May 31, 2008

When Bullets Lose Their Magic

German chemist Paul Ehrlich coined the term 'magic bullets' (he also used the term chemotherapy), in connection with the dyes used to visualize histology samples. He assumed that if these dyes could specifically stain the pathogens then these substances could also be used to deliver toxins that would specifically kill the rogue cells. Based on these assumptions, he developed Salvarsan (arsphenamine), a drug used in syphilis.

Medicines do not always act so magically. Sometimes medicines end up doing just the same thing it was made to cure. Such boomeranging is not uncommon. Consider the case of aspirin (acetyl salicylic acid). It is used in the treatment of fever and inflammation, among others. It inhibits the enzyme cyclo-oxygenase (COX 1 &2), thereby reducing the production of prostaglandins which works on the hypothalamus to bring about fever. Thus it acts as an antipyretic. However, in higher doses, it causes fever. This occurs as uncoupling of oxidative phosphorylation occurs at higher doses, liberating free energy in the form of heat. Oxidative phosphorylation is normally associated with the formation of ATP (high energy phosphates, the energy currency of the cells).

In cancer chemotherapy drugs used to treat cancer (usually given to lessen the tumor burden, these drugs rarely cure cancer) often cause cancer themselves. Nitrogen mustards such as lomustine (or carmustine) are examples of such antimalignancy drugs. Historically, sulfur mustard was used on the British by Germans in 1917, in a chemical warfare. It caused blisters on the skin and mucus membranes and bone marrow suppression. Its effectiveness in cancer was discovered later, nitrogen mustards came in. These agents are alkylating since they form highly reacting immonium ions in neutral or alkaline water. These immonium ions being nucleophilic, attack the DNA of the malignant cells and cross links them. The cell replication stops; the reckless and relentless progress of cancer growth is tamed.

But the most heart rendering of these are, funnily enough, the medicines for the heart themselves. Nitrates are used in angina pectoris, a medical term for chest pain or discomfort due to coronary heart disease. Nitroglycerin explodesThese compounds liberate nitric oxide or EDRF(Endothelium Derived Relaxing Factor) in our bodies, which then increase the amount of one intracellular compound called cyclic GMP (cGMP). cGMP acts on the vascular smooth muscle cells and these relax. This vasodilation brings relief in painful occlusive (spastic, atherothrombotic) coronary heart diseases. (vasodilation, incidentally, is also the basic principle of action of Sildenafil citrate, known popularly as viagra). But nitrates (polyol esters of nitric acid) such as Nitroglycerine (known variously as NTG, GTN or NG) are explosives too. Alfred Nobel found a way to stabilize this, in his discovery dynamite. Another highly explosive antianginal drug is Pentaerythrityl tetranitrate or PETN (also spelled Pentaerythritol tetranitrate). This drug (or substance!), a terrorist's pet, is often used in the making of Semtex, a deadly plastic explosive which is very tough to detect. Thus it appears that what appears life saving may be a killer too. By the way, you can safely touch (or kiss) a person who is on PETN or GTN. He (she) won't blow up, I can assure you this.
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