Oral benzquinamide in the treatment of nausea and vomiting The clinical antiemetic effect of benzquinamide by oral route at a dosage of JOO mg 3 times daily was evaluated by a controlled double-blind method in 183 studies of patients treated with 5-fiuorouracil. The incidence of nausea and vomiting in benzquinamide-treated patients was equal to that in placebo-treated patients and significantly higher than that in patients treated with prochlorperazine. 10 mg 3 times daily. Sedation was the only significant side effect observed. and this occurred at essentially equal rates in benzquinamide- and prochlorperazine-treated patients.
c.
G. Moertel, M.D., A. J. Schutt, M.D., R. G. Hahn, M.D., and J. R. O'Fallon, Ph.D.
Rochester. Minn. Mayo Clinic and Mayo Foundation
Nausea and vomiting are symptoms that present therapeutic challenges to physicians in all aspects of medical practice. To date only the phenothiazines have shown consistent antiemetic effectiveness. Therapeutic activity of these drugs, however, is frequently less than desirable and their utility has been limited by their side effects. There is an obvious need for useful therapeutic alternatives. Benzquinamide (Emete-Con) * is a benzoquinolizine derivative not structurally related to any other drug used clinically as an antiemetic agent. It is currently marketed only for intravenous or intramuscular administration. The only marketed indication is for the prevention and the treatment of nausea and vomiting associated with anesthesia and surgery. Benzquinamide is rapidly absorbed when administered orally. When administered orally in man, it has been found effective against apomorphine-induced vomiting.!' 6 In a single reported clinical study,2 benzquinamide by oral route, Received for publication July 3, 1975. Accepted for publication Aug. 25, 1975. 'Supplied by Roerig Pharmaceuticals.
554
administered to subjects with nausea and vomiting of various etiologies, was claimed significantly superior to both trimethobenzamide and prochlorperazine. 5-Fluorouracil administered by an intensive course for advanced cancer has in our hands produced nausea in approximately 80% of patients and vomiting in 50% for first-course therapy with a lesser incidence with subsequent courses of treatment. In our previous studies, 3. 5 this circumstance has proved suitable for controlled clinical trials of antiemetic agents. Prochlorperazine has been an effective antiemetic in this system and can serve as a control of established activity. The purpose of this study is to evaluate, by controlled double-blind method, the efficacy of oral benzquinamide in preventing nausea and vomiting induced by 5-fluorouracil and to compare with that of prochlorperazine. Materials and methods
All patients selected for study were adults with proved unresectable gastrointestinal carcinoma. They were ambulatory outpatients maintaining a reasonable state of nutrition and
they were not experiencing vomiting prior to entry in the study. They were not allowed concurrent therapy with any known antiemetics, sedatives, or tranquilizers during the study period. Patients were studied during either their first or second course of 5-fluorouracil therapy. 5Fluorouracil was administered in 5-day courses by either oral or rapid intravenous injection methods. Dosage for the rapid intravenous method was l3.5 mg/kg/day X 5 days. For the oral method the dosage was 20 mg/kg/day X 5 days. Prior to randomization patients were stratified according to whether they were receiving 5-fluorouracil by oral or intravenous route and whether they were receiving their first or second course of 5-fluorouracil. Each study drug was prepared in identical opaque gelatin capsules. The capsules contained benzquinamide, 100 mg, prochlorperazine, 10 mg, or placebo (lactose). The drugs were dispensed in identical screw-cap vials identified only by code number. Patients were told they were participating in a controlled study to evaluate an investigational drug for the treatment of nausea and vomiting. They were instructed to take 1 capsule 3 times daily 20 min before each regular meal time. Patients were seen by the investigators each day. They were first allowed to volunteer the occurrence of nausea, vomiting, sedation, or other symptoms by a general question regarding their well-being. They were then specifically queried regarding the occurrence of nausea or vomiting during the preceding 24-hr period. The occurrence of nausea and vomiting was scored each day in the following manner: no nausea or vomiting, 0; nausea only on questioning, 1; nausea volunteered as a significant symptom, 2; vomiting, only once during the preceding 24-hr period, 3; vomiting, 2 or more times during the past 24-hr period, 4. Patients were studied only during the first 4 days of their 5-day course. If at any time during this period they vomited more than once during 24 hr, they were instructed to discontinue their initial study drug for a 24-hr washout period. They were then crossed over to a drug of known or presumed antiemetic activity. Patients initially treated with placebo were crossed over in a
555
Oral benzquinamide
Volume 18 Number 5, Part 1
Table I. Incidence of nausea and vomiting during a course of 5-fiuorouracil therapy Per cent of 63 study periods
Treatment
Nausea
Vomiting
No nausea or vomiting
Placebo Benzquinamide Procblorperazine
54* 59* 37*
27 35 19
46* 41 * 63*
*x(~)=
6.90 = P 0.03.
randomized manner to either benzquinamide or prochlorperazine. Patients initially treated with prochlorperazine were crossed over to benzqinamide and patients initially treated with benzquinamide were crossed over to prochlorperazine. The crossover drugs were double-blind in the same manner as the initial treatment drugs. Results
A total of 189 initial drug studies were observed as well as a total of 16 crossover drug studies. Sixty-three patients each were initially studied with placebo, benzquinamide, or prochlorperazine. For each drug and placebo, 26 patients were observed during their initial course of 5-fluorouracil by intravenous injections, 16 patients were observed during their second course of intravenous therapy, 12 patients were observed during their first course of oral therapy, and 9 patients were observed during their second course of oral therapy. The incidence of nausea and vomiting observed during 63 study periods is listed in Table I according to the antiemetic used. The differences in incidence of nausea are statistically significant at the p < 0.05 level, with prochlorperazine showing the lesser incidence and benzquinamide the greater incidence. Prochlorperazine is superior at the p < 0.05 level over both placebo and benzquinamide. There is no significant difference in the incidence of nausea between placebo and benzquinamide. The differences in the incidence of vomiting are not overall statistically significant but when compared individually prochlorperazine is superior to benzquinamide at the p < 0.05 level. In Table II, the daily incidence of nausea
556
Moertel et al.
Clinical Pharmacology and Therapeutics
Table II. Incidence of nausea and vomiting during each day of 5-jluorouracil therapy Per cent nausea and vomiting per day Treatment
Days of therapy
Nausea
Placebo Benzq uinamide Prochlorperazine
243 237 248
37* 38* 21*
*x,i) = tx,~) =
I
Vomiting
I
No nausea or vomiting
63* 62* 79*
1St 22t 7t
22.3 P < 0.01. 21.2 P < 0.01.
Table III. Nausea and vomiting score during a course of 5-jlurouracil therapy
Table IV. Incidence of sedation during a 4-day course of therapy
Score for 63 study periods Treatment
Total
Mean
Placebo Benzquinamide Prochlorperazine
85
1.35
93
55
1.48 0.87
Treatment
Per cent sedation for 63 study periods
Placebo Benzq uinamide Prochlorperazine
22 24
II
p < 0.02 by Kruskal-Wallis one-way analysis of variance on patient's average scores.
and vomiting is listed for each treatment. The total numbers of days studied with each differ because it was occasionally necessary to stop a course of 5-fluorouracil because of specific toxicity e.g., stomatitis, diarrhea, or a falling leukocyte count. Observations were therefore recorded only during the days patients received 5-fluorouracil. If, however, it was necessary to discontinue the antiemetic study drug because of the occurrence of repeated vomiting, patients were scored as having vomiting during the remainder of the planned 4-day treatment. The differences in incidence of nausea and vomiting recorded by this method are significant, with prochlorperazine showing the least incidence and benzquinamide the greatest. In Table III, the nausea and vomiting scores are presented according to the scoring method stated above. The difference between the three is statistically significant, with prochlorperazine showing the most favorable score and benzquinamide the least. Eight patients were crossed over to either benzquinamide or prochlorperazine after failure on placebo. Seven patients were crossed to prochlorperazine after failure on benzquinamide treatment, and 1 patient was crossed to benz quinamide after failure on prochlorperazine ther-
apy. Five of 7 continued to vomit after benzquinamide (71 %), whereas only 4 of 9 (44%) continued to vomit after a change to prochlorperazine. Among the 7 patients who crossed from benzquinamide to prochlorperazine, 3 continued to vomit, but 4 were completely relieved of both nausea and vomiting. The single patient crossed from prochlorperazine to benzquinamide continued to vomit. Table IV shows the incidence of sedation volunteered as a significant symptom during each initial study period. Sedation occurred at comparable rates with benzquinamide and prochlorperazine and for both was approximately twice the rate of that with placebo. Sedative effects were mild for both drugs and in no instance were they disabling. The difference in incidence between benzquinamide and placebo and prochlorperazine and placebo did not reach the traditional level of statistical significance. With the exception of sedation, there were no other side effects that could be clearly ascribed to any of the study treatments. Discussion
It is apparent that under the conditions of this study, where prochlorperazine demonstrated a significant therapeutic effect, benz-
Oral benzquinamide
Volume 18 Number 5, Part 1
quinamide by oral route was devoid of any evidence of antiemetic activity, The results of this study stand in contrast to the only other published evaluation of benzquinamide used by oral route for clinical nausea and vomiting, in which Medoff2 reported that the response of vomiting in 14 patients treated with benzquinamide was significantly superior to that in 13 patients treated with prochlorperazine. These patients had a variety of causes of nausea and vomiting, a total of 16 different etiologies in all. No attempt was made to stratify according to etiology of vomiting; and the most common etiology treated, epidemic nausea and vomiting, was disproportionately represented in the benzquinamide and prochlorperazine patients (9/14 vs 4/13). In the study a positive result was recorded if the patient showed improvement during 48 hr following initiation of drug therapy. Epidemic nausea and vomiting is characterized by very quick spontaneous improvement. It could therefore be anticipated that most of these patients would have improved with no treatment. Since 9 of the 14 patients treated with benzquinamide were in this very favorable group, it must also be anticipated that benzquinamide would show an advantage over prochlorperazine, which was given to only 4 of 13 patients in this favorable group. In addition, Medoff did not include a placebo control, so there is no basis against which to compare what would have happened if no treatment whatsoever had been used in these patients.
557
Whereas our study involved only a single etiology for nausea and vomiting, the study was randomized, stratified, and double-blind and included a large enough volume of patients to draw significant conclusions. The strongly negative results cannot, however, be applied directly to other etiologies for nausea and vomiting, nor can it be assumed that the dosage and schedule we used were optimal for demonstrating antiemetic effect. Nevertheless, we could find no evidence that benzquinamide administered by oral route is a clinically useful antiemetic.
References 1. Klein, R. L., Graves, C. L., Kim, Y. II, and Blatnick, R.: Inhibition of apomorphine-induced vomiting by benzquinamide, CUN. PHARMACOL. THER. 11:530-537, 1970. 2. Medoff, J.: A double-blind evaluation of the anti-emetic efficacy of benzquinamide, prochlorperazine, and trimethobezamide in office practice, Curr. Ther. Res. 12:706-710, 1970. 3. MoerteI, C. G., and Reitemeier, R. J.: Controlled clinical studies of orally administered antiemetic drugs, Gastroenterology 57:262-268, 1969. 4. Moertel, C. G., and Reitemeier, R. J.: Controlled studies of metopimazine for the treatment of nausea and vomiting, J. CIin, Pharmacol. 13: 283-287, 1973. 5. Moertel, C. G., Reitemeier, R. J., and Gage, R. P.: A controlled clinical evaluation of antiemetic drugs, J. A. M. A. 186:116-118, 1963. 6. Pitts, N. E.: A clinical pharmacological evaluation of benzquinamide: A new antiemetic agent, Curr. Ther. Res. 11:325-337, 1969.
c.
G. Moertel, M.D., A. J. Schutt, M.D., R. G. Hahn, M.D., and J. R. O'Fallon, Ph.D.
Rochester. Minn. Mayo Clinic and Mayo Foundation
Nausea and vomiting are symptoms that present therapeutic challenges to physicians in all aspects of medical practice. To date only the phenothiazines have shown consistent antiemetic effectiveness. Therapeutic activity of these drugs, however, is frequently less than desirable and their utility has been limited by their side effects. There is an obvious need for useful therapeutic alternatives. Benzquinamide (Emete-Con) * is a benzoquinolizine derivative not structurally related to any other drug used clinically as an antiemetic agent. It is currently marketed only for intravenous or intramuscular administration. The only marketed indication is for the prevention and the treatment of nausea and vomiting associated with anesthesia and surgery. Benzquinamide is rapidly absorbed when administered orally. When administered orally in man, it has been found effective against apomorphine-induced vomiting.!' 6 In a single reported clinical study,2 benzquinamide by oral route, Received for publication July 3, 1975. Accepted for publication Aug. 25, 1975. 'Supplied by Roerig Pharmaceuticals.
554
administered to subjects with nausea and vomiting of various etiologies, was claimed significantly superior to both trimethobenzamide and prochlorperazine. 5-Fluorouracil administered by an intensive course for advanced cancer has in our hands produced nausea in approximately 80% of patients and vomiting in 50% for first-course therapy with a lesser incidence with subsequent courses of treatment. In our previous studies, 3. 5 this circumstance has proved suitable for controlled clinical trials of antiemetic agents. Prochlorperazine has been an effective antiemetic in this system and can serve as a control of established activity. The purpose of this study is to evaluate, by controlled double-blind method, the efficacy of oral benzquinamide in preventing nausea and vomiting induced by 5-fluorouracil and to compare with that of prochlorperazine. Materials and methods
All patients selected for study were adults with proved unresectable gastrointestinal carcinoma. They were ambulatory outpatients maintaining a reasonable state of nutrition and
they were not experiencing vomiting prior to entry in the study. They were not allowed concurrent therapy with any known antiemetics, sedatives, or tranquilizers during the study period. Patients were studied during either their first or second course of 5-fluorouracil therapy. 5Fluorouracil was administered in 5-day courses by either oral or rapid intravenous injection methods. Dosage for the rapid intravenous method was l3.5 mg/kg/day X 5 days. For the oral method the dosage was 20 mg/kg/day X 5 days. Prior to randomization patients were stratified according to whether they were receiving 5-fluorouracil by oral or intravenous route and whether they were receiving their first or second course of 5-fluorouracil. Each study drug was prepared in identical opaque gelatin capsules. The capsules contained benzquinamide, 100 mg, prochlorperazine, 10 mg, or placebo (lactose). The drugs were dispensed in identical screw-cap vials identified only by code number. Patients were told they were participating in a controlled study to evaluate an investigational drug for the treatment of nausea and vomiting. They were instructed to take 1 capsule 3 times daily 20 min before each regular meal time. Patients were seen by the investigators each day. They were first allowed to volunteer the occurrence of nausea, vomiting, sedation, or other symptoms by a general question regarding their well-being. They were then specifically queried regarding the occurrence of nausea or vomiting during the preceding 24-hr period. The occurrence of nausea and vomiting was scored each day in the following manner: no nausea or vomiting, 0; nausea only on questioning, 1; nausea volunteered as a significant symptom, 2; vomiting, only once during the preceding 24-hr period, 3; vomiting, 2 or more times during the past 24-hr period, 4. Patients were studied only during the first 4 days of their 5-day course. If at any time during this period they vomited more than once during 24 hr, they were instructed to discontinue their initial study drug for a 24-hr washout period. They were then crossed over to a drug of known or presumed antiemetic activity. Patients initially treated with placebo were crossed over in a
555
Oral benzquinamide
Volume 18 Number 5, Part 1
Table I. Incidence of nausea and vomiting during a course of 5-fiuorouracil therapy Per cent of 63 study periods
Treatment
Nausea
Vomiting
No nausea or vomiting
Placebo Benzquinamide Procblorperazine
54* 59* 37*
27 35 19
46* 41 * 63*
*x(~)=
6.90 = P 0.03.
randomized manner to either benzquinamide or prochlorperazine. Patients initially treated with prochlorperazine were crossed over to benzqinamide and patients initially treated with benzquinamide were crossed over to prochlorperazine. The crossover drugs were double-blind in the same manner as the initial treatment drugs. Results
A total of 189 initial drug studies were observed as well as a total of 16 crossover drug studies. Sixty-three patients each were initially studied with placebo, benzquinamide, or prochlorperazine. For each drug and placebo, 26 patients were observed during their initial course of 5-fluorouracil by intravenous injections, 16 patients were observed during their second course of intravenous therapy, 12 patients were observed during their first course of oral therapy, and 9 patients were observed during their second course of oral therapy. The incidence of nausea and vomiting observed during 63 study periods is listed in Table I according to the antiemetic used. The differences in incidence of nausea are statistically significant at the p < 0.05 level, with prochlorperazine showing the lesser incidence and benzquinamide the greater incidence. Prochlorperazine is superior at the p < 0.05 level over both placebo and benzquinamide. There is no significant difference in the incidence of nausea between placebo and benzquinamide. The differences in the incidence of vomiting are not overall statistically significant but when compared individually prochlorperazine is superior to benzquinamide at the p < 0.05 level. In Table II, the daily incidence of nausea
556
Moertel et al.
Clinical Pharmacology and Therapeutics
Table II. Incidence of nausea and vomiting during each day of 5-jluorouracil therapy Per cent nausea and vomiting per day Treatment
Days of therapy
Nausea
Placebo Benzq uinamide Prochlorperazine
243 237 248
37* 38* 21*
*x,i) = tx,~) =
I
Vomiting
I
No nausea or vomiting
63* 62* 79*
1St 22t 7t
22.3 P < 0.01. 21.2 P < 0.01.
Table III. Nausea and vomiting score during a course of 5-jlurouracil therapy
Table IV. Incidence of sedation during a 4-day course of therapy
Score for 63 study periods Treatment
Total
Mean
Placebo Benzquinamide Prochlorperazine
85
1.35
93
55
1.48 0.87
Treatment
Per cent sedation for 63 study periods
Placebo Benzq uinamide Prochlorperazine
22 24
II
p < 0.02 by Kruskal-Wallis one-way analysis of variance on patient's average scores.
and vomiting is listed for each treatment. The total numbers of days studied with each differ because it was occasionally necessary to stop a course of 5-fluorouracil because of specific toxicity e.g., stomatitis, diarrhea, or a falling leukocyte count. Observations were therefore recorded only during the days patients received 5-fluorouracil. If, however, it was necessary to discontinue the antiemetic study drug because of the occurrence of repeated vomiting, patients were scored as having vomiting during the remainder of the planned 4-day treatment. The differences in incidence of nausea and vomiting recorded by this method are significant, with prochlorperazine showing the least incidence and benzquinamide the greatest. In Table III, the nausea and vomiting scores are presented according to the scoring method stated above. The difference between the three is statistically significant, with prochlorperazine showing the most favorable score and benzquinamide the least. Eight patients were crossed over to either benzquinamide or prochlorperazine after failure on placebo. Seven patients were crossed to prochlorperazine after failure on benzquinamide treatment, and 1 patient was crossed to benz quinamide after failure on prochlorperazine ther-
apy. Five of 7 continued to vomit after benzquinamide (71 %), whereas only 4 of 9 (44%) continued to vomit after a change to prochlorperazine. Among the 7 patients who crossed from benzquinamide to prochlorperazine, 3 continued to vomit, but 4 were completely relieved of both nausea and vomiting. The single patient crossed from prochlorperazine to benzquinamide continued to vomit. Table IV shows the incidence of sedation volunteered as a significant symptom during each initial study period. Sedation occurred at comparable rates with benzquinamide and prochlorperazine and for both was approximately twice the rate of that with placebo. Sedative effects were mild for both drugs and in no instance were they disabling. The difference in incidence between benzquinamide and placebo and prochlorperazine and placebo did not reach the traditional level of statistical significance. With the exception of sedation, there were no other side effects that could be clearly ascribed to any of the study treatments. Discussion
It is apparent that under the conditions of this study, where prochlorperazine demonstrated a significant therapeutic effect, benz-
Oral benzquinamide
Volume 18 Number 5, Part 1
quinamide by oral route was devoid of any evidence of antiemetic activity, The results of this study stand in contrast to the only other published evaluation of benzquinamide used by oral route for clinical nausea and vomiting, in which Medoff2 reported that the response of vomiting in 14 patients treated with benzquinamide was significantly superior to that in 13 patients treated with prochlorperazine. These patients had a variety of causes of nausea and vomiting, a total of 16 different etiologies in all. No attempt was made to stratify according to etiology of vomiting; and the most common etiology treated, epidemic nausea and vomiting, was disproportionately represented in the benzquinamide and prochlorperazine patients (9/14 vs 4/13). In the study a positive result was recorded if the patient showed improvement during 48 hr following initiation of drug therapy. Epidemic nausea and vomiting is characterized by very quick spontaneous improvement. It could therefore be anticipated that most of these patients would have improved with no treatment. Since 9 of the 14 patients treated with benzquinamide were in this very favorable group, it must also be anticipated that benzquinamide would show an advantage over prochlorperazine, which was given to only 4 of 13 patients in this favorable group. In addition, Medoff did not include a placebo control, so there is no basis against which to compare what would have happened if no treatment whatsoever had been used in these patients.
557
Whereas our study involved only a single etiology for nausea and vomiting, the study was randomized, stratified, and double-blind and included a large enough volume of patients to draw significant conclusions. The strongly negative results cannot, however, be applied directly to other etiologies for nausea and vomiting, nor can it be assumed that the dosage and schedule we used were optimal for demonstrating antiemetic effect. Nevertheless, we could find no evidence that benzquinamide administered by oral route is a clinically useful antiemetic.
References 1. Klein, R. L., Graves, C. L., Kim, Y. II, and Blatnick, R.: Inhibition of apomorphine-induced vomiting by benzquinamide, CUN. PHARMACOL. THER. 11:530-537, 1970. 2. Medoff, J.: A double-blind evaluation of the anti-emetic efficacy of benzquinamide, prochlorperazine, and trimethobezamide in office practice, Curr. Ther. Res. 12:706-710, 1970. 3. MoerteI, C. G., and Reitemeier, R. J.: Controlled clinical studies of orally administered antiemetic drugs, Gastroenterology 57:262-268, 1969. 4. Moertel, C. G., and Reitemeier, R. J.: Controlled studies of metopimazine for the treatment of nausea and vomiting, J. CIin, Pharmacol. 13: 283-287, 1973. 5. Moertel, C. G., Reitemeier, R. J., and Gage, R. P.: A controlled clinical evaluation of antiemetic drugs, J. A. M. A. 186:116-118, 1963. 6. Pitts, N. E.: A clinical pharmacological evaluation of benzquinamide: A new antiemetic agent, Curr. Ther. Res. 11:325-337, 1969.
