Antihistamines 1937 – A Turning Point in Drug Development

Dr David Healy says: "From a technical standpoint, antihistamines mark a turning point in drug development”. 

Early research on these simple chemicals led scientists into fields ranging from allergy-fighting drugs to antipsychotics and treatments for stomach ulcers.

Histamines occur in many plants and insect venoms and are also present in most human tissues. They are stored in white blood cells (especially mast cells and basophils). Histamine, which plays a role in immune responses such as allergic reactions and inflammation, is found in virtually all tissues, although its concentration varies. The lungs, skin and gastrointestinal tract contain high concentrations. 

Histamine is stored in granules in mast cells. In these granules, it forms an inactive complex with heparin, a polysulphated anion, and another anionic protein. When not stored, histamine is inactivated by enzymes called amine oxidases. Histamine increases capillary permeability to white blood cells, helping them fight foreign invaders. Fluid escaping from the capillaries clears the area, which may cause a runny nose. Histamine also occurs in certain neurons (brain cells). It also functions as a neurotransmitter in these cells. In the stomach, histamine-secreting cells help stimulate acid production.

In 1910, British chemists George Barger and Henry Dale first isolated histamine from ergot, a fungus that grows on plants. 

In humans, histamine works by binding to four types of histamine receptors on cell surfaces. The two best-known receptors are:

• H1, found in smooth muscle, cells lining internal walls and central nervous system tissue.
• H2, found in gastric parietal cells.

In 1937, Swiss pharmacologist Daniel Bovet and his student Anne-Marie Staub produced the first antihistamine. However, it was too toxic for humans. Bovet and his team persisted and, in 1944, produced Neo-Antergan (pyrilamine), which was useful in humans. First-generation antihistamines used for nasal allergies and insect stings worked by binding to H1 receptors, but caused drowsiness as an adverse effect. Later antihistamines could not cross the blood-brain barrier, preventing this problem. The structure of the antipsychotic drug chlorpromazine is not very different from that of the antihistamine promethazine. 

Several neurological diseases, such as Alzheimer's disease and multiple sclerosis, are associated with significant changes in the brain's histamine system.

Description of the article image: Bee venom contains melittin (a toxin), histamine and other substances that cause pain and itching.

Historical figures mentioned in the article: Henry Hallett Dale (1875 – 1968), George Barger (1878 – 1939), Daniel Bovet (1907 – 1992), Anne-Marie Staub (b. 1914)

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