الفهرس 
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Abstract
Since its discovery as component of the tea leaf in 1888, the
history of theophylline has been successful one. At the turn of the century, theophylline became less expensive due to chemical synthesis. Despite the trends towards newer therapeutic agents, theophylline continues to play a major role in the treatment of reversible airway obstruction and it still occupies a central position in the treatment of these conditions.
Being a methylxanthine, theophylline exerts physiologic effects on CNS, gastrointestinal, smooth muscle, metabolic and cardiovascular systems. For many years, the proposed main mechanism of action of the xanthines was inhibition of phosphodiesterase, which results in an increase in cyclic adenosine monophosphate (cAMP). However, inhibition of the extracellular adenosine, stimulation of endogenous catecholamines, antagonism of prostaglandins PGE2 and PG2a or direct effect on mobilization of intracellular calcium resulting in smooth muscle relaxation are recent suggested mechanisms.
Clinical use of theophylline is complicated by a relatively narrow therapeutic index and a long list of drug interaction. Theophylline poisoning is one of the serious poisoning, evidenced by its case-fatality ratio of 0.6%, a rate which exceeds that of antidepressants. In Poison Control Center, Ain Shams University Hospitals, from which we selected our patients, theophylline poisoning mainly acute overmedication with sustained-release form, is becoming the most common drug poisoning in the last few years.
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H2-receptor antagonists, the largest selling drugs in the world, specially cimetidine, are one of the common groups that interact, not only with theophylline, but with other drugs metabolized in the liver. Cimetidine, like other substituted imidazole compounds, binds strongly to and inhibits the cytochrome P450 mixed function oxidase involved in hepatic
metabolism of certain drugs. Cimetidine decreases total body clearance
of theophylline by 25% and extends its plasma half-life. Ranitidine, with its furan ring is thought not to affect theophylline metabolism. Famotidine, a recently available H2-receptor antagonist, has no available studies on its interaction with theophylline.
The aim of the present work is to study theophylline poisoning, expressing its extent. H2-receptor antagonists were chosen as a possible drug interacting with theophylline affecting its course and increasing its toxicity. Cimetidine, ranitidine and famotidine, a traditional, most common and recent member in this group were studied. Theophyl line toxicity:
The clinical study showed that theophylline induced significant elevation in blood sugar, CPK and kidney function tests (BUN and serum creatinine) and significant lowering in serum potassium. On the other hand an insignificant changes were observed in liver function tests compared to the control group.
The biochemical results confirmed by the histopathological findings of the experimental study are concomitant with those of the clinical study in both acute and short-term chronic toxicity studies, where theophylline
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induced cardiotoxicity evident by the elevation of CPK, ECG changes (9 patients = 14.5%), arrhythmia and hypotension (20% of patients) encountered in the clinical study and also by the histopathological findings
of myocardial necrosis and interstitial infiltration observed in the experimental study. Theophylline also induced hyperglycaemia, hypokalemia and nephrotoxicity which was evident both in the biochemical and histopathological (in the experimental study) findings. Nephrotoxicity
may be secondary to rabdomyolysis. In the clinical study, hemodialysis was used in 10 patients (15%) to manage both the theophylline induced acute renal failure and to increase theophylline clearance.
Theophylline is not a hepatotoxic drug as observed in the biochemical results both in the clinical and experimental studies and confirmed by histopathological findings in rats liver in which hydropic degeneration was detected and minimal necrosis or hemorrhage. Clinical study:
This study was conducted on eighty five individuals of both sexes. Twenty apparently healthy subjects constituting the control group and sixty five patients with acute theophylline poisoning were selected from Poison Control Center, Ain Shams University Hospitals.
After thorough history taking, patients and control groups were subjected to full clinical examination to assess the vital signs, central nervous, gastrointestinal and cardiovascular systems and ECG. They were also subjected to the following laboratory investigations:
- Blood sugar, serum potassium and creatine phosphokinase.
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- Kidney function tests BUN and creatinine.
- Liver function tests serum bilirubin, ALT, AST and alkaline phosphatase. Experimental studies:
These studies were conducted on 400 male adult albino rats of 100-150 g weight. There were divided into 2 main groups, the first group
comprised 240 rats and used in the acute toxicity study, the second group (160 rats) used in the short-term chronic toxicity study.
In the acute study, the animals were classified into eight groups, 30 in each group in order to evaluate the toxic effects which might occur from the acute oral toxic dose of theophylline (Theo), cimetidine (C), ranitidine (R) and famotidine (F). In these groups, the animals were given the median lethal dose ”LD50” of each drug. Before giving the drug combination, Theo+C, Theo+R and Theo+F, a pilot study was conducted, where the animals were given the ”LD50” of these combinations. All animals in this model study died, so the dose was reduced to ”1/2 LD50” of these combination. The 8th. group was not given any drugs and used as a control group and kept under the same environmental and dietary conditions.
24 hours after the acute oral toxic dose of the drugs (dead animals were excluded), six rats from each group were sacrificed after collecting the blood sample. Another six were left for two weeks (were not given any drugs) and then sacrificed in order to study the after effect of these drugs. In the short term chronic study, 160 adult male albino rats were divided into the same 8 groups, twenty rats in each group. Animals in
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each group were given a daily oral dose of 1/10 the ”LD50” of the drug or drug combination for 4 weeks. After 2 and 4 weeks from starting drug administration, six rats from each group were sacrificed after collecting the blood sample. Two weeks after stopping drugs administration, another 6 rats were sacrificed in order to study the after effects of the studied drugs. All groups were carefully observed for any toxic manifestations as well as any mortalities that might occur as a result of drug administration. Venous blood samples were obtained by means of capillary glass tubing from retro-orbital plexus under light ether anaesthesia and used for quantitative determination of blood sugar, serum potassium, CPK, BUN, serum creatin-ine, serum bilirubin, ALT, AST and alkaline phosphatase for assessment of metabolic effect, kidney and liver functions. Histopathological examination of kidney, liver and heart were done at the end of 2 and 4 weeks and 2 weeks after stopping drug administration. liz-antaoonists toxicity:
The three studied H2-receptor antagonists, cimetidine ranitidine and famotidine when given separately alone. In the acute or two and four weeks of short term chronic toxicity studies, they induced significant elevation in all liver function tests compared to the control group which were more at the end of the short-term chronic study. This indicate that the three studied H2-antagonists have hepatotoxic effect which is time dependent with some different extent. These biochemical findings (clinical and experimental) were confirmed by the histopathological study which showed that cimetidine is more hepatotoxic than ranitidine, and famotidine is the least affecting the liver. Also, the three groups induced insignificant changes in blood sugar, serum potassium and CPK compared to the
Summary & Conclusion - 201
control group. Kidney function tests (BUN, creatinine) were significantly elevated in the three groups compared to the control group. Highly significant in the acute and short-term chronic studies in ranitidine group indicating that ranitidine is more nephrotoxic than either cimetidine or famotidine confirmed by the histopathological findings time dependent and significance increased in both of them. Theophylline Hfantacionists interaction:
The concomitant administration of theophylline and cimetidine, ranitidine or famotidine induced significant elevation in liver function tests, blood sugar, CPK and significant lowering in serum potassium, also significant elevation of BUN and serum creatinine compared to the control group in the acute or two and four weeks of short term chronic toxicity studies.
These three combination groups when compared to its corresponding H2-antagonists, e.g., Theo+C compared to C group. An insignificant changes of all the liver parameters were observed. This indicates that although cimetidine, ranitidine and not famotidine increased theophylline toxicity, it did not increase any of their hepatotoxic effects.
Two weeks after either the acute or after stopping drug administration in the short term chronic toxicity studies. All the parameters in the different groups showed insignificant changes compared to the control group. This indicates that all these toxic effects of the different studied drugs or drug combinations are due to reversible effect or damage.