The effect of an inhaled steroid on the hypothalamic-pituitary-adrenal axis--which tests should be used?

Inhaled corticosteroids may produce systemic effects which include decreased hypothalamic-pituitary-adrenal (HPA) axis activity. Four tests of HPA axis function were assessed in 12 healthy volunteers, during inhalation of two actuations of beclomethasone dipropionate (250 micrograms) aerosol four times daily for 15 days, to determine the most appropriate test for this effect of inhaled corticosteroids. Measurement of basal adrenal activity showed that both 24-hr urinary free cortisol and 0900 hr plasma cortisol were decreased by the fourth day of steroid treatment. All 12 subjects had decreases in basal adrenal activity. Overall the 24-hr urinary free cortisol showed the greater change, with mean pre-steroid baseline values of 497 and 515 nmol/24 hr reduced to 167 nmol/24 hr on the ninth day of treatment (P less than 0.001). The single-dose metyrapone test showed marked changes in each of the six subjects tested. The mean 11-deoxycortisol response was 96 nmol/l on the eleventh day of treatment, compared to baseline and eight-day post-treatment values of 439 and 407 nmol/l respectively (P less than 0.001). In contrast, no consistent treatment-related changes were observed with the short tetracosactrin test. Only two out of six subjects had an abnormal short tetracosactrin test, although all showed a decrease in basal adrenal activity. From these results, the 24-hr urinary free cortisol and single-dose metyrapone test at 0600 hr are recommended to assess the effect of inhaled glucocorticoids on the HPA axis.(ABSTRACT TRUNCATED AT 250 WORDS)

Safety, tolerance and pharmacokinetics of 2.0 g cefpirome (HR 810) after single and multiple dosing.

After intravenous injection of a single dose of 2.0 g cefpirome (HR 810) and multiple doses of 2.0 g b.i.d. (11 doses) to 10 healthy male volunteers in an open design, concentrations of unchanged drug were measured at various times in serum and urine over 24 and 96 h, respectively. Cefpirome concentrations were determined using high-pressure liquid chromatography (HPLC). The biological half-life (t1/2, beta) found by fitting a two-compartment open model to the data was 2 h. No accumulation of the serum levels could be detected during the multiple-dose phase. Urinary concentrations of unchanged cefpirome effective against most clinically relevant bacteria were detected for at least 36 h. The drug was safe and well tolerated. No drug-related changes were observed for blood pressure, heart rate, ECG, haematology, clinical chemistry or urinalysis, including beta 2-microglobulin in serum and creatinine clearance.

Plasma ranitidine concentrations after intravenous administration in normal volunteers and haemodialysis patients.

A comparison was made of the plasma concentrations of ranitidine base in 12 normal volunteers after the administration of 100 mg intravenously and in 6 patients with terminal renal failure after 40 mg intravenously off and then during haemodialysis. The plasma ranitidine concentrations were determined by radioimmunoassay. The results suggest that reduced elimination of the drug occurs in patients with severe renal failure and that there is significant removal of the drug during haemodialysis. It is suggested that dosage reduction is advisable in patients with severe renal failure and a suitable schedule for such patients is described.

Ranitidine--a new H2-receptor antagonist.

The pharmacokinetics and gastric antisecretory effects of a new histamine H2-receptor antagonist, ranitidine hydrochloride, have been investigated in healthy subjects. In the pharmacokinetic study six subjects received 20 mg, 40 mg, and 80 mg ranitidine, both orally and intravenously. Plasma levels of ranitidine were dose-related and in most subjects after oral drug the concentration time curve was bimodal. The estimated elimination half-life was 140 minutes and the bioavailability of the oral drug was about 50%. Five subjects received bolus intravenous injections of ranitidine 20 mg, 40 mg, and 80 mg during continuous gastric stimulation with pentagastrin. There was a dose-related reduction in acid output (P less than 0.05).

The gastric antisecretory activity of 3-methyl-5,6,7,8-tetrahydroquinoline-8-thiocarboxamide hydrochloride (tiquinamide).

3-Methyl-5,6,7,8-tetrahydroquinoline-8-thiocarboxamide hydrochloride (tiquinamide) possesses potent gastric antisecretory activity in a number of animal species. It causes a marked inhibition in the volume and concentration of basal and chemically-stimulated gastric acid secretion in the conscious rat and guinea-pig, and of chemically-stimulated secretion in the anaesthetised cat, dog and monkey. Marked activity is also seen in conscious Heidenhain-pouch dogs, against secretion stimulated by betazole and gastrin tetrapeptide. In the pylorus-ligated rat preparation, the antisecretory effect of 30 mg/kg tiquinamide persists for 8-9 h. The possible mode of action of this drug, in view of its wide non-selective antisecretory profile, is discussed.

The gastrointestinal and autonomic effects of 3-methyl-5,6,7,8-tetrahydroquinoline-8-thiocarboxamide hydrochloride (tiquinamide).

3-Methyl-5,6,7,8-tetrahydroquinoline-8-thiocarboxamide hydrochloride (tiquinamide), a potent gastric anti-secretory compound, affords good protection against stress- and chemically-induced gastric and duodenal erosions. It causes a dose-related delay in gastric emptying and intestinal transit, and does not have a primary effect on gastric mucosal blood flow. The only actions of tiquinamide on the peripheral autonomic nervous system are weak, but apparently specific, histamine H2-receptor blocking activity, and non-competitive inhibition of acetylcholine and histamine responses at 10(-3) mol/l. Since no other effect on isolated tissues can be detected, it seems unlikely that the antisecretory action of tiquinamide involves a direct action on the peripheral autonomic nervous system.

5,6,7,8-Tetrahydroguinolines. 4. Antiulcer and antisecretory activity of 5,6,7,8-tetrahydroquinolinenitriles and -thioamides.

A number of 5,6,7,8-tetrahydroquinoling-8-nitriles and -8-thioamides and related compounds have been found to be potent inhibitors of basal gastric secretion in the pylorus-ligated rat and to afford protection against gastric erosions induced in rats by cold-restraint stress. Molecular manipulation has proved useful in determining factors necessary for such activity and structure-activity relationships are discussed. It has been shown that the most necessary requirements for activity are a pyridine nitrogen with its available lone pair and a primary or secondary thioamide. Also desirable is a six-membered carbocyclic ring with relative freedom from steric hinderance around the 8 position.

Efficacy of antihypertensive drugs.

The magnitude of the fall in blood-pressure in response to an antihypertensive drug depends on the level of the pretreatment pressure, and there is a direct relationship between the two in that the higher the pretreatment pressure the greater the fall in pressure in response to treatment. This simple relationship is inherent in the practical situation of titrating the diastolic blood-pressures of a group of hypertensive patients to a predetermined level. It is assumed that notionally the dose of an antihypertensive drug can be increased in all patients until the diastolic pressure is reduced to the predetermined level. When the fall in diastolic pressure (deltaD.P.) is plotted against pretreatment diastolic pressure (P.T.D.P.), the points for all patients lie on a straight line of slope unity and negative deltaD.P.-intercept numerically equal to the predetermined diastolic-pressure level. This straight-line relationship is termed the predetermined ideal response line. Analysis of data from clinical trials shows that, despite the variability inherent in the practical situation, the data appear to conform to this straight-line relationship. The method of assessing the efficacy of antihypertensive agents is essentially a comparison of each experimental point with the theoretical predetermined response line. In its simplest form the method consists in constructing a scatter diagram of deltaD.P. against P.T.D.P. for all patients. Patients can then be classified as responders or non-responders according to their position on the diagram relative to the predetermined response line. This method of assessing the efficacy of antihypertensive agents has several advantages, the most important of which is that it provides a simple method for displaying all the relevant information in a readily comparable form.