214 THE NATIONAL MEDICAL JOURNAL OF INDIA VOL. 5, NO.5

Single daily dose of carbimazole in the treatmentof hyperthyroidismS. K. GUPTA, A. MITRAL, M. M. GODBOLE

ABSTRACTBackground. The antithyroid drugs, methimazole and

carbimazole, are conventionally used in divided daily doses.However, these drugs have a longer intra thyroidal than aplasma half-life. We undertook this prospective, controlledstudy, in an area of mild iodine deficiency, to compare theefficacy of a single daily dose of carbimazole with divideddoses in the treatment of hyperthyroidism.

Methods. Nineteen patients with hyperthyroidismreceived 30 mg of carbimazole daily at bed time (group A)while 14 received 10 mg of carbimazole every 8 hours (groupB). These patients were assessed clinically and biochemicallyby estimation of serum total thyroxine, total triiodothyronineand thyrotropin before and 1, 2, 3, 4 and 6 weeks aftertreatment.

Results. There was no significant difference between meanbaseline concentrations of thyroxine and triiodothyronine.After 1, 2, 3, 4 and 6 weeks there was a decline in their con-centrations which was similar in both groups (p>0.05).Euthyroidism was achieved in 4.6±1.4 weeks (range2-6 weeks) in group A and in 3.8±1.2 weeks (range3-6 weeks) in group B (p>0.05).

Conclusions. We conclude that carbimazole in a singledaily dose is an effective method for treating hyperthyroidismin an area of mild iodine deficiency and its efficacy is compar-able to divided dose therapy. This practical and acceptablemethod of treatment can be specially useful in patients whofind it difficult to remember to take divided doses.

INTRODUCTIONPatients with hyperthyroidism' are usually recommendedmethimazole, carbimazole or propylthiouracil in divideddaily doses (every 6 to 8 hours) because these drugs haveshort plasma halt-Iives.? However, recent studies haveshown that the antithyroid effects of these thionamides arerelated to their intrathyroidal rather than plasma half-lives. 3

Methimazole has a plasma half-life of 6.8 hours" but has beenshown to exist in high concentrations in thyroid tissue forup to 20 hours.! It has been found to be biologically activeeven 40 hours after oral administration as evidenced by anincreased perchlorate discharge test.>

Sanjay Gandhi Postgraduate Institute of Medical Sciences,PO Box 373, Lucknow 226001, Uttar Pradesh, India

S. K. GUPTA, A. MITHAL, M. M. GODBOLECentre for Endocrine Sciences

Correspondence to A. MITHAL

© The National Medical Journal of India 1992

This difference in pharmacokinetics and bioactivity has ledsome workers to use these drugs in a single daily' doseschedule. A single daily dose is likely to improve the com-pliance of patients, which is of considerable importance inlong term antithyroid treatment. However, only a fewreports on the use of methimazole's" and propylthiouracil's?in a single daily dose schedule are available.

Carbimazole is known to be rapidly and completely bio-activated to methimazole after oral intake. 10 There has beenno study on the effect of carbimazole in a single daily doseschedule, particularly from India where iodine intake is oftenmuch lower than in the USA or Europe. We therefore.compared the efficacy of a single daily dose of carbimazole(30 mg/day) with divided doses (10 mg 8-hourly) in themanagement of patients with hyperthyroidism.

PATIENTS AND METHODSNineteen patients with hyperthyroidism diagnosed by clinicaland biochemical criteria were given carbimazole (Neo-Mercazole'P Nicholas Laboratories India Ltd, Bombay) in anoral dose of 30 mg daily at bed time (group A). Fourteenhyperthyroid patients who were administered carbimazole10 mg 8-hourly served as controls (group B). All the patientsin both the groups had diffuse thyromegaly and increasedradioactive iodine uptake.

The mean age of patients in group A was 44±12.6 years(range 18-60 years) and in group B was 40±1O.8 years (range20-60 years). Group A had 10 males and 9 females whilegroup B had 6 males and 8 females. There was no statisticaldifference in goitre size between groups A and B (group A:48±26 g, range 20-80 g; group B: 48±27 g, range 20-100 g;p>0.05). The duration of symptoms was also similar in bothgroups (group A: 3.5±2 months, group B: 4.2±1.5 months;p>0.05). None of the patients included in the study wereunder treatment prior to starting carbimazole.

Clinical examination was done before treatment and after1,2,3,4 and 6 weeks of therapy. The blood samples for theestimation of serum thyroid hormones and thyrotropin weredrawn by venepuncture. Serum was separated after centri-fugation and stored at -20°C till the time of assay.Euthyroidism was defined as normal serum TT3 and TT4.

The estimations of serum total thyroxine (TT4) , totaltriiodothyronine (TT3) and thyrotropin (TSH) were done byradioimmunoassay (RIA) using commercially available kits.The sensitivity of TT3, TT4 and TSH was 0.18 nmollL,32 nmollL and 1 !&IU/ml respectively. The interassay andintraassay variations of TT3, TT4 and TSH were less than

GUPTA et al. : SINGLE DAILY DOSE CARBIMAZOLE IN HYPERTHYROIDISM 215

10%. The normal range of serum TT3, TT4 and TSH in ourlaboratory is 1.03-3.00 nmol/L, 70-170 nmol/L and less than5".IU/ml respectively. We did not use a 'sensitive' TSH assayas it was not available to us at the start of the study.

Statistical analysis was done by the two-way analysis ofvariance. A p value of 0.05 or less was considered to be sig-nificant.!'

RESULTSThe mean basal serum TT4 and TT3 concentrations in groupA were 258±46 nmol/L (range 180-340 nmol/L) and 7.5±2.4nrnol/L (range 3.6-10.7 nmol/L) , while in groupB they were255±95 nmol/L (range 180-375 nmol/L) and 7±3.95 nmol/L(range 3.5-13.8 nmol/L) respectively. There was no significantdifference in the mean basal serum TT3 and TT41eveis bet-ween groups A and B (p>0.05). There was a progressivedecline in the concentrations ofTT3 and TT4 in both groupsand there was no statistical difference after 1, 2, 3, 4 and6 weeks of treatment (p>0.05; Figs. 1 and 2). The serumTSH remained suppressed in all the patients throughout thestudy period.

Euthyroidism was achieved in 4.6±1.4 weeks (range2-6 weeks) in group A and 3.8± 1.2 weeks (range 3-6 weeks)in group B (p>0.05). All the patients in both groups wereeuthyroid by the' end of 6 weeks. No side-effects of carbimazolewere observed.

DISCUSSIONAdministration of a drug in a single daily dose is convenientand ensures better patient compliance. Attempts to usepropylthiouracil as a single daily dose were made more thantwo decades ago" with some initial success but other workersfound this regime to be ineffective. 12 This practice has, there-fore, not been generally accepted. The successful use ofmethimazole in a single daily dose has been reported 6,7 butthere has been only one prospective study in whichmethimazole in a dose of 40 mg per day was used. 7 There hasbeen no report of a trial evaluating the use of carbimazole ina single daily dose.

Our patients came mainly from the state of Uttar Pradesh,the inhabitants of which are among the most severely iodinedeficient in India.P However, after the supply of iodated saltthis situation has improved and the urinary iodine excretionpresently ranges from 5-10/1 g/dl in the urban areas of thisstate (unpublished data). A high iodine intake is known tomodify the response to antithyroid drugs by severalmechanisms. Iodine enhances the immunological response inautoimmune thyroid disorders'< and -also increases therelapse rate of patients with Graves' disease after anti-thyroid drugs." We have earlier shown that in a mildlyiodine deficient population, a moderate dose of carbimazoleof 30 mg/day is effective for control of hyperthyroidism. 16 Wetherefore used carbimazole in the same dose. As the durationof treatment was 6 weeks, we cannot speculate on the longterm outcome and relapse rate in these patients.

Our study showed that there was no difference in theresponse to a single or a divided dose schedule. Although theserum thyroid hormone levels remained slightly higher inpatients given a single dose and euthyroidism was achievedin those patients given divided doses a few days earlier, thedifferences were not statistically significant. Using the con-ventional assay, we did not observe any increase in TSHlevels after 6 weeks of treatment.

••cOJ..J 100 -------------------------------------------Ee•..w _•••caJ:.v

~c

.~

~C 40••vcoV

GroupB

~ 20...E"..~ OL-----.-----._---.-----.-----------.-----

234Duration (Wl!l!ks)

6

FIG 1. The percentage changes in mean serum TT3concentrations from baseline values

...!:~ 100o.0

c.2"0-E 40..ucou

~ 20...Ez~ oL-----.---~._---.-----.--~-------.----

GroupB

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6

FIG 2. The percentage changes in mean serum TT4concentrations from baseline values

Our results suggest that administration of carbimazole in a30 mg single daily dose is an effective, convenient and safeway of treating patients with hyperthyroidism in areas of mildiodine deficiency.

ACKNOWLEDGEMENTSWe are grateful to Mr Rajesh Srivastava for laboratoryassistance and Mr Sher Singh for secretarial assistance.

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Besser GM (eds). Endocrinology. Volume 1. Philadelphia:W. B.Saunders, 1989:646-83.

2 Alexander WO, Evans V, MacAulay A, GallagherlF Jr, LondonoJ. Metabolism of 35S-labelled antithyroid drugs in man. Br Med J1969;2:290-3.

3 Jansson R, Dahlberg PA, Johansson H, Lindstrom B. Intrathyroidal

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concentrations of methimazole in patients with Graves' disease.1Clin Endocrinol Metab 1983;57:129-32.

4 Cooper DS. Which anti-thyroid drug? Am 1 Med 1986;80:1165--8.5 Wartofsky L, Ingbar SH. A method for assessing the latency,

potency and duration of action of antithyroid agents in man. In:Fellinger K, Hofer R (eds). Further advances in thyroid research.Vienna:Verlagder Wiener Medizinischen Akademie, 1971:121-35.

6 Shiroozu A, Okamura K, Ikenoue H, et al. Treatment of hyper-thyroidism with a small single daily dose of methimazole. 1ClinEndocrinol Metab 1986;63:125--8.

7 Roti E, Gardini E, Minelli R, Salvi M, Robuschi G, Braverman LE.Methimazole and serum thyroid hormone concentrations in hyper-thyroid patients: Effects of single and multiple daily doses. AnnIntern Med 1989;111:181-2.

8 Greer MA, Meihoff WC, Studer H. Treatment of hyperthyroidismwith a single daily dose of propylthiouracil. N Engl 1 Med 1965;272:888-91.

9 Kammer H, Srinivasan K. The use of antithyroid drugs in a singledaily dose: Treatment of diffuse toxic goitre. lAMA 1969;209:1325-7.

10 Nakashima T, Taurog A. Rapid conversion of carbimazole to

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methimazole in serum: Evidence for an enzymatic mechanism. ClinEndocrinol (Ox!) 1979;10:637.

11 Armitage P, Berry G. Statistical methods in medical research.Oxford:Blackwell Scientific Publications, 1990:214-63.

12 Gwinup G. Prospective randomized comparison of propylthiouracil.lAMA 1978;239:2457-9.

13 Pandav CS, Godbole MM, Kochupillai N, Karmarkar MG.Endemic goitre and endemic cretinism in India: Current status ofextent, severity and control measures. In: Dunn IT, PreteU EA(eds). Towards the eradication of endemic goitre, cretinism andiodine deficiency. Washington:Pan American Health Organization,WHO, 1986:341-56.

14 Eisenbarth GS. Autoimmune endocrine disorders. In: DeGroot U,Besser GM (eds). Endocrinology. Vo13. Philadelphia: WB Saunders,1989:2632-48.

15 Azizi F. Environmental iodine intake affects the response tomethimazole in patients with diffuse toxic goitre. 1Clin EndocrinolMetab 1985;61:347-77.

16 Jones T, Mithal A, Kochupillai N, et al. Drug treatment ofthyrotoxicosis: Rapid responses in iodine deficiency. 1AssocPhysicians India 1988;36:13A.

Eligibility Criteria for Registering Studies inThe Cochrane Register of Randomized

Controlled Trials of Health CareThe Cochrane Register of Randomized Controlled Trials (RCTs) of Healthcare isbeing compiled to facilitate systematic, up.•to-date reviews of RCTs, and thus toobtain unbiased estimates of the differential effects of alternative forms of health-care. The Centre wishes to obtain information on RCTs conducted in India orelsewhere and published in Indian non-indexed journals for inclusion in theCochrane Register of RCTs. Those interested may write to the address givenbelow. Reviewers vary in the criteria they use to decide whether or not a particularcontrolled trial can be considered to have been randomized. Because the main aimof the Register is inclusion of as high a proportion as possible of all RCTs of health-care, the eligibility criteria for deciding whether or not a controlled trial should beregistered have been left relatively 'liberal'. A consequence of this strategy is thatthe controlled trials on the Register will not always meet the more stringent inclu-sion criteria that reviewers will often wish to apply in systematic, focused reviews.

1. Main register: A trial is eligible for inclusion in the main register if, on the basisof the best available information, it is judged that the individuals (or other units*)followed in the trial were assigned, prospectively, to one of two (or more) alter-native forms of healthcare using either random allocation, or some quasi-random method of allocation (such as alternation, date of birth, or case recordnumber).

Crossover trials in which random or quasi-random allocation to alternativeforms of care has been used are eligible for inclusion in the register.

2. Subsidiary register: A trial is eligible for inclusion in the subsidiary register if, onthe basis of the best available information, it is judged that assignment to alter-native forms of care may have been by one the methods described above.

If The Cochrane Centre is provided with clear evidence that a trial registered in theCentre's main or subsidiary register, does not, in fact, meet the eligibility criteria setout above, the trial record will be transferred to a reject register, after annotationto explain the reasons for the transfer.

• Units of randomization may be individuals, groups (such as communities or hospitals),' organs (such as eyes),or other parts of the body (such as teeth).

I