Safety testing of dibutyrl cAMP (db cAMP) questions

mk99 · 12-11-2004, 03:36 PM

Dr. Young, you recently wrote in the ( So Long) thread about some the things we still need to know about dibutyrl cAMP before administering it in humans.

Assuming a lab is going full time on answering these questions, how long do you think it would take to prove a reasonable level of safety and to get some idea of proper dosages, etc?

Does Chonroitinase have similar unanswered safety questions before it could be administered in a human trial?

Wise Young · 12-11-2004, 07:25 PM

Mike, it is not an easy task. To my knowledge, no dose-response data is available. Let me describe to you the kind of experiment that we would do if there were funds to do so.

1. Small animal safety study. We would do a dose-escalation study with short-term outcomes first to look for tissue damage. This would probably require two separate experiments since tissue damage needs to be looked at several hours, several days, and several weeks after the injection of the db cAMP. The acute effects of the db cAMP wll need to be before.

2. Small animal efficacy study. This probably needs to be done wth anesthesia and without anesthesia. Optimizing the cAMP for efficiacy is the more difficult study. It would require waiting for the animal to regenerate. This may take several weeks. Obviously, the toxicity study needs to be done first, to find the range of doses where the treatment does not acutely harm the spinal cord. The animals probably need to be kept for 6-12 weeks to see if they regenerate and regain function, compared against control untreated animals.

3. Large animal safety stuy. Once the studies are completed in a small animal, a large animal study would be required. The FDA requries safety data from a large species and a small species (usually rodent). In the larger species, obviously, you want to minimize the number of animals used and you want to do it only once for long term followup purposes.

I think that the small animal study will probably require 200 rats and 12 months to complete and about $200,000 of animals, supples, and personnel to carry out. The large animal study may cost $100,000 and again 6-12 months to complete for both safety and efficacy indications.

Wse.

mk99 · 12-12-2004, 01:31 PM

Thanks again Dr. Young. Doesn't sound too bad... I think this should be a priority to investigate as it could be a key component of a combo therapy.

Does Chondroitinase have similar safety concerns before it could be administered in a human trial?

I wonder what effects may occurr if one was to add Chondroitinase to a Rolipram, db cAMP & OEC combo. You'd kind of be hitting the inhibitor "problem" with 2 simultaneous but different techniques wouldn't you?

Schmeky · 12-12-2004, 01:39 PM

Quote:

Chondroitinase to a Rolipram, db cAMP & OEC combo

Sounds like a potentially very good combo to me.

DA · 12-12-2004, 02:40 PM

mk, do an internet search and you will find dbCamp is already being used in humans. ofcourse the real reason its not used in sci is bush policy.

mk99 · 12-12-2004, 04:20 PM

hmmm... here's one study from 1975. Doesn't sound like it was in the spinal cord though:

"Experimental study of dibutyryl cyclic AMP; its metabolic effects observed in anesthetized human subjects.

Metabolic effects of N6,O2-dibutyryl adenosine 3',5'-monophosphate (DBcAMP) were studied in 10 anesthetized patients who were divided at random into two groups each consisting of 5 patients. DBcAMP dissolved in 200 ml of physiological saline was administered intravenously at a rate of 10 mg/min for 20 min in one group and 20 mg/min for 20 min in the other group. DBcAMP infusion at either rate increased levels of blood glucose, immunoreactive plasma insulin, blood pyruvate and blood redox-potential while it reduced levels of glycerol, non-esterified fatty acid and inorganic phosphate. These findings suggest that 200 and 400 mg of DBcAMP stimulates glycogenolysis and glycolysis but inhibits lipolysis in man."

Source

[This message was edited by mk99 on 12-12-04 at 10:02 PM.]

Christopher Paddon · 12-12-2004, 07:13 PM

Why can't OEG and chondroitinaise be tried together?

Wise Young · 12-13-2004, 08:58 AM

chris2, that is what a number of people are doing in animals. Chondroitinase unfortunately does not last long in the spinal cord. It loses activity quickly. The way that Liz Bradbury got regeneration in the spinal cord was to inject the enzyme several times directly into the spinal cord. There is also the intriguing report from Wutian Wu and Kwok-fai so, who found that chondroitinase combined with Lithium chloride are synergistic in getting more axona regeneration in the spinal cord. Interesting that a drug used to treat depression appears to be synergistic in stimulating axonal growth with chondroitinase, don't you think? Wise.

12-11-2004, 03:36 PM	#1
mk99 Senior Member Join Date: Jul 2001 Location: toronto, canada Posts: 3,494	Safety testing of dibutyrl cAMP (db cAMP) questions Dr. Young, you recently wrote in the ( So Long) thread about some the things we still need to know about dibutyrl cAMP before administering it in humans. Assuming a lab is going full time on answering these questions, how long do you think it would take to prove a reasonable level of safety and to get some idea of proper dosages, etc? Does Chonroitinase have similar unanswered safety questions before it could be administered in a human trial?

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12-11-2004, 07:25 PM	#2
Wise Young Administrator Join Date: Jul 2001 Location: New Brunswick, NJ, USA Posts: 37,988	Mike, it is not an easy task. To my knowledge, no dose-response data is available. Let me describe to you the kind of experiment that we would do if there were funds to do so. 1. Small animal safety study. We would do a dose-escalation study with short-term outcomes first to look for tissue damage. This would probably require two separate experiments since tissue damage needs to be looked at several hours, several days, and several weeks after the injection of the db cAMP. The acute effects of the db cAMP wll need to be before. 2. Small animal efficacy study. This probably needs to be done wth anesthesia and without anesthesia. Optimizing the cAMP for efficiacy is the more difficult study. It would require waiting for the animal to regenerate. This may take several weeks. Obviously, the toxicity study needs to be done first, to find the range of doses where the treatment does not acutely harm the spinal cord. The animals probably need to be kept for 6-12 weeks to see if they regenerate and regain function, compared against control untreated animals. 3. Large animal safety stuy. Once the studies are completed in a small animal, a large animal study would be required. The FDA requries safety data from a large species and a small species (usually rodent). In the larger species, obviously, you want to minimize the number of animals used and you want to do it only once for long term followup purposes. I think that the small animal study will probably require 200 rats and 12 months to complete and about $200,000 of animals, supples, and personnel to carry out. The large animal study may cost $100,000 and again 6-12 months to complete for both safety and efficacy indications. Wse.

12-12-2004, 01:31 PM	#3
mk99 Senior Member Join Date: Jul 2001 Location: toronto, canada Posts: 3,494	Thanks again Dr. Young. Doesn't sound too bad... I think this should be a priority to investigate as it could be a key component of a combo therapy. Does Chondroitinase have similar safety concerns before it could be administered in a human trial? I wonder what effects may occurr if one was to add Chondroitinase to a Rolipram, db cAMP & OEC combo. You'd kind of be hitting the inhibitor "problem" with 2 simultaneous but different techniques wouldn't you?

12-12-2004, 02:40 PM	#5
DA Senior Member Join Date: Jul 2001 Location: beaumont tx usa Posts: 32,390	mk, do an internet search and you will find dbCamp is already being used in humans. ofcourse the real reason its not used in sci is bush policy.

12-12-2004, 04:20 PM	#6
mk99 Senior Member Join Date: Jul 2001 Location: toronto, canada Posts: 3,494	hmmm... here's one study from 1975. Doesn't sound like it was in the spinal cord though: "Experimental study of dibutyryl cyclic AMP; its metabolic effects observed in anesthetized human subjects. Metabolic effects of N6,O2-dibutyryl adenosine 3',5'-monophosphate (DBcAMP) were studied in 10 anesthetized patients who were divided at random into two groups each consisting of 5 patients. DBcAMP dissolved in 200 ml of physiological saline was administered intravenously at a rate of 10 mg/min for 20 min in one group and 20 mg/min for 20 min in the other group. DBcAMP infusion at either rate increased levels of blood glucose, immunoreactive plasma insulin, blood pyruvate and blood redox-potential while it reduced levels of glycerol, non-esterified fatty acid and inorganic phosphate. These findings suggest that 200 and 400 mg of DBcAMP stimulates glycogenolysis and glycolysis but inhibits lipolysis in man." Source [This message was edited by mk99 on 12-12-04 at 10:02 PM.]

12-12-2004, 07:13 PM	#7
Christopher Paddon Senior Member Join Date: Oct 2001 Location: New Zealand Posts: 3,207	Why can't OEG and chondroitinaise be tried together?

12-13-2004, 08:58 AM	#8
Wise Young Administrator Join Date: Jul 2001 Location: New Brunswick, NJ, USA Posts: 37,988	chris2, that is what a number of people are doing in animals. Chondroitinase unfortunately does not last long in the spinal cord. It loses activity quickly. The way that Liz Bradbury got regeneration in the spinal cord was to inject the enzyme several times directly into the spinal cord. There is also the intriguing report from Wutian Wu and Kwok-fai so, who found that chondroitinase combined with Lithium chloride are synergistic in getting more axona regeneration in the spinal cord. Interesting that a drug used to treat depression appears to be synergistic in stimulating axonal growth with chondroitinase, don't you think? Wise.