mission (Ross et al., 1987; Ghigo et al., 1990a,b; Giustina et al., 1991; Bellone et al., 1992). Anticholinergic drugs abolish the GH response to certain physiological and pharmacological stimuli (Massara et al., 1986; Casanueva et al., 1990), while PB, an AChE inhibitor, stimulates GH secretion when administered alone (Ghigo et al., 1990b) and enhances the GH response when administered with GHRH or arginine (Giustina et al., 1990).

Mediated by a cholinergically provoked decrease in the hypothalamic release of somatostatin, PB substantially augments the dose–response relationship of GHRH to GH secretion in normal subjects and patients with a variety of pathological disorders (Giustina et al., 1990; Ghigo et al., 1990a, 1996a,b). These physiological effects of PB have been studied extensively in normal volunteers, and the drug has been widely used to test the hypothalamic–pituitary responses, particularly those of GH, of patients with many different disorders. In fact, combining GHRH with PB or arginine—substances that inhibit hypothalamic somatostatin release—is the most powerful means of testing the secretory capacity of human pituitary somatotrope cells (the GH response is always greater than 19 μg/L), which accounts for its wide clinical use (Ghigo et al., 1996b). Accordingly, there is considerable information about the acute administration of PB given as a diagnostic test of hypothalamic–pituitary function in normal volunteers and patients.

As a diagnostic test, PB is generally administered as a single 30–180-mg dose, usually with GHRH, which sometimes produces acute transient symptoms. Among several thousand patients, reported in numerous studies (e.g., Ross et al., 1987; Ghigo et al., 1990a,b,c, 1996a,b; Giustina et al., 1990, 1991; Murialdo et al., 1991,1993; Bellone et al., 1992; O’Keane et al., 1992, 1994; Cordido et al., 1995; Yang et al., 1995; Arvat et al., 1997a,b; Coiro et al., 1998) to whom PB was administered as a diagnostic test, the most common symptoms were muscarinic; abdominal or muscular symptoms usually appeared within 1 or 2 hours of ingesting PB and typically lasted 1–2 hours. Symptoms were monitored for several hours in most studies, and none reported long-term follow-up of symptoms. Abdominal symptoms were described as cramps, increased digestive sounds (due to the movement of gas in the intestines), pain, diarrhea, and nausea, and the principal nicotinic cholinergic symptoms were skeletal muscle and tongue fasciculations (sometimes accompanied by dysarthria).

No central nervous symptoms were reported following PB ingestion, which is particularly noteworthy since it was given to patients with mania (Dinan et al., 1994), depression (O’Keane et al., 1992; Thakore and Dinan, 1995; Coiro et al., 1998), dementia (Murialdo et al., 1991, 1993), schizophrenia (O’Keane et al., 1994), and alcoholism (Coiro and Vescovi, 1997).

A clear dose–response effect on symptoms was not apparent from a review of these studies, although none of the studies were designed to test this effect. However, there was a trend toward greater reporting of symptoms at higher PB dose ranges among subjects given several different doses in the same study. This point is particularly well documented in the results of a study by Yang and colleagues (1995) in which side effects were graded from 1 (mild) to 3 (severe): a

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