A U.S. patent issued this summer to the National Institute on DrugAbuse (NIDA) is titled "Attenuation of the Opioid WithdrawalSyndrome by Inhibitors of Nitric Oxide Synthase." Its text asserts upfront: "The approach....encompassed by the present invention isradically different from any approach in current clinical use."
To help move this approach from animal models to human trials andearly clinical use, NIDA has advertised in the Federal Register for anindustrial partner to license its new patent, number 5,225,440, whichissued July 6.
Opioid withdrawal syndrome in heroin addicts who are trying to kicktheir addiction is a dire litany of symptoms. Some of them, saysinventor Alane Kimes of NIDA, "resemble a bad case of the flu."These miseries include, in random order: lacrimation (tearing);rhinorrhea (runny nose), frequent yawning, profuse sweating,tossing, restless sleep, dilated pupils, anorexia (appetite loss), weightloss, waves of gooseflesh, irritability, tremors, severe sneezing, chillsand hot flushes, spontaneous ejaculation (in men), and spontaneousorgasm (in women).
Heroin dependence is commonly treated with methadone, whichsubstitutes one addiction -- albeit legal -- for another. Methadonedoesn't abolish the opiate withdrawal syndrome, so the adreno-agonist clonidine, an anti-hypertensive drug, is often prescribed forpatients trying to shake their dependence on methadone. But there'sa catch: As the patent points out, "Clonidine is an effective attenuatorof the opioid withdrawal syndrome. The major problem with its use,however, is that it lowers blood pressure."
Recent research has linked opioid withdrawal with activation ofglutamatergic neurotransmission and shown that inhibition of aglutamate receptor, N-methyl-D-aspartate (NMDA), reduces bizarrejumping behavior in rats undergoing opiate withdrawal.
Some of the adverse consequences of activating the NMDA receptorare now known to be mediated through nitric oxide (NO), a highlyreactive free radical produced by nitric oxide synthase (NOS). Aprime inhibitor of NOS is nitroarginine, which the NIDA patentinventors are testing on rodent models.
The researchers addict rats to opiates by implanting delayed-releasemorphine pellets under their skin, then deny them further fixes tofeed their dependence. In withdrawal, the animals display typicalsymptoms, of which the most striking is "wet-dog shakes." Otherhallmarks of their withdrawal are diarrhea, abnormal posturing,aberrant jumping, penile licking in males, and excessive grooming.
Dosed with the nitroarginine, as the inventors will report in aforthcoming issue of the journal Psychopharmacology, the NOSinhibitors reduced wet-dog shakes and weight loss in the rats butincreased teeth-chattering. "This divergent effect of NOS blockers onthese signs of withdrawal remains to be explained," the paper'sprincipal author, pharmacologist Edythe London, told BioWorld. Sheheads the Neuroimaging and Drug Action Section of NIDA's AddictionResearch Center.
Back at their drawing boards, she and her associate, biochemist andneuroscientist Kimes, are planning "a complete opiate screen of theNOS inhibitor in rodents and primates," and trying the nitroargininein combination with other drugs, such as clonidine, which the patentalso covers. They expect to submit an investigational new drug (IND)application to the FDA, "optimistically, within a year," said Kimes.
The NIDA researchers wonder whether their nitric-oxide inhibitorswill work on other receptors for other addictions, such as alcohol andnicotine. "There's not quite as strong evidence for its effect on them,"said Kimes. "We'll know when we test it."
London expresses interest in "a pharmaceutical company pick-up" toapply their patent. The licensing specialist handling NIDA's offer atthe NIH Office of Technology Transfer is Arthur J. Cohn, (301) 496-7735.
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.