picumast and Hypersensitivity

Picumast dihydrochloride (PDH), (3,4-dimethyl-7-[4-chlorobenzyl) piperazine-1-yl]propoxycoumarin dihydrochloride) is a prophylactically active anti-allergic compound which combines inhibition of mediator release and action. The activity profile of PDH differs clearly from that of known prophylactic anti-allergic drugs such as DSCG and ketotifen. Other inhibitory actions of PDH in addition to its H1-antagonism (and that of its metabolites M2 and M1) may be the cause of the suppression of immediate and late phase allergic reactions in animals as well as allergic rhinitis and bronchial responsiveness and symptom scores in asthmatic patients.

Topics: Anaphylaxis; Animals; Bronchial Spasm; Clinical Trials as Topic; Conjunctivitis, Allergic; Coumarins; Cromolyn Sodium; Eosinophilia; Eosinophils; Histamine Antagonists; Histamine H1 Antagonists; Humans; Hypersensitivity; Neutrophils

In a pilot study 8 patients with allergic obstructive airway disease were treated with the new compound picumast dihydrochloride (3,4-dimethyl-7-[4-(4-chlorobenzyl)piperazine-1-yl]propoxycoumarine++ + dihydrochloride) 2 x 2 mg daily orally during a period of 8 days additionally to a usual therapy of bronchodilators and corticoids in a steady state. It was demonstrated that the compound inhibited the allergen induced histamine liberation of patients basophils significantly. Compared with a collective of patients without an additional picumast dihydrochloride treatment the effect of the substance was shown more clearly. From reasons of these experimental data picumast dihydrochloride may be of a considerable value as a prophylactic agent in allergic bronchial asthma when given orally.

Topics: Asthma; Chromatography, High Pressure Liquid; Coumarins; Female; Histamine H1 Antagonists; Histamine Release; Humans; Hypersensitivity; Leukocytes; Male; Middle Aged

Picumast dihydrochloride (3,4-dimethyl-7-[4-(4-chlorobenzyl)piperazine-1-yl]propoxycoumarin dihydrochloride) was compared with cromoglycate, ketotifen and mepyramine as an inhibitor of allergic and anaphylactoid reactions. 1. In guinea-pigs, pretreatment with picumast dihydrochloride given intravenously, orally or by inhalation prevented bronchospasm induced by antigen or histamine. The fraction of the bronchospasm remaining after mepyramine pretreatment was further reduced by picumast dihydrochloride. 2. Systemic administration of picumast dihydrochloride inhibited antigen-induced conjunctivitis, whereas mepyramine and ketotifen were inactive. 3. Intravenous and oral pretreatment with picumast dihydrochloride inhibited the antigen-induced mast cell degranulation in rat mesentery. The effective doses of cromoglycate given intravenously were twice as high as those of picumast dihydrochloride. Picumast dihydrochloride did not inhibit antigen-induced bronchoconstriction in rats. 4. The cutaneous reaction induced with Ascaris antigen in atopic monkeys was insensitive to the antihistaminic action of ketotifen, whereas it was inhibited by low doses of picumast dihydrochloride. Both compounds suppressed skin reactions induced by histamine. 5. Picumast dihydrochloride decreased IgE production in atopic high responder mice. It did not prevent autoimmune nephritis in NZB/W mice. 6. In rats, picumast dihydrochloride did not reduce cotton pellet granuloma, nor adjuvant arthritis. The inhibition of carrageenin oedema is presumably due to its anti-oedematous properties rather than to an antiproliferative activity. In conclusion, the inhibition of allergic and anaphylactoid reactions by picumast dihydrochloride can be attributed to a combined inhibition of liberation and action of histamine and other mediators.

Topics: Airway Resistance; Animals; Arthritis, Experimental; Bronchial Spasm; Conjunctivitis; Coumarins; Dogs; Edema; Female; Granuloma; Guinea Pigs; Histamine H1 Antagonists; Hypersensitivity; Immunization, Passive; Immunoglobulin E; Lung Compliance; Macaca; Male; Mice; Passive Cutaneous Anaphylaxis; Rats; Rats, Inbred Strains

In this study the effects of picumast dihydrochloride (3,4-dimethyl-7-[4-(4-chlorobenzyl)piperazine-1-yl]propoxycoumarine++ + dihydrochloride) a novel antiallergic agent, on antigen-induced early and late responses in allergic sheep were examined. For all studies picumast dihydrochloride was administered as an aerosol approximately 20 min before airway challenge with Ascaris suum antigen. Allergic sheep were challenged on four occasions each greater than or equal to 14 days apart: one placebo trial and after 1 mg, 2.5 mg, and 5 mg picumast dihydrochloride aerosol (total dose nebulized). Specific lung resistance (SRL) was used as an index of the airway response to antigen and was measured before and serially after antigen challenge. In the placebo trial (n = 11) antigen challenge resulted in significant early and late airway responses (i.e. 382% and 185% increases in SRL, respectively). Picumast dihydrochloride at 1.0 mg (n = 7) did not protect against the antigen-induced increases in SRL. At 2.5 mg (n = 7), picumast dihydrochloride gave 48% and 55% (both p less than 0.05) protection against the early and late airway responses, respectively. These effects were slightly enhanced with 5 mg picumast dihydrochloride (n = 7) giving 63% protection against the early response and 81% against the late response. These results suggest that the antiallergic agent picumast dihydrochloride may provide some benefit in the treatment of allergic airway disease.

Topics: Administration, Oral; Aerosols; Animals; Antigens; Ascaris; Coumarins; Histamine H1 Antagonists; Hypersensitivity; Injections, Intravenous; Respiratory System; Sheep