**4. Pharmacodynamics of thiamine**

Thiamine diphosphate binds to a evolutionarily highly conserved domain located in a deep cleft in the active sites of the thiamine dependant enzymes resulting in the activity of these enzymes [196]. The physiological function of thiamine is mainly fulfilled by TPP (TDP). Structurally the basis of thiamine action and activation of all ThDP-dependent enzymes lies in thiamine catalysis and deprotonation of the thiazolium ring and contribution of the aminopyrimidine side chain in this effect [197-198] while the pyrimidine ring with its dual proton donor and acceptor capability functioning as a proton transfer system. On the basis of these chemical alterations TPP functions as coenzyme for mitochondrial enzymes pyruvate dehydrogenase (PDH [199] and α ketoglutarate dehydrogenase [200] of the citric acid cycle.

#### **4.1. Symtoms of severe thiamine deficiency**

Thiamine derivatives and thiamine dependant enzymes are universally present in all cells of the body thus a thiamine deficiency would seem to affect all organ systems especially the heart and the nervous system due to their high oxidative metabolism as witnessed in its severest form as beriberi (dry, wet or infantile) [195]. Symptoms occur rarely include tachycardia, warmth, flushing, irritability, sweating, nausea, restlessness and allergic reactions. Pharma‐ cokinetic interactions at the level of drug metabolism include microsomal enzyme induction by prolonged anticonvulsant pheytoin resulting in decreased plasma levels of thiamin in patients with seizure disorders such as epilepsy. The water soluble thiamine HCl form is safe in humans in oral doses less than or equal to several hundred milligrams via oral route. A UK EVM found that a small clinical trial in Alzheimers patients revealed no adverse effects of thiamineHCl at daily oral intakes of 6000 to 8000mg for five to six months. A randomized double blind placebo controlled trial was conducted in India for therapy of primary dysme‐ norrhea, a daily oral dose of 100mg thiamine was given to 556 females for 60-90 days and no adverse effects were noted.In extremely rare cases of allergic sensitivity were noted solely in patients using thiamine by the parenteral route and were probably due to the injection vehicle and it not been reported to be carcinogenic or mutagenic. No known genetic microsomal variations increase susceptibility to thiamine toxicity [214].
