i e s t o a n t a z o l i n e were

CH2--CH2--N(CH3)

2 . HC[

H Fig. 1.

Eutarpan (clobenzepan).

detected. Moreover complement consumpt i o n was f o u n d to occur. The diagnosis of drug-induced immune haemolytic anaemia t h e r e f o r e seems m u c h m o r e likely t h a n a t o x i c m e c h a n i s m . One o t h e r case o f t h r o m b o c y t o p e n i a h a s b e e n described o n an earlier occasion, b u t it was n o t clear w h e t h e r an i m m u n e m e c h a n i s m was involved ( 2 4 c ) . BROMPHENIRAM1NE, CHLORPHENIRAMINE AND FACIAL DYSKINESIA Oral a n d facial dyskinesia have b e e n described d u r i n g acute t r e a t m e n t w i t h L-dopa a n d d o p a m i n e r e c e p t o r agonists and a f t e r t h e r a p y w i t h a n t i - p s y c h o t i c drugs, especially p h e n o t h i a z i n e a n d b u t y r o p h e n o n e derivatives (see C h a p t e r 5). In 1973 WSrz described a case of a 60year-old w o m a n in w h o m oral dyskinesia d e v e l o p e d a f t e r p r o l o n g e d use o f a n o n phenothiazine antihistamine mehydrolin(25c). T h a c h et aL ( 1 9 c ) described 2 cases of oral facial dyskinesia associated w i t h p r o l o n g e d use of a n t i h i s t a m i n e decongestants, w h i c h m u s t be briefly discussed here, since t h e drugs involved are very widely used, o f t e n for trivial i n d i c a t i o n s . Case 1. A 55-year-old housewife with recurrent rhinitis had taken two medications on a regular basis for 10 years. The first of these was a timed-release capsule containhag brompheniramine maleate, 12 rag, phenylephrine hydrochloride, 15 mg, and phenylpropanolamine hydrochloride, 15 rag. She took 2 tablets a day for 8 years, and then took 2 tablets every other day. The other tablets contained phenindamine tartrate, 10 mg, and phenylephrine hydrochloride, 5 mg. She took 4 - 8 of these tablets weekly. Three months before the onset of abnormal movements, she took fluphenazine hydrochloride in a dose of 1 mg daily for

Antihistamines

8 days. After 5 years of medication, blepharospasm developed, and was followed over the next 6 months by the gradual appearance of involuntary movements of the lace, tongue and hands. She had pharyngeal dysphagia, with incomplete swallowing, nasal regurgitation of food, and dysarthria. On examination, sbe had frequent episodes of blepharospasm and grimacing associated with intermittent irregular tic-like bobbing movements of the head. ~llle movements interrupted speaking. Her hands exhibited constant semipurposive movement~ There were no indications of psychiatric disease or of intellectual impairment. All medications were discontinued, with little clinical change during 2 months of observation. An oral probenecid tolerance test to estimate the central turnover of dopamine showed a Immovanillic acid accumulation in lumbar cerebrospinal fluid of l 12 ng per ml as compared with 166 + 24 ng per ml for 8 normal controls. A therapeutic double-blind trial of brompheniramine maleate slowly increasing in dosage to 16 mg 4 times a day resulted in a marked worsening of the dyskinesia. When the drug was replaced with placebo, symptoms returned to the pretreatment level of severity after 3 days. Haloperidol (maximum dose, 2 mg four times a day) led to relief of dyskinesia within 3 days. hnprovement was sustained for tim duration of the 13-day trial and was followed by clinical worsening on placebo. Case 2. A 65-year-old woman had taken capsules containing chlorpheniramine maleate, 8 mg, phenylpropanolamine, 50 mg, and isopropamide, 2.5 mg, for control of allergic rhinitis. In the third year of this medication she took talbutal (5-allyl-5sec-butyl-barbituric acid), 120 mg at bedtime, and chlordiazepoxide hydrochloride, 10 mg twice weekly. Two years before this medication she had taken dexamphetamine for 6weeks. Blepharospasm developed after 3 years of use of the chlorpheniramine compound. Two years later she had progressive difficulty keeping her mouth closed and stiffness in her neck. Her speech became severely impaired. She occasionally choked or had nasal regurgitation. Examination confirmed irregular spasms of the facial muscles with open-mouthed gaping lasting 2 3 seconds. The tongue moved about continuously in the mouth. A three-persecond tremor involved the mandible and soft palate. Eight weeks after discontinuation of medications, mandibular tremor was relieved, oral gaping was lessened, and speech was markedly improved. The abnormal movements did not improve further in the next 4 months. The probenecid-induced accumulation of homovanillic acid was 43 ng per ml. During progressive chlorpheniramine hydrochloride medication (to a maximal dose of 12 mg four times a day), mandibular tremor returned after one week, and other abnormal movements worsened during the next 2 weeks. The abnormalities improved after replacement of drug with placebo. One month later, a trial of haloperidol (2.5 mg four times a day) resulted in symptomatic improvement after 7 days.

14 5

The only m e d i c a t i o n s t a k e n by the above p a t i e n t s b e f o r e o n s e t o f s y m p t o m s were t h e d e c o n g e s t a n t preparations. The increase in dyskinesia w h e n t h e suspect a n t i h i s t a m i n e alone was given to each p a t i e n t suggests the causal relation o f this t y p e of drug to the symptoms. O t h e r e x p l a n a t i o n s for the observed s y m p t o m s are possible. It cannot be excluded for e x a m p l e that the dyskinesia in such cases is elicited by a c o m b i n e d e f f e c t o f 2 or more substances in the preparations. Since detailed i n f o r m a t i o n on m a n y fixedc o m b i n a t i o n p r e p a r a t i o n s is lacking, particularly with regard to the u n w a n t e d e f f e c t s , clinical s t u d y o f this p r o b l e m is n e e d e d . So far n o definite conclusions can be drawn. The publication o f Thach et al. has led t o 3 letters to t h e e d i t o r in the same j o u r n a l in w h i c h some f u r t h e r evidence has been presented in s u p p o r t o f the view that there is a causal relationship b e t w e e n a n t i h i s t a m i n e therapy and persistent dyskinesia ( 2 0 c - 2 2 c ) . Davis (21 c ) described a p a t i e n t on c h l o r p h e n i r a m i n e t h e r a p y (12 mg daily) since 1965, who had had progressive leftsided facial dyskinesia since 1968. A f t e r publication o f the p a p e r cited above the pat i e n t was advised to d i s c o n t i n u e his antih i s t a m i n e m e d i c a t i o n . In the 6 weeks after c h l o r p h e n i r a m i n e was d i s c o n t i n u e d d r a m a t i c i m p r o v e m e n t o f t h e facial dyskinesia occurred. A careful s t u d y o f m a n y cases with t h e same clinical s y m p t o m s may evaluate the relative i m p o r t a n c e o f a n t i h i s t a m i n e s in the aetiology o f drug-induced facial dyskinesia. CHLORPHENIRAMINE AND BONE-MARROW DEPRESSION C h l o r p h e n i r a m i n e is considered to be a relatively harmless drug in view o f its widespread use and the rarity with w h i c h serious side e f f e c t s are r e p o r t e d in the literature. In a d d i t i o n to the cases o f facial h y p e r k i n e s i a discussed above Deringer and Maniatis (26 c ) described a 32-year-old p a t i e n t who develo p e d p a n c y t o p e n i a a f t e r m e d i c a t i o n with a p r e p a r a t i o n o f c h l o r p h e n i r a m i n e and p h e n y l p r o p a n o l a m i n e . A m a r k e d decrease o f the n u m b e r o f platelets and l e u k o c y t e s occurred. A year later the patient was p r e s c r i b e d c h l o r p h e n i r a m i n e alone a f t e r w h i c h the w h i t e b l o o d cell and the t h r o m b o c y t e counts again s h o w e d a significant fall. The c h l o r p h e n i r a m i n e was d i s c o n t i n u e d and 3 days later t h e platelet c o u n t had risen to a

E. Bleumink

146 n o r m a l value. Since t h e n she had b e e n well w i t h o u t f u r t h e r h a e m a t o l o g i c a l abnormalities. These observations may be coincidental and an isolated case of u n w a n t e d e f f e c t says little a b o u t the relative t o x i c i t y o f t h e particular drug. One may agree with t h e comm e n t o f S p r y ( 2 7 c) t h a t 'since previous

reports of chlorpheniramine-induced bone m a r r o w d e p r e s s i o n have n o t proved to be correct and since the drug is very widely prescribed, o n e should be c a u t i o u s in attrib u t i n g this d a n g e r o u s side e f f e c t to a safe a n t i h i s t a m i n e . Every a t t e m p t should be m a d e t o find a n o t h e r cause; failure to do so m a y prove fatal if a n o t h e r drug is involved'.

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