Asthma platelet-activating factor

Platelet activating factor (PAF) was first identified by its ability (at low levels) to cause platelet aggregation and dilation of blood vessels, but it is now known to be a potent mediator in inflammation, allergic responses, and shock. PAF effects are observed at tissue concentrations as low as 10 M. PAF causes a dramatic inflammation of air passages and induces asthma-like symptoms in laboratory animals. Toxic-shock syndrome occurs when fragments of destroyed bacteria act as toxins and induce the synthesis of PAF. This results in a drop in blood pressure and a reduced... 

It is a cromolyn analogue. It is an antihistaminic (H antagonist) and probably inhibits airway inflammation induced by platelet activating factor (PAF) in primate. It is not a bronchodilator. It is used in asthma and symptomatic relief in atopic dermatitis, rhinitis, conjunctivitis and urticaria. It is absorbed orally and well tolerated. Bioavailability is 50% due to first pass metabolism and is primarily metabolized. The common side effects include dry mouth, sedation, dizziness and nausea. 

Corticosteroids and cromolyn are also useful in asthma. Corticosteroids inhibit eicosanoid synthesis and thus limit the amounts of eicosanoid mediator available for release. Cromolyn appears to inhibit the release of eicosanoids and other mediators such as histamine and platelet-activating factor from mast cells. 

Beer JH, Wuthiidt B, von Felten A. Allergen exposure in acute asthma causes the release of platelet-activating factor. Int Arch Aller hmnun 1995 106 291-2%... 

Previous work with A6-Tetrahydrocannabinol [(3R,4R) 6a,7,10,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-l -ol, hereinafter referred to as A6-THC], has indicated that derivatives of this compound may prove clinically useful. The 7-carboxy derivative of A6-THC [A6-THC-7-oic acid] has been reported to be a non-psychoactive, potent antagonist to endogenous platelet activating factor and, thus, a useful treatment for PAF-induced disorders, such as asthma, systemic anaphylaxis, and septic shock. (U.S. Pat. No. 4,973,603, issued Nov. 27, 1990 to Sumner Burstein). Another derivative, (3S,4S)-7-hydroxy-A6-THC-l,l-dimethylheptyl, has been reported to possess analgesic and antiemetic activities. (U.S. Pat. No. 4,876,276). 

Many studies have demonstrated that ginkgolides are capable of inhibiting platelet activating factor (PAF), which is involved in platelet aggregation and inflammatory processes such as are seen in asthma, ulcerative colitis, and allergies. These studies have been reviewed elsewhere (Kleijnen and Knipschild, 1992 Nemecz and Combest, 1997 Chavez and Chavez, 1998). 

KUITERT, L.M., ANGUS, R.M., BARNES, N.C., BARNES, P.J., BONE, M.F., CHUNG, K.F., FAIRFAX, A.J., HIGENBOTHAM, T.W., O CONNOR, B J. PIOTROWSKA, B. (1995) Effect of a novel potent platelet-activating factor antagonist, modipafant, in clinical asthma. American Journal of Respiratory and Critical Care Medicine, 151, 1331-1335. 

Fig. 3. Major mediators in asthma. PAF, platelet-activating factors ASA, aspirin-sensitive asthmatic. Copyright 2003 by AOCS Press.

Levels of platelet-activating factor are elevated in several neurological and visceral disorders, including brain trauma, seizures, stroke, multiple sclerosis, and viral and bacterial infections, as well as in a variety of other conditions such as asthma, thrombosis, toxic shock, and dermatitis. Administration of PAF antagonists slows down the progression of these disorders. Thus, the development of new non-toxic PAF antagonists would result in better treatment of visceral and neurological disorders. 

---