Gut 1995; 37: 325-328 325 Low dose famotidine and cimetidine in single a postprandial doses: placebo controlled Gut: first published as 10.1136/gut.37.3.325 on 1 September 1995. Downloaded from comparative study of overnight pH T G Reilly, S G Mann, M Z Panos, R P Walt Abstract four smokers who were able to abstain from To investigate the relative abilities of low smoking on the days of the study. Median doses of famotidine and cimetidine to weekly ethanol consumption ascertained by raise intragastric pH after a single post- questionnaire was 13 units (range 0-30). Each prandial evening dose, 16 healthy volun- volunteer gave his or her written informed teers were recruited to a four period consent and the study protocol was approved crossover trial offamotidine 10 mg, cime- by South Birmingham Health Authority Ethics tidine 100 mg and 200 mg compared with Committee. placebo. Intragastric pH was monitored between 1800 and 0730 with a nasogastric pH electrode. Median gastric pH rose Study design from 1.35 (interquartile range 1-1-1-65) The investigation was designed as a four period with placebo to 1 95 (1.6-5.35, p<O.OOl crossover study with all subjects receiving the Friedman rank) after dosing with famo- four different preparations in a random order. tidine 10 mg, to 1.46 (1.3-2.0, 0.05<p<0.1) The study was partially blinded in that the after cimetidine 200 mg, and remained drugs were recognisably different but the 1.35 (1-1-1.6, p>0.2) after cimetidine subjects were not aware of which was which. 100 mg. Intragastric pH was above 3 for Of the two principal investigators one (RPW) 34% (p<0.005) of the time after dosing was blinded to the drugs. There was a wash out with famotidine, compared with 13.6% period of at least six days between studies. (p>0.2) after cimetidine 200 mg, 9.5% On each study day subjects arrived at 1700 (p>02) after cimetidine 100 mg, and 4.7% on the investigation unit having fasted for six after placebo. The rise of intragastric pH hours. Bipolar glass pH electrodes (Ingold after famotidine 10 mg is significantly M440) were calibrated in standard buffer solu- http://gut.bmj.com/ greater than that after either 200 mg or tions of pH 7.00 and 4.01 and calibration was 100 mg cimetidine when the drugs are verified at pH 1.69. These electrodes were used postprandially. passed by the nasogastric route. A drop in pH (Gut 1995; 37: 325-328) to less than 2 was taken as evidence of the tip of the probe having entered the stomach, and Keywords: H2 receptor antagonist, intragastric pH, the electrode was advanced a further 8 cm famotidine, cimetidine. from this point. At 1830 a standard meal was on September 24, 2021 by guest. Protected copyright. given, which consisted of a supermarket ready meal of cottage pie, peas, and carrots, followed Low dose H2 receptor antagonists have by chocolate coated ice cream and two choco- recently been marketed for 'over the counter' late mints to give a total of 700 kcal, provided use in dyspepsia. They are recommended for by 22 g protein, 70 g carbohydrate, and 37 g postprandial and nocturnal dyspepsia and fat, accompanied by 250 ml mineral water. acidity. It is assumed that the symptomatic The drugs were given as tablets (famotidine 10 responses of dyspeptic patients will relate mg and cimetidine 200 mg) or as elixir (cime- directly to the antisecretory effects of these tidine 100 mg) with 50 ml mineral water at agents and thus the pharmacodynamic activity 1930. The placebo was a tablet containing no of the drugs may be used as a surrogate active ingredient. Subjects had nothing further measure of clinical efficacy. We therefore to eat before the end of the study period, but sought to compare the antisecretory properties had a further 250 ml of mineral water at 2100. of famotidine 10 mg (Pepcid AC, Centra The subjects retired to bed at 2300 and the pH Healthcare), cimetidine 100 mg and 200 mg electrodes were removed at 0730 after an Department of (Tagamet, SKB) in a controlled study. The overnight stay on the investigation unit under Medicine, Queen relative effect of such doses has the one Elizabeth Hospital, antisecretory supervision of of the investigators Birmingham not previously been published. (TGR). T G Reilly S G Mann M Z Panos R P Walt Methods Analysis ofdata pH measurements were recorded using Correspondence to: Dr R P Walt, Birmingham Subjects GastrograpH recorders (Medical Instruments Heartlands Hospital, Sixteen healthy subjects (eight males, eight Corporation, Solothurn, Switzerland). These Boardsley Green East, Birmingham B9 5SS. females) median age 21 years (range 19-25) instruments measure the potential difference Accepted for publication and median weight 71 kg (range 53-80) were between the electrode and the reference 18 January 1995 recruited into the study. The subjects included electrode in the tip of the tube four times per 326 Reilly, Mann, Panos, Walt Meal Drug Gut: first published as 10.1136/gut.37.3.325 on 1 September 1995. Downloaded from 5 * Placebo o Famotidine 10 mg 4 * Cimetidine 100 mg O Cimetidine 200 mg Q ._ 3 a) 2 1800 1900 2000 2100 2200 2330 0000 0100 0200 0300 0400 0500 0600 0700h Figure 1: Half hourly median pHforfour different treatments. These plots represent the median values of 16 individual halfhourly medians. second. Median pH values are stored giving recording device necessitated a study being data on pH 10 times per minute. The data repeated. On both occasions the finishing time were transferred to a computer for graphic and was incorrectly entered so that on the first numerical analysis. Half hourly medians for occasion the recording ceased at midnight, each study period were extracted from the raw and on the second it ceased at 0630. On both data and all subsequent data summaries and occasions the repeat study was the one used for analyses were based on these half hourly medi- analysis. All studies were well tolerated and no ans. Friedman's rank test based on the x2 dis- significant adverse events were reported during tribution was used to compare different or after any study. treatments. Figure 1 shows the group median halfhourly The principal study periods analysed were as pH over the whole study period for all studies follows: the period from the drug being given and shows that pH rose substantially after to the end of the study (drug to end); and from famotidine and less after cimetidine 200 mg. http://gut.bmj.com/ the drug to seven hours (drug plus 7). The pH/time curve after cimetidine 100 mg Secondary descriptive analyses were per- was indistinguishable from that with placebo. formed in an attempt to define onset of action The period when the difference between the using the periods from drug administration to H2 receptor antagonists was most easily one hour, 11/2 hours, and two hours after dos- visualised was from seven hours after the drug ing. administration. on September 24, 2021 by guest. Protected copyright. Results Primary analyses Sixteen volunteers participated in all parts of Drug to end - Figures 2-4 show the indi- the study. On two occasions in two different vidual median pH values from drug adminis- volunteers an error in programming the tration to the end of the study for all dosings 6.00 r 6.00 r 5.00 5.00 4.00 4.00 [- I 3.00 | I 3.00 2.00 2.00 1.00 F- 1.00 0.00 L Placebo Cimetidine 0.00 L Placebo Cimetidine 200 mg Figure 2: Median pHplacebo comparisons for 16 subjects Figure 3: Median pHplacebo comparisonsfor 16 subjects after cimetidine 100 mg: drug to end period. after cimetidine 200 mg: drug to end period. Low dosefamotidine and cimetidine in single postprandial doses: a placebo controlled comparative study ofovernight pH 327 6.00 r famotidine 10 mg with placebo at earlier times after drug administration. Famotidine 10 mg showed a significant difference at two hours 5.00 (p<0O02) but not before. After cimetidine Gut: first published as 10.1136/gut.37.3.325 on 1 September 1995. Downloaded from 200 mg we could not show a significant differ- ence from placebo at any time when the 4.00 median pH was used for analysis. : 3.00 e Discussion Low dose preparations of H2 receptor antago- nists are of interest at present because they 2.00 have recently become available to the public without prescription as over the counter drugs. 1.00 This study sought to show whether there were differences in the pharmacodynamic activities of famotidine 10 mg, cimetidine 100 mg, and Placebo Famotidine cimetidine 200 mg. In planning this investiga- 0.00 10 mg tion we designed a protocol that would closely Figure 4: Median pHplacebo comparisons for 16 subjects afterfamotidine 10 mg: drug to end period. mimic the use of these drugs for self treatment. We believe that postprandial heartburn is the symptom for which these drugs are likely to be for the different drugs. After placebo the group used and therefore arranged to study the median pH (interquartile range) was 1.35 effects of the drugs taken soon after a realisti- (1 1-1 65); after cimetidine 100 mg it was 1. 35 cally typical evening meal rather than at bed- (1 1-1 6; p>0 2 compared with placebo); after time or in the fasted state. Healthy volunteers cimetidine 200 mg it was 1.46 (1.3-2.0; rather than patients were used for practical 0*05<p<O01); and after famotidine 10 mg it reasons and because in many cases self treat- was 1.95 (1.6-5.35; p<0 001).