The Pharmacological Basis of Therapeutics A Textbook of Pharmacology, Toxicology and Therapeutics for Physicians and Medical Students. By Prof. Louis Goodman and Prof. Alfred Gilman. Pp. xiii + 1383. (New York: The Macmillan Company, 1941.) 50s. net.

The Pharmacological Basis of Therapeutics

Occult (silent) gastroesophageal reflux disease (GER, GERD) is believed to be an important etiologic factor in the development of many inflammatory and neoplastic disorders of the upper aerodigestive tract. In order ot test this hypothesis, a human study and an animal study were performed. The human study consisted primarily of applying a new diagnostic technique (double-probe pH monitoring) to a population of otolaryngology patients with GERD to determine the incidence of overt and occult GERD. The animal study consisted of experiments to evaluate the potential damaging effects of intermittent GER on the larynx. Two hundred twenty-five consecutive patients with otolaryngologic disorders having suspected GERD evaluated from 1985 through 1988 are reported. Ambulatory 24-hour intraesophageal pH monitoring was performed in 197; of those, 81% underwent double-probe pH monitoring, with the second pH probe being placed in the hypopharynx at the laryngeal inlet. Seventy percent of the patients also underwent barium esophagography with videofluoroscopy. The patient population was divided into seven diagnostic subgroups: carcinoma of the larynx (n = 31), laryngeal and tracheal stenosis (n = 33), reflux laryngitis (n = 61), globus pharyngeus (n = 27), dysphagia (n = 25), chronic cough (n = 30), and a group with miscellaneous disorders (n = 18). The most common symptoms were hoarseness (71%), cough (51%), globus (47%), and throat clearing (42%). Only 43% of the patients had gastrointestinal symptoms (heartburn or acid regurgitation). Thus, by traditional symptomatology, GER was occult or silent in the majority of the study population. Twenty-eight patients (12%) refused or could not tolerate pH monitoring. Of the patients undergoing diagnostic pH monitoring, 62% had abnormal esophageal pH studies, and 30% demonstrated reflux into the pharynx. The results of diagnostic pH monitoring for each of the subgroups were as follows (percentage with abnormal studies): carcinoma (71%), stenosis (78%), reflux laryngitis (60%), globus (58%), dysphagia (45%), chronic cough (52%), and miscellaneous (13%). The highest yield of abnormal pharyngeal reflux was in the carcinoma group and the stenosis group (58% and 56%, respectively). By comparison, the diagnostic barium esophagogram with videofluoroscopy was frequently negative. The results were as follows: esophagitis (18%), reflux (9%), esophageal dysmotility (12%), and stricture (3%). All of the study patients were treated with antireflux therapy. Follow-up was available on 68% of the patients and the mean follow-up period was 11.6 +/- 12.7 months.(ABSTRACT TRUNCATED AT 400 WORDS)

The Otolaryngologic Manifestations of Gastroesophageal Reflux Disease (GERD): A Clinical Investigation of 225 Patients Using Ambulatory 24‐Hour pH Monitoring and an Experimental Investigation of the Role of Acid and Pepsin in the Development of Laryngeal Injury

Dissolution tests are used for many purposes in the pharmaceutical industry: in the development of new products, for quality control and, to assist with the determination of bioequivalence. Recent regulatory developments such as the Biopharmaceutics Classification Scheme have highlighted the importance of dissolution in the regulation of post-approval changes and introduced the possibility of substituting dissolution tests for clinical studies in some cases. Therefore, there is a need to develop dissolution tests that better predict the in vivo performance of drug products. This could be achieved if the conditions in the gastrointestinal tract were successfully reconstructed in vitro. The aims of this article are, first, to clarify under which circumstances dissolution testing can be prognostic for in vivo performance, and second, to present physiological data relevant to the design of dissolution tests, particularly with respect to the composition, volume, flow rates and mixing patterns of the fluids in the gastrointestinal tract. Finally, brief comments are made in regard to the composition of in vitro dissolution media as well as the hydrodynamics and duration of the test.

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Dissolution Testing as a Prognostic Tool for Oral Drug Absorption: Immediate Release Dosage Forms

We evaluated the mechanisms of gastroesophageal reflux in 10 patients with reflux esophagitis and compared the results with findings from 10 controls. The patients had more episodes of reflux (35 +/- 15 in 12 hours, as compared with 9 +/- 8 in the controls) and a lower pressure of the lower esophageal sphincter (13 +/- 8 mm Hg as compared with 29 +/- 9 in the controls) (P less than 0.001). Reflux occurred by three different mechanisms: transient complete relaxation of the lower esophageal sphincter, a transient increase in intra-abdominal pressure, or spontaneous free reflux associated with a low resting pressure of the lower esophageal sphincter. In controls 94 per cent of reflux episodes were caused by transient sphincter sphincter relaxation. In the patients 65 per cent of episodes of reflux accompanied transient sphincter relaxation, 17 per cent accompanied a transient increase in intra-abdominal pressure, and 18 per cent occurred as spontaneous free reflux. The predominant reflux mechanism in individual patients varied: some had normal resting sphincter pressure and reflux that occurred primarily during transient sphincter relaxation, whereas others with low resting sphincter pressures had spontaneous free reflux or reflux that occurred during an increase in intra-abdominal pressure.

Mechanisms of Gastroesophageal Reflux in Patients With Reflux Esophagitis

Purpose. In this paper we seek to verify the differences in dissolution behavior between class I and class II drugs and to evaluate the suitability of two new physiologically based media, of Simulated Gastric Fluid (SGF) and of milk for their ability to forecast trends in the in vivo performance of class II compounds and their formulations. 
Methods. Dissolution behavior of two class I drugs, i,e, acetaminophen and metoprolol, and of three class II drugs, i.e. danazol, mefenamic acid and ketoconazole, was studied with USP Apparatus 2 in water, SGF, milk, Simulated Intestinal Fluid without pancreatin (SIFsp) and in two media simulating the small intestinal contents in the fed (FeSSIF) and fasted (FaSSIF) states, respectively. 
Results. Class I powders dissolved rapidly in all media tested. Acetaminophen dissolution in milk was slow from one tablet formulation, in all other cases dissolution was more than 85% complete in 15 minutes. The dissolution rate of metoprolol was shown to be dependent on formulation and manufacturing method, and one of the three tablet formulations did not meet compendial specifications (80%/30 minutes). Dissolution behavior of class II drugs was greatly affected by choice of medium. Dissolution from a capsule formulation of danazol proved to be dependent on the concentration of solubilizing agents, with a the 30-fold increase in percentage dissolved within 90 minutes upon changing from aqueous media without surfactants to FaSSIF. Use of FeSSIF or milk as the dissolution medium resulted in an even greater increase in percentage dissolved, 100 and 180-fold respectively. Dissolution of the weak acid mefenamic acid from a capsule formulation is dependent on both pH and bile salt concentration, which leads to an offset between increased bile salt concentration and lower pH in the fed state compared to the fasted state medium. The weak base ketoconazole showed complete dissolution from a tablet formulation in Simulated Gastric Fluid without pepsin (SGFsp) within 30 minutes, 70% dissolution in 2 hours under fed state simulated upper jejunal conditions but only 6% dissolution in 2 hours under fasted state conditions. 
Conclusions. As predicted, dissolution of class II drugs proved to be in general much more dependent on the medium than class I drugs. With the array of compendial and physiological media available, it should be possible to design a suitable set of tests to predict the in vivo dissolution of both class I and II drugs from immediate release formulations.

Evaluation of Various Dissolution Media for Predicting In Vivo Performance of Class I and II Drugs

https://www.gastrojournal.org/article/S0016-5085(83)80232-7/pdf

Regulation of the Gastric Emptying of Glucose

https://www.gastrojournal.org/article/S0016-5085(96)00211-9/pdf

Botulinum toxin for achalasia: long-term outcome and predictors of response.

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The internal anal sphincter response: manometric studies on its normal physiology, neural pathways, and alteration in bowel disorders*

The clinical diagnosis of esophagitis is suggested by the presence of severe heartburn which is aggravated by the recumbent position. The symptom is generally worse after eating and is relieved by antacids. It is generally held that increased reflux of gastric contents leads to the development of esophagitis and that the pain is associated with an inflammatory process. In many patients with symptoms that suggest a diagnosis of esophagitis, however, there is, no endoscopic or histologic evidence of inflammation. The poor correlation between the clinical diagnosis of esophagitis and the endoscopic and histologic observations led to an investigation of esophageal motor function in these patients.

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Esophageal motor abnormalities induced by acid perfusion in patients with heartburn

When glycine-1–14C-cholate was given orally and 14CO2 specific activity of expired air measured by a breath-analysis technic, the results clearly separated patients with either ileal resection or bacterial-overgrowth syndromes from subjects without abnormalities of bile-salt metabolism. The normal subjects and the patients with steatorrhea unrelated to abnormalities of bile-salt metabolism had no appreciable rise in 14CO2 excretion (2.2 ± 0.60 [S.E.] and 1.3 ± 0.31 per cent administered dose, respectively) whereas subjects with ileal resection and bacterial-overgrowth syndromes had a rapid appearance of 14CO2 in expired breath (31.4 ± 4.62 and 23.4 ± 6.78 per cent of administered dose, respectively). Elimination of bacterial overgrowth with antibiotics or surgical fistula repair returned 14CO2 excretion (0.7 ± 0.23 per cent) to normal. Thus, the breath test will detect increased bacterial deconjugation of bile salts and assess effective antibiotic management of bacterial-overgrowth syndromes.

Thomas R. Hendrix

Papers

Regulation of the Gastric Emptying of Glucose

Botulinum toxin for achalasia: long-term outcome and predictors of response.

The internal anal sphincter response: manometric studies on its normal physiology, neural pathways, and alteration in bowel disorders*

Esophageal motor abnormalities induced by acid perfusion in patients with heartburn

Detection of bacterial deconjugation of bile salts by a convenient breath-analysis technic.