The term "ergot" is generally used to describe species of the fungus Claviceps, the sclerotia formed by the fungi specifically Claviceps purpurea and the wide range of unique alkaloids produced by the fungi following infestation of grain. In the Middle Ages, contaminated grain caused plagues of ergotism characterized by gangrene and an intense peripheral burning pain (known as "St. Anthony's fire"), spontaneous abortion and occasional episodes of mania and hallucinations. Initially used therapeutically by European midwives to hasten labor (with many untoward effects), ergot derivatives eventually found a life-saving role in the treatment of postpartum hemorrhage. Ergotamine was first used in the treatment of acute migraine in 1926. Common adverse effects of ergotamine and dihydroergotamine (DHE) are nausea, vomiting, abdominal pain, diarrhea, peripheral paresthesia, swollen fingers, generalized weakness, and peripheral and coronary vasoconstriction. The drugs are contraindicated in people with peripheral vascular disorders, coronary artery disease, stroke, severe hypertension, pregnancy, hepatic or renal failure, or sepsis.
Caffeine has been consumed by humans for hundreds if not thousands of years. Throughout the world, the preferred mode for consuming caffeine occurs in markedly different forms (e.g., drinking coffee, tea, mate, soft drinks; chewing cola nuts; consuming coca and guarana products). Caffeine tends to produce a pattern of subjective effects that varies as a function of dose. Although low doses, in the range of 200 to 290 mg. generally produce mild positive subjective effects (e.g., increased feeling of well-being, alertness, energy), higher doses, in the range of 200 to 800 mg. can produce negative effects (e.g., nervousness, anxiety).
There are many papers describing the physiology, pharmacology and phannacokinetics of ergotamine, but there is not much data available on the histopathology and haematology of these drugs.
The aim of the present study was the histopathological, haematological and microbiological evaluation of ergotamine and caffeine in a male albino rat model.
Following points summarize the study;
1Male albino rats were employed in this study as animal model and three different drug dosages of ergotamine and caffeine were orally administrated. Prior to administration of drugs, the tissues (liver, heart and kidney), blood and fecal samples of normal healthy animals were studied for haematological and microbiological parameters.
2Besides, acute dosages of these drugs were administered to animals, so as to evaluate the histopathological and haematological effects of the acute/over dosage.
3On expiration of the test period, animals were first bled and then dissected for the tissues.
4The blood was used for the haematological and microbiological evaluation and the findings were compared with that of un-treated normal animals (control).
5The tissues were processed for histopathological evaluation and the sections were observed for any abnormalities within.
6In the animals administered with acute doses of the drugs it was found that, there was slight increase in Total Leukocytes Count (TLC) and there was a decrease in the RBC and hemoglobin where as, for other doses, very slight change on haematological parameters was observed.
7The albino rats treated with various doses indicated that with higher dose of ergotamine severe damage to the liver was caused. At 0.03 mg/0.5 ml dose the liver showed changes but still the architectural condition was identifiable, but at higher dose prominent changes in hepatocytes, central veins and portal tract area occurred. At a highest dose (1.25 mg/3 ml), the changes were very severe and normal pattern of hepatocytes and architecture of the liver tissue was totally lost.
8When treated with a dose of 0.03 mg/0.5 ml of ergotamine heart was severely affected. The histological sections revealed shrinkage of muscles leaving large cavities in between. Due to this shrinkage the nuclei of muscle fibres became more prominent. At a relatively higher dose (0.06 mg/1.5 ml) condensation of muscle fibres was more severe and a homogeneous tissue was seen with the fragmentation of the nuclei. Blood vessels were also affected.. At an acute dose (1.25 mg/3 ml) the destruction and necrosis of muscle fibres was seen. This necrotic area had a large number of inflammatory cells including plasma cells, lymphocytes and macrophages. The most predominant among these were the lymphocytes.
9In kidney tissues, by the action of ergotamine the interstitium and the glomeruli were affected. Higher doses caused greater damage to the glomeruli, which resulted in abscess formation. At a dose of 0.03 mg/O.5 ml there were slight changes in the interstitium and glomeruli, the parietal layer of the glomeruli inside the Bowman's capsule was intact, 3glomerular spaces were reduced and the mesangium was obliterated. Inflammation with increase in the cellularity of the glomeruli was obvious. At a slightly higher dose, (0.06 mg/1.5 ml) proliferative glomerulonephritis was obvious; increased cellularity of the glomerulus was due to proliferation of the endothelial and visceral epithelial cells and the endothelial cells were also swollen. Higher dose (0.09 mg/3ml) affected the convoluted tubules as well as the glomerular morphology. Dilatation of the tubules and obliteration of glomerular spaces and mesangium occurred. Sclerosis due to inflammation and disintegration of glomerulus and parietal epithelium was obvious. Very high dose (1.25 mg/3 ml) totally destroyed the glomerular structure and Bowman's capsule and replaced by lesions consisting of polymorphonuclear leukocytes, lymphocytes, plasma cells and macrophages. Interstitium was also indistinguishable.
10The Albino rats treated with various doses of caffeine showed almost similar histopathological findings. In liver tissues, hepatocytes became rounded with ill-defined cell wall and stained brighter. Hepatic cells around the central vein were badly affected and lost their morphological structure. At a little higher dose (6 mg/1.5 ml), cellular integration was lost and cellular boundaries were hardly identifiable. When the concentration of the dose was increased (9 mg/3 ml), severe damage occurred to the hepatocytes and the central veins. Nuclei of the hepatocytes disappeared; vascular degeneration of hepatocytes produced specially in the central vein. Slugging in the central vein was more prominent.
11When the animals were treated with a dose of 3 mg/0.5 ml of caffeine, heart tissues were affected. The histological sections revealed that shrunken and condensation of heart muscles. At a higher dose (9 mg/3 ml), blood vessels were affected, loosing their normal structure of various layers and converted into indistinct tissue with numerous chromatin particles. Muscular condensation was also occurred and individual muscle fibres were not, 'distinct. At an acute dose (125 mg/3 ml), blocking of vessel and obliteration of vessel observed. Yellowish-brown pigment lipofuscin tend to accumulated in many tissues.
12In kidney tissues, by the action of caffeine (3 mg/O.5 ml) the glomerular spaces reduced and mesangium was not obvious. Slight edema of interstitium was also present. At a higher dose of caffeine (6 mg/1.5 ml) atrophy of glomerulus structure resulted into a larger surrounding spaces in the Bowman's capsule. At a dose (9 mg/3.0 ml) of caffeine, severe damages to the cellular structure of kidney noted. Edema of interstitium was obvious. Cellular differentiation in the glomeruli was not possible. At an acute dose (125 mg/3 ml) of caffeine coagulated necrosis has occurred with loss of cellular detail but tubular outlines were preserved and abscesses were formed.
13The blood profile of the treated animals was not very much altered by the action of the drugs on low doses. However, there was slight increase in the WBCs and it might be due to the inflammatory responses, which were produced in the affected tissues. Slight decrease in haemoglobin was also evident. Ergotamine was found to be more toxic as compared to caffeine. Acute doses of both drugs produced significant effects on blood profiles of the test animals and the findings were altered as compared to normal ranges of the control animals.
14Microbiological analysis of the blood of the treated animals did not reveal presence of any bacteria i.e., no bacteremia was detected. It means that the drugs neither alter the defense mechanism of the animals nor make them susceptible to the infection. Fecal samples of the treated animals were also normal and there was no marked difference among the samples regarding the species of the bacteria. Almost same normal flora of GIT was found in the treated rats. However, there was slight difference in the count of the normal flora. This finding indicates that the drugs did not alter the GIT micro flora of the animals.