The evolution of peptic ulcer therapy. A role for temporal control of drug delivery.

The treatment of acid peptic disease has involved a series of attempts to control gastric acid secretion in order to heal and to prevent recurrence of duodenal ulcers. Early treatment attempted to heal by neutralizing gastric acid with diet modification, the Sippy diet, and Doll's milk drip. Just before the turn of the century, surgeons began performing gastric resections. In 1943, Dr. Lester Dragstedt performed the first truncal vagotomy to limit cholinergic stimulation of gastric acid secretion. This led to surgery that combined gastric resections with vagotomy. In 1970, the first parietal cell vagotomy was performed. This microsurgical technique limited vagal initiation of acid secretion while minimizing the impact on other gastrointestinal functions. By the 1960s, pharmacological intervention included antacids to neutralize acid and anticholinergics to reduce the amount of acid produced. These treatments varied in their effectiveness, and some of them caused significant side effects. In 1976, treatment of acid peptic disease began a new phase with the introduction of the first H2 receptor antagonist, cimetidine. Ranitidine, the second H2 receptor antagonist, produced greater acid suppression in the morning and at night with bid dosing than cimetidine with quid dosing. The knowledge that there is a circadian pattern in acid production, with higher levels between 10 PM and 2 AM, resulted in the development and use of a single evening dose of ranitidine. Ongoing research continues to investigate the effects of dose timing and the influence of more potent acid-suppressing agents. Finally, the issue of maintenance therapy and gastric acid secretion was addressed. The clinical advantage that ranitidine has over cimetidine in the prevention of ulcer recurrence can be attributed to its control of nocturnal acid suppression.

Pharmacokinetics of ranitidine in morbidly obese women.

The pharmacokinetics of a single dose of ranitidine 50 mg iv were determined in ten normal-weight and ten morbidly obese (greater than 90 percent ideal body weight) age-matched female subjects. No significant difference between normal and obese subjects was found in ranitidine peak serum concentration, volume of distribution, clearance, and elimination rate constant. Ranitidine volume of distribution and clearance were significantly smaller in the obese subjects per kilogram of total body weight (1.45 vs. 0.80 L/kg and 0.59 vs. 0.33 L/h/kg, respectively; p less than 0.001) but not when normalized to ideal body weight (1.65 vs. 1.45 L/kg and 0.68 vs. 0.59 L/h/kg). We conclude that obese patients receiving ranitidine therapy should be treated with standard dosages or dosages based on ideal body weight.

Effect of ranitidine on gastroduodenal mucosal damage induced by nonsteroidal antiinflammatory drugs.

The effect of ranitidine in preventing mucosal damage caused by nonsteroidal antiinflammatory drugs (NSAIDs) was evaluated for eight weeks in a prospective study of 144 patients requiring NSAIDs. Patients with normal endoscopic findings were randomly assigned to receive either ranitidine 150 mg twice daily or placebo for eight weeks, along with either ibuprofen, indomethacin, naproxen, sulindac, or piroxicam. Duodenal damage was significantly less in the ranitidine group compared with the placebo group by weeks 4 and 8 (P less than or equal to 0.01). Duodenal ulcers did not develop in any patients on ranitidine (0/57) compared with 4/49 patients (8%) on placebo (P = 0.02). No significant difference was found between treatment groups with respect to gastric damage; 6/60 (10%) in the ranitidine group compared with 6/50 (12%) in the placebo group developed gastric ulcers. These findings suggest that acid suppression is of greater importance for mucosal protection in the duodenum than in the stomach, where other defense mechanisms may be operative. While ranitidine is an effective prophylaxis for NSAID-induced damage in the duodenum, further studies are needed to define specific risk groups and to assess the potential usefulness of more complete acid suppression in preventing gastric mucosal damage.

Ranitidine accumulation in patients undergoing chronic hemodialysis.

Ranitidine accumulation was assessed in 20 patients undergoing chronic hemodialysis following oral daily doses of 150 mg ranitidine for 10 days. Serum ranitidine concentrations prior to dialysis were 191 +/- 115 mcg/l and 207 +/- 172 mcg/l for patients dialyzed three and two times per week, respectively. The amount of ranitidine recovered in the dialysate during the final dialysis session of the study was negligible and ranged from 308-3036 mcg, representing less than 3% of the administered dose. Clearance by hemodialysis was 3.0 +/- 1.1 l/hr. Once daily dosing of 150 mg ranitidine does not result in excessive accumulation, and drug loss during hemodialysis is small. These data suggest that supplemental dosing after hemodialysis is not indicated.

The role of pharmacokinetics in determining the response of rodent embryos to teratogens in whole-embryo culture.

The rodent embryo's response to teratogenic insult in whole-embryo culture during the period of neurulation was characterized by determining the role of pharmacokinetics and embryonic recovery in producing abnormal growth and development. Five known teratogens, hydroxyurea, cyclophosphamide, cadmium, diphenylhydantoin, and the ketone body beta-hydroxybutyrate were employed. The dose and exposure times in vitro were designed to reproduce the peak serum concentrations and half-life of the compounds present following the administration of a teratogenic or maximum maternally tolerated dose of the agents in vivo. The results showed: first, that both the serum concentration and duration of exposure to an agent play a role in determining the embryonic response in vitro; secondly, that compounds that do not produce effects during the period of neurulation or that require maternal metabolic activation are not teratogenic in culture; and thirdly, that embryos have the capacity to recover from certain teratogenic insults in vitro. Thus, both pharmacokinetics and the potential for embryonic recovery should be considered when applying the whole-embryo culture technique to studies in teratology and toxicology.

Ranitidine protects against gastroduodenal mucosal damage associated with chronic aspirin therapy.

A randomized, double-blind, placebo-controlled study examined whether concomitant administration of ranitidine could protect against the gastroduodenal mucosal damage associated with long-term aspirin therapy in healthy men. Twenty-four subjects received ranitidine (150 mg twice daily) plus aspirin (650 mg four times daily), and 19 received placebo twice daily plus aspirin (650 mg four times daily) for four weeks. Gastric injury and duodenal injury were assessed separately according to a numerical rating scale for incidence and severity of lesions observed during endoscopic examinations at baseline and after four weeks of treatment. The ranitidine/aspirin group had significantly less mucosal damage in the stomach and duodenum than the placebo/aspirin group. Mean serum salicylate levels were similar between treatment groups after two and four weeks of aspirin therapy. Therefore, the protective effect of ranitidine was achieved with no compromise in salicylate absorption.

Reduction of aspirin-induced gastroduodenal mucosal damage with ranitidine.

A randomized, double-blind, placebo-controlled study was conducted to determine if concomitant administration of ranitidine, an H2-receptor antagonist, could reduce the gastroduodenal mucosal damage associated with short-term (3 day) aspirin therapy. Nineteen subjects received ranitidine 150 mg b.i.d. plus aspirin 650 mg q.i.d., and 21 received placebo b.i.d. plus aspirin 650 mg q.i.d. for 3 days. Gastric injury and duodenal injury were assessed separately on the basis of pre- and posttreatment endoscopic examinations. The ranitidine/aspirin group had significantly less mucosal damage in the stomach (p less than or equal to 0.01) and duodenum (p less than 0.05) than the placebo/aspirin group. There was no significant difference in mean serum salicylate levels between treatment groups after 3 days of aspirin consumption, indicating that the protective effect was achieved without compromising salicylate absorption.

Zinc amelioration of cadmium-induced teratogenesis in vitro.

Mouse embryos were exposed to cadmium (5.35 micrograms/ml) for either 0.5h or 1h and then transferred to fresh serum for the duration of the experiment. Embryos exposed for 0.5h developed numerous malformations that were primarily localized to the craniofacial region. Embryos exposed for 1h to the same level of cadmium all failed to thrive. In a separate series of experiments zinc (10 micrograms/ml) was added 15 minutes prior to the addition of cadmium. Embryos treated with cadmium for 30 min. after the addition of zinc, resulted in 15 of 16 embryos developing normally. The second group of embryos treated for 1h after preincubation with zinc resulted in 93% of the embryos surviving after 48h, albeit malformed. These results suggest that: 1) Exposure time to a teratogen is a critical parameter to consider when designing in vitro experiments 2) zinc is effective in protecting embryos against cadmium induced teratogenesis and 3) the whole embryo culture system is effective in demonstrating biological interactions between agents.

A comparison of the in vivo and in vitro response of mammalian embryos to a teratogenic insult.

This study serves to further define the capabilities of the whole embryo culture system using the known teratogen, hydroxyurea (HU). An initial in vivo study was performed whereby day 9 pregnant mothers were injected i.p. with 300 mg/kg HU. Dams were sacrificed 2 days later and embryos were analyzed for malformations and total embryonic protein. In addition, the peak plasma value from injected dams was found to be approximately 300 micrograms/ml with a plasma half-life of 30 min. These values were then reproduced in the culture system with results noted in cultured embryos with respect to the types of malformations found. Additional in vitro experiments were performed varying both exposure time and drug level concentrations. Results indicate that both of these parameters are important considerations when designing in vitro experiments.

Influence of abdominal temperature and luminal contents on the cauda epididymidis of the rat.

In an attempt to determine if changes previously described in the epididymides of cryptorchid testes were related to the elevated environmental temperature or to the absence of normal luminal constituents, rats were divided into four test groups. Group I animals were made unilaterally cryptorchid. Animals in Group II had only the cauda epididymidis of one side maintained within the abdominal cavity (cryptepididymal) while the caput epididymides and testes remained in the scrotum. The testes of animals in Group III remained in the scrotum but had their efferent tubules ligated on one side. Testes of unoperated rats and contralateral testes of the test animals served as controls. The histochemical demonstration of sorbitol dehydrogenase (SDH) was used to determine differences in functional activity and light and electron microscopy were used to determine structural changes. SDH activity could not be demonstrated in the cauda epididymidis of cryptorchid and efferent tubule-ligated animals; animals in which the luminal contents were obviously changed. These same groups of animals showed abnormal folding of the basal surface of the epididymal epithelium at the ultrastructural level. Activity of SDH could be demonstrated in control epididymides and in those that contained normal luminal contents but were maintained at the temperature of the abdominal cavity. The basal surface of the epididymal epithelium was not unusual in these animals. The results indicate that the epididymis is influenced to a greater extent by changes in luminal contents than by temperature elevation.

Whole embryo culture: a screening technique for teratogens?

Head-fold and early somite stages of mouse and rat embryos maintained in whole-embryo culture throughout much of the period of organogenesis demonstrate normal growth and morphogenesis. Embryos directly exposed to teratogens in the culture system and embryos cultured in serum from adult animals treated with toxic compounds develop congenital abnormalities that resemble malformations induced in vivo by these same agents. Furthermore, the defects are dose- and stage-dependent, such that higher doses produce a greater percentage of malformed embryos, and younger embryos are more susceptible than older ones. These results--together with the observations that 1) data are rapidly produced, 2) quantifiable endpoints can be measured in mammalian systems at costs considerably below those inherent in in vivo analyses, and 3) the potential exists for monitoring serum toxicity in humans and primates--suggest that the whole-embryo culture system may be useful as a screening technique for potentially teratogenic substances.