Alimentary Pharmacology & Therapeutics

MELIA, C. D.; DAVIS, S. S.

doi: 10.1111/j.1365-2036.1989.tb00243.xpmid: 2518865

SUMMARY Optimal drug dissolution is crucial to the success of oral drug therapy. Slow dissolution has frequently been correlated with poor or erratic performance of oral dosage forms in vivo, and drugs of low aqueous solubility provide a major challenge to the designer of modern oral dosage forms. In this second of two reviews, we briefly describe the physical process of dissolution, the principal factors controlling drug dissolution from tablets and capsules, and the strategies that are utilized by pharmaceutical scientists to enhance drug dissolution of orally administered drugs. Dissolution, Tablets, Drug release, Bioavailability.

KARNES, W. E.; MAXWELL, V.; SYTNIK, B.; CHEW, P.; WALSH, J. H.

doi: 10.1111/j.1365-2036.1989.tb00244.xpmid: 2518866

SUMMARY Single subcutaneous doses of the somatostatin analogue, SMS 201–995, were evaluated for the degree and duration of effects on acid secretion, serum gastrin levels, and gastric emptying in eight human male subjects (mean age 44 years) over an 8‐h period. All the subjects received subcutaneous 50‐μg and 100‐μg doses of SMS 201–995 and placebo on three separate days in a double‐blind random order. Drug or placebo was administered at time 0 followed by peptone meals at time 0, 2, 4, and 6‐h. Peptone meals were evacuated at time 1, 3, 5 and 7‐h to create ‘basal’conditions between alternate hours. Gastric acid secretion was determined hourly beginning at time −1. Both the 50‐μg and 100‐μg doses of SMS 201–995 significantly inhibited ‘basal’and peptone meal‐stimulated gastric acid secretion throughout the 8‐h measurement period. The minimum effective plasma concentration of SMS 201–995 for inhibition of peptone meal‐stimulated gastric acid secretion was approximately 1000 pg/ml. Peptone meal‐stimulated plasma gastrin

ENCK, P.; ARPING, H. G.; ENGEL, S.; BIELEFELDT, K.; ERCKENBRECHT, J. F.

doi: 10.1111/j.1365-2036.1989.tb00245.xpmid: 2518867

SUMMARY To investigate the effects of cisapride, a motility‐inducing agent, on anorectal sphincter functions, standard manometry was performed in 10 healthy male volunteers after 5 days on a 20‐mg dose of cisapride in a placebo‐controlled double‐blind randomized crossover fashion. All subjects kept stool diaries during the experiment. Cisapride significantly increased stool frequency by adding soft and liquid stools; in addition, anal resting pressure was reduced with cisapride in seven of the 10 subjects; mean resting pressure decreased by 16%, while all other measurements were not altered. This suggests that cisapride may act directly on the smooth muscle of the internal anal sphincter. It also supports the view that enhanced defaecation in chronic constipation induced by cisapride may not be achieved by propulsive motor activity in the colon but also by a decreased anal sphincter tone.

BERGER, V.; ARMBRECHT, U.; HEUSINGER, A.; WIENBECK, M.; STOCKBRÜGGER, R.

doi: 10.1111/j.1365-2036.1989.tb00246.xpmid: 2518868

SUMMARY In order to elucidate whether or not the increased stool frequency that occurs during cisapride treatment is a result of malabsorption of water, fat, and bile acids, 12 healthy volunteers were dosed with either tablets of placebo q.d.s. or tablets of 10 mg cisapride q.d.s. during two periods of 5 days in a double‐blind, crossover study. Stool frequency, stool consistency, and side‐effects were recorded each day. Total faecal mass, faecal water content, and faecal excretion of fat and bile acids were determined during the last 72 h of each study period. Mean daily stool frequency was 18.8% higher during cisapride (1.68 ± 0.12 (S.E.M.)) administration than during placebo (1.42 ± 0.12); P= 0.038. The stool consistency score increased by 11.8% towards softer stools during cisapride dosing (N.S.). There were no significant differences in total faecal mass (placebo 399.4 g/72 h; cisapride; 414.5 g/72 h), faecal water content (placebo; 75.6%: cisapride 76.2%), or faecal excretion of fat (placebo; 12.7 g/72 h: cisapride; 11.6 g/72 h) and total bile acids (placebo; 2212 μmol/72 h: cisapride; 2261 μmol/72 h). The side‐effects reported during placebo were constipation (n = 3), and during cisapride meteorism (n = 4) and increased appetite (n = 2). The increased stool frequency during cisapride treatment is not caused by malabsorption of water, fat, or bile acids, but seems to be the consequence of a direct motor effect.

FORBES, A.; BRITTON, T. C.; HOUSE, I. M.; GAZZARD, B. G.

doi: 10.1111/j.1365-2036.1989.tb00247.xpmid: 2518869

SUMMARY In a prospective open study, 10 patients with intractable proctitis were treated with acetarsol suppositories (250 mg b.d. for 4 weeks) and were monitored clinically, biochemically and toxicologically. Proctitis resolved symptomatically and sigmoidoscopically within 2 weeks in nine patients; one patient was unaffected. The only side‐effect was of transient thrombocytosis in a single patient. Maximal blood and urinary arsenic concentrations occurred after 1 week's treatment with a total inorganic arsenic in the hazardous range in six patients; subsequent concentrations fell despite continuing therapy and at 4 weeks potentially hazardous values persisted in only two patients. Continued renal excretion and diminished absorption across an improved rectal mucosa is thought to be responsible for this paradox. Arsenic levels fell rapidly when acetarsol was withdrawn and were indistinguishable from pretreatment values within 4 weeks. Short‐term acetarsol therapy offers a useful additional measure when local steroids have failed to control ulcerative proctitis; it appears to be safe and formal controlled comparisons with other therapeutic options are therefore legitimate.

GAVEY, C. J.; SMITH, J. T. L.; NWOKOLO, C. U.; POUNDER, R. E.

doi: 10.1111/j.1365-2036.1989.tb00248.xpmid: 2577500

SUMMARY In a double‐blind, placebo‐controlled study of SK&F 94482 (BMY‐25368) (400‐mg, post‐evening meal, for 7 days in 11 healthy subjects), there was a significant 75% decrease in median integrated 24‐h intragastric acidity during dosing with the drug (218 mmol h/L) compared with placebo (883 mmol h/L; P= 0.003). The single daily dose of 400 mg SK&F 94482 decreased median hourly intragastric acidity until the time of the next dose 24 h later. There was also a sustained and significant 80% rise in median 24‐h integrated plasma‐gastrin concentration during dosing with SK&F 94482 (364 pmol h/L) when compared with placebo (202 pmol h/L; P= 0.003). The study demonstrates a significant inverse correlation between 24‐h integrated intragastric acidity and 24‐h plasma gastrin concentration (rs=−0.484; P < 0.001). The study shows that a single oral daily dose of an H2‐antagonist can provide control of intragastric acidity throughout the day and night, decreased acidity being associated with statistically significantly, but modestly elevated plasma‐gastrin levels.

HUNT, I. B.; ELLIOTT, E. J.; FARTHING, M. J. G.

doi: 10.1111/j.1365-2036.1989.tb00249.xpmid: 2518870

SUMMARY Human triple‐lumen intestinal perfusion was used to compare water and solute absorption from the oral rehydration solution (ORS) most widely used in the United Kingdom and a new experimental hypotonic ORS (HYPO‐ORS). HYPO‐ORS (osmolality 210 mOsm/kg) promoted significantly greater water absorption than UK‐ORS (7.03 ± 1.1 vs 2.73 ± 1.0 ml cm−1 h−1; P < 0.01). HYPO‐ORS produced net sodium and chloride absorption whereas the low sodium UK‐ORS produced a net secretion of these ions. Bicarbonate absorption was also greater from HYPO‐ORS although potassium and glucose absorption were similar from both solutions. This study suggests that UK‐ORS may not promote optimal water and solute absorption and that clinical studies with HYPO‐ORS are indicated.

FRANK, W. O.; YOUNG, M. D.; PALMER, R.; ROCKHOLD, F.; KARLSTADT, R.; MOUNCE, W.; O'CONNELL, S.

doi: 10.1111/j.1365-2036.1989.tb00250.xpmid: 2518871

SUMMARY This multicentre, double‐blind study evaluated the efficacy of cimetidine 800 mg nocte compared to placebo for ulcer healing and pain relief in patients with endoscopically confirmed, benign gastric ulcers treated for up to 8 weeks. Cimetidine accelerated ulcer healing throughout the study. More cimetidine‐treated patients (35 of 82, 43%) than placebotreated patients (26 of 79, 33%) had healed ulcers after 4 weeks of therapy. Similarly, after 6 and 8 weeks of treatment, cimetidine continued to have superior healing rates, 76% (59 of 78, P= 0.02) and 91% (69 of 76, P= 0.02) heal rates for cimitidine recipients compared with 58% (42 of 73) and 74% (52 of 70) for placebo. For every week of the study except the second, a greater proportion of cimetidine‐treated patients were free of daytime and night‐time pain than placebo‐treated patients; the differences were statistically significant for night‐time pain. Adverse reaction profiles were similar for the cimetidine and placebo groups. In conclusion, cimetidine 800 mg nocte was comparably safe and significantly more effective than placebo in accelerating healing and relieving pain in the treatment of acute, benign gastric ulcer.

BERSTAD, K.; HARAM, E.‐M.; WEBERG, R.; BERSTAD, A.

doi: 10.1111/j.1365-2036.1989.tb00251.xpmid: 2518872

SUMMARY Twenty healthy volunteers participated in a double‐blind, crossover study to evaluate endoscopically whether low‐dose antacids have any prolonged and pH‐independent protective capacity against gastroduodenal mucosal damage induced by acetylsalicylic acid. Antacid or placebo one tablet q.d.s. was given for 1.5 days. Acetylsalicylic acid (1.5 g) was administered 3 h after the last dose of antacid/placebo, and gastroscopy was performed 1 h thereafter. Thirteen of 20 subjects showed a decrease in total damage with antacids as compared with placebo, but the difference did not reach statistical significance. Thus, protection by antacids against acetylsalacylic acid‐induced gastric mucosal lesions could not be documented at a time when intragastric pH presumably had returned to normal.

BAUER, F. E.; GHATEI, M. A.; ZINTEL, A.; BLOOM, S. R.

doi: 10.1111/j.1365-2036.1989.tb00252.xpmid: 2485092

SUMMARY Galanin was infused intravenously into eight healthy volunteers at a dose of 40 pmol kg−1 min−1 for 1 h to investigate the pharmacological effects of this peptide on the postprandial sialagogical response in man. Galanin significantly increased the salivary volume and the saliva output of sodium, chloride and bicarbonate compared to control saline infusion, but had no effect on the output of potassium and α‐amylase. An increase in salivary pH was also observed. The increase in salivary volume may indicate a physiological role of galanin in the control of salivary secretion.