Possible role of cAMP in successful antiviral therapy

hsmith at sun.olympia.com hsmith at sun.olympia.com
Fri Jul 28 13:59:20 EST 1995


	Being new to the Internet, the response to my posting was startling.  Several of you expressed an 
interest in seeing my report on antiviral therapy.  This report has an interesting history which won't be gone 
into now.  Some of you will glance through this and say "Oh, that's been done..." and "Didn't I see a report 
by the Mayo Clinic saying that's not effective?...., etc.  It's a remarkably simple approach.  So simple that 
others will say "If it's that simple, why hasn't someone done it before?"  What I'm looking for is one or more 
scientists who are interested enough in the possibilities to try to replicate my results.  All I want is for 
someone with a well-equipped lab to pick this thing us up and go with it.  Be warned, however, that this is 
quite risky if you have a grant from the pharmaceutical industry or for the government.  If this really works as 
described, you can imagine the horrible economic consequences.   I have seen dogs lying on their sides in 
the terminal stages of infectious canine distemper .  Within 24 hrs. of initial treatment, these dying dogs were 
jumping around in their pens yapping, wagging their tails, and eating.   I have seen an asthma attack 
terminated within minutes with oral ascorbic acid given at the rate of 50 mg/kg of body weight.  I have held 
a rabies-infected mouse in my hand to hand feed him when he was paralyzed from the neck down.  He 
ultimately regained the use of his muscles.  Maybe none of you can get these results.  But if you can--ah!  if 
you can, then there is going to be quite a fuss made about this, isn't there?  Think how much fun you'll 
have defending yourselves against charges of quackery and worse!
	There are two very critical points that need to be made here.  (1) The dosage is critical, and must 
be based on body weight.  One dose doesn't fit all.  (2) I assume absolutely no responsibility for the 
consequences of your efforts based on this report.  DO NOT ATTEMPT SELF-TREATMENT, AND BY
NO MEANS SHOULD A PREGNANT WOMAN BE GIVEN THESE DOSAGES.  I have no concrete 
information on the potential for birth defects, but work with pregnant mice gave me an uneasy feeling.  
There was something not quite right about the litters, but I couldn't identify what it was.  This information is 
being given strictly for your consideration in carrying out controlled laboratory experiments.
	With that wordy pronouncement, let's get on with it.

       SIMILARITIES IN THE ANTIVIRAL ACTION OF THEOPHYLLINE AND ASCORBIC ACID, 
         INCLUDING EXISTENCE OF A CRITICAL DOSE SIZE FOR SUCCESSFUL THERAPY

                                                       Howard Smith	

	In an effort to develop a successful, broad-spectrum anti-viral drug formulation, I attempted to find 
one or more reagents that would stimulate a natural, physiological resistance to virus infection.  A number of 
possible reagents were screened at varying concentrations and in random mixtures based on latin-square 
designs.  All reagents tested proved to be of little or no value except for ascorbic acid and theophylline, 
both of which have been used with varying degrees of success in treatment of virus infections (1 - 5).
When repeated tests with these two reagents at varying dosage levels gave encouraging but inconsistent 
results, it was determined that either more or less of either reagent than a specific dosage size would give 
unsatisfactory results in repeated trials.  When the apparently correct dosage was determined by 
experiments with rabid mice, the same relative dosages were applied successfully to treatment of a variety 
of virus infections in dogs, cats, and human volunteers.
	For tests with dogs, cats, and mice, theophylline was prepared as an injectable formulation in 15% 
polyvinylpyrrolidone (GAF #K-90), with a dosage of 4 mg/kg per day for five days.  For mice, ascorbic acid 
was prepared as in injectable formulation in 15% PVP, with a dosage of 200 mg/kg per day for five days.
Theophylline was not tested in humans, but ascorbic acid U.S.P. was given orally in tablet form.  For human 
treatment, the oral dosage of 200 mg/kg per day was divided into four daily doses of 50 mg/kg each.
In all tests, treatment was initiated only after the onset of typical early symptoms of infection, and was 
continued for a total of five conscutive days (with the exception of four human volunteers who discontinued 
treatment after three days).  In cases of canine distemper, felline rhinotracheitits, herpes simplex infections in 
humans, and rhinovirus(?) infections in humans, there was a marked remission of symptoms within 24 - 48 
hr. of the initial dosage.  Only with experimental rabies infections in mice did the symptoms persist without a 
noticeable remission for 72 hr. or more.  In some cases the treated mice developed a partial paralysis typical 
of the infection, but would subsequently recover almost complete muscle function as the disease declined.  
Conversely, paralysis induced in untreated controls was invariably followed by death within 48 hr.  
	Treatment of rabies infections in mice inoculated intracranially with rabies was not as successful 
as treatment of less mortal diseases in other species, but the difference between survival of rabid mice 
treated with either ascorbic or theophylline was shown to be highly significant (P< .001).  In tratment of the 
limited number of cases of virus infections reported in Tables 2 - 5, treatment was considered effective 
when it was followed by early and complete remission of symptoms.
	There have been several reports of the use of ascorbic acid in cases of human respiratory 
infections (1, 4), but in these relatively unsuccessful cases the dosage was considerably below 200 mg/kg 
per day.  More encouraging results were reported when a parainfluenza III infection in marmosets was 
treated with a dosage of 500 mg/kg per day (6).  Using dosages still closer to 200 mg/kg per day other 
investigators experienced complete recovery of more than 90% of dogs naturally infected with canine 
distemper (2, 5).  The lack of 100% effectiveness was probably due at least in part to the fact that they 
gave the same dose to all dogs, regardless of size.  Their average patients were of a size that would have 
resultled in a daily dose of about 150 - 300 mg/kg, thus the encouraging results in such a large percentage 
of animals treated.
	`After losing treated animals from bacterial superinfection during the course of my experiments, it 
became evident that both theophylline and ascorbic acid had an immunosuppresssive effect, an 
observation that has been made by other authors for theophylline and cAMP (7 - 10), but apparently not for 
ascorbic acid.  On pursuing this, I found other reported similarities between the action of cAMP and 
ascorbic acid, including interferon enhancement (11 - 12), and an antihistamine effect (7, 10).  In later 
experiments I found that combining either an optimum dosage of theophylline with an optijmum dosage of 
ascorbic acid, ro combining an optimum dosage of one with a lesser dosage of the other would give less 
satisfactory results than the use of an optimal dosage of only one of the two..  It would thus seem that 
ascorbic acid and theophylline have the same inhibitory effect on phosphodiesterase, and that the optimum 
effect for antiviral therapy is closely related to a critical dose size.  
	I have tentatively concluded, then, that a natural physiological response to virus infection 
probably involves a virus-induced (interferon?) phosphdiesterase inhibition with a subsequent rise in 
intracellular levels of cAMP.  If this is true, cAMP immunsuppression with its subsequent enhanced 
likelihood of a bacterial superinfection such as that encountered in the 1918 epidemic of human influenza 
(13) may well be a natural--albeit sometimes fatal--mechanism of defense against virus infection in the animal 
body.  As this report has shown, there is a strong possibility that enhancement of intracellular cAMP levels 
with theophylline or with ascorbic acid is a practical key to successful antiviral therapy.

                                                         TABLE I

          SURVIVAL OF RABID MICE TREATED WITH THEOPHYLLINE (4 mg/kg) OR WITH
            ASCORBIC ACID (200 mg/kg),  COMPARED TO UNTREATED CONTROLS*

    Treatment                              Survival of Treated Animals                Survival of Controls

Theophylline                               35/319  (10.0%)                                    2/92  (2.0%)

Ascorbic Acid                              29/358   (8.0%)                                     2/80  (2.5%)

            *White Swiss mice, NIH C3H strain, weighing 16 - 18 grams each at time of 
              intracranial inoculation with 100 LD50 of mouse-virulent ERA strain rabies



         Note:  I'm running of posting space here.  If anyone is interested in seeing the remaining tables or in 
looking at the list of references, let me know and I'll continue.  
         Hopefully, at least one of you has come this far.  If my conclusions are valid, and I have every reason 
to believe they are, it would be a terrible thing if this gets dropped and forgotten.  	

                 Howard Smith (hsmith at sun.olympia.com)




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