Journal of International Medical Research

Understanding of the use of corticosteroids has been aided by knowledge of their effect on cellular protein synthesis and by an appreciation of how modification of their molecular structure alters their pharmacological action. Their ability to modulate the immune response and to diminish inflammation make them useful in rheumatology, respiratory diseases, allergies, endocrine and metabolic disorders, blood disorders, gastro-intestinal diseases, neurological and muscular diseases, renal diseases, cardiovascular disorders and skin diseases. They have been widely tried empirically and, sometimes, they have proved unequivocally effective. Often there has been a need for cooperative clinical trials to establish their efficacy, and initial enthusiasm for corticosteroids has been tempered by a better appreciation of their limitations, especially in infections and ophthalmology. Those areas where either controlled trials or other persuasive evidence has established a place for their use are reviewed.

The effects of inhaled terbutaline, a β₂-adrenergic agonist, administered via a 750-ml spacer device were studied in young asthmatic subjects with exercise-induced asthma. A double-blind, randomized, placebo-controlled study of the effects of inhaled 0.5 mg terbutaline and placebo was conducted in 10 asthmatic children (age range 6–16 years) with documented exercise-induced asthma. Forced expiratory volume in 1 s (FEV₁) was measured at baseline, 15 min after inhaling terbutaline or placebo, and at intervals up to 60 min after exercising. Subjects exercised using a cycle ergometer for 5 min at a submaximal, constant work-load while breathing dry air at room temperature. Terbutaline induced bronchodilation at rest in all subject and fully prevented exercise-induced asthma in nine out of the 10 subjects; the exercise-induced fall in FEV₁ was markedly reduced in the remaining subject. It is concluded that exercise-induced asthma can be inhibited by pretreatment with inhaled terbutaline, administered via a spacer, in a majority of young asthmatics.

As Ca²⁺ is known to play a fundamental role in platelet function, the effect of combining two platelet aggregating agents (adrenaline and the ionophore A23187) with different effects on Ca²⁺ was studied at levels subthreshold for aggregation using platelet-rich plasma from eight atherosclerotic patients. Adrenaline lowered the A23187 threshold required to induce aggregation. The effects of treating patients with the antiplatelet agents, indobufen and ticlopidine, on A23187 and adrenaline induced aggregation of platelets prepared in hirudin or sodium citrate was also evaluated. Aggregation was also studied using platelets resuspended in Ca²⁺-free and Ca²⁺-enriched Tyrode solution. Before treatment hirudin treated platelet-rich plasma, which has physiological extraplatelet Ca²⁺ levels, was more sensitive to A23187 and adrenaline than was citrated platelet-rich plasma, which has suppressed Ca²⁺ levels. Ticlopidine significantly raised the concentration of A23187 required to induce aggregation in citrated but not hirudin treated platelet-rich plasma. Indobufen did not significantly affect A23187 induced aggregation. Ticlopidine acts by inhibiting the glycoprotein IIb – IIIa complex on the platelet membranes. Low levels of extracellular Ca²⁺ and ticlopidine may act synergistically to reduce the aggregatory response of stimulated platelets.

The effects of clinofibrate on serum lipoprotein concentrations, lecithin cholesterol acyl transferase activity and atherogenic index were studied in 10 diabetes mellitus patients. The patients comprised five with well-controlled non-insulin-dependent diabetes, and five with poorly controlled insulin-dependent diabetes; six non-insulin-dependent diabetics acted as placebo controls. No adverse side-effects were reported and there were no significant changes in total cholesterol, triglyceride or high-density lipoprotein 3-cholesterol concentrations following 600 mg/kg clinofibrate treatment for 4 weeks in either insulin-dependent or non-insulin-dependent diabetics. High-density lipoprotein-cholesterol concentrations and lecithin cholesterol acyl transferase activity were significantly (P<0.05) increased by clinofibrate treatment in insulin-dependent and non-insulin-dependent diabetics and high-density lipoprotein 2-cholesterol concentrations were significantly (P<0.05) increased by clinofibrate in insulin-dependent diabetics. The atherogenic index was significantly (P<0.01) reduced in non-insulin-dependent diabetics. It is suggested that the enhanced plasma lecithin cholesterol acyl transferase activity following clinofibrate therapy is the result of increased high-density lipoprotein-cholesterol and high-density lipoprotein 2-cholesterol concentrations and may play a central role in the efficacy of clinofibrate.

Urinary oxalate concentrations were measured in 45 patients with quiescent Crohn's disease, four patients with chronic pancreatitis and five healthy subjects after a normal oxalate (150 g/day) diet, after a high-fat (150 g/day), normal oxalate diet and after a high-oxalate (500 mg/day) diet. Urinary oxalate concentrations were significantly (P<0.05) higher in patients with Crohn's disease and steatorrhoea, but not in those with chronic pancreatitis, after administrating a high-oxalate diet compared with healthy subjects. Mean oxalate values were 19.1 mg/24 h in controls compared with 65.8 mg/24 h in Crohn's disease patients. A direct correlation (r=0.37, P<0.01) was established between faecal fats and urinary oxalate after oral oxalate load; this correlation (r=0.43, P<0.01) is closer when only patients with Crohn's disease are considered. The study, therefore, confirmed a correlation between steatorrhoea and hyperoxaluria in patients with Crohn's disease; however, the high percentage of false positive results limits the use of urinary oxalate concentrations as a reliable indicator of lipid malabsorption. It is concluded that, at present, measurement of urinary oxalate cannot be recommended as a valid alternative to the Van de Kamer method for diagnosing lipid malabsorption.

Oral bioavailability of ampicillin when bound to sulbactam (sultamicillin) compared with ampicillin alone and that of amoxycillin with a ligand of clavulanic acid versus amoxycillin alone were assessed in 16 healthy subjects using an open label, multiple crossover study. After a single administration of the drugs, the bioavailability of ampicillin released from sultamicillin was more than twice (2.17) that of ampicillin administered alone, whereas that of amoxycillin was increased by a factor of 1.64 by the presence of clavulanic acid. Higher peak concentrations and areas under the curves, along with shorter lag times, were observed in both cases. The increased oral bioavailability of these aminopenicillins when associated with a β-lactamase inhibitor was well demonstrated in this study, the bioavailability of ampicillin being more enhanced by sulbactam than that of amoxycillin by clavulanic acid.

Regulation of blood glucose involves the integration of the central nervous system with both hormonal and neural mechanisms. Considerable evidence suggests that β-endorphin is involved in the regulation of feeding in experimental animals and man. Previous studies have shown that β-endorphin plays an important role during hypergiycaemia. Glipizide has been shown to increase glucose metabolism by both pancreatic and extrapancreatic actions. This study indicates that glipizide may exert its pharmacological action in obese cafeteria rats through a modification of β-endorphin secretions via central and peripheral mechanisms.

Cefuroxime axetil was compared with amoxycillin in the treatment of acute and acute on chronic sinusitis in a multicentre general practice study. A total of 160 patients were randomized to receive 250 mg cefuroxime axetil orally twice daily, or 250 mg amoxycillin orally three times daily for 10 days. Of the 45 assessable patients with acute sinusitis 43 (96%) were cured or improved using cefuroxime axetil compared with 49 (94%) of the assessable patients in the amoxycillin-treated group. In patients with acute on chronic sinusitis, cefuroxime axetil resulted in an 80% (16/20) cure or improvement, with a 68% (13/19) response in the case of amoxycillin. Adverse events were mainly gastro-intestinal and none was considered serious in either treatment group, although three patients receiving cefuroxime axetil were withdrawn from treatment. It is concluded that cefuroxime axetil is at least as clinically efficacious as amoxycillin in the treatment of acute sinusitis in adults.

The effect of 30 mg/day slow-release frusemide given orally for 12 months was studied in 64 patients previously treated with thiazides for mild to moderate essential hypertension. Frusemide had a significant antihypertensive effect (P<0.001), and compared to thiazides significantly reduced fasting serum glucose (P<0.015), haemoglobin A_1c (P<0.025), albumin (P<0.025) and serum calcium (P<0.025), and significantly increased serum sodium and chloride concentrations (P<0.0001). There was also a non-significant trend for frusemide to reduce serum total cholesterol, triglycerides and urate, and to increase serum potassium. Frusemide was well tolerated in all but three patients. It is concluded that slow-release frusemide has a comparable antihypertensive effect to that of thiazide diuretics, but has fewer metabolic side-effects, and should be used in preference to thiazides for the treatment of arterial hypertension when a diuretic is indicated.

The effect of slow-release isosorbide dinitrate, given orally four times daily for 14 days, on the portal circulation was studied in 10 patients with liver cirrhosis and oesophageal varices. Mean arterial pressure and heart rate were not influenced significantly by isosorbide dinitrate. Statistically significant dilation of the portal vein by 11.9% and an increase in blood flow velocity by 35.4% and in portal blood flow rate by 54.3% were observed at the end of therapy. The average wedged hepatic vein pressure was 32.9 mmHg before therapy and after therapy it was decreased to 60.5%. The slight decrease observed in free hepatic vein pressure was not statistically significant. Before treatment the portohepatic gradient was four times above normal and after therapy it fell to 9.5 mmHg. The results indicate that, in patients with portal hypertension, an improvement in haemodynamics can be achieved by the use of isosorbide dinitrate. This improvement may lead to the prevention of bleeding from oesophageal varices.

The pharmacokinetic and clinical properties of a modified release formulation of the α₂-adrenergic agonist tizanidine are reviewed. Therapy with conventional tizanidine tablets is effective in the relief of spasticity, but it has a short half-life, resulting in it having to be administered three or four times daily. The modified release capsules have retard characteristics which allow the drug to be given as a once-daily dosage. Single- and multiple-dose pharmacokinetic studies in healthy volunteers have shown that the relative bioavailability of the modified release formulation is similar to that of conventional tablets and is unaffected by food. Clinical studies have shown that modified release tizanidine improved spasticity and disability in approximately 94% and 79%, respectively, of spastic patients. Adverse effects were observed in about 33% of patients. Mild, transient muscular weakness was the most common effect, but it did not require termination of treatment. Body weight, blood pressure, heart rate and haematological or biochemical measures were not adversely affected. The initial recommended dose of modified release tizanidine is one capsule per day of 6 mg, which may be increased gradually to 24 mg. A daily dose of 12 mg modified release tizanidine was used in 50% of patients studied.