X-Message-Number: 7513
Date: 16 Jan 97 06:09:32 EST
From: "Steven B. Harris" <>
Subject: Cryopreservation Premedication 7 (end)

The following is a BioPreservation, Inc. (BPI)
technical briefing on premedication of human
cryopreservation patients to mitigate the injury 
associated with antemortem and post mortem 
hypoxia/ischemnia. 

Contents copyright 1997 by BioPreservation, Inc. 
All rights reserved. 
 
Premedication of the Human Cryopreservation Patient 
Part VII (end) 
by Michael Darwin 
 
[continued from part VI). 


Category 3 Drugs 
 
	Ketorolac tromethamine (Toradol) 60 mg IM or IV may be given  
when the patient becomes frankly agonal to inhibit  
cyclooxygenase, prostaglandin A2 and leukotriene production. More  
than 2 doses of Toradol should not be given due to the risk of GI  
bleeding. Gastric protection with misoprostol and an H2 blocker  
such as famotidine or IV cimetidine is recommended. The side  
effect profile of Toradol is essentially the same as discussed  
above for naproxen. 
 
	Pepcid (famotidine) 20-IM or IV for agonal GI bleed  
prophylaxis  May be used to decrease risk of GI distress and  
bleeding with parenteral Toradol administration. Famotidine is an  
H2 receptor blocker which decreases hydrochloric acid secretion  
by the gastric parietal cells. Onset of action is rapid (30  
minutes to 1 hours after p.o. administration) and duration of  
action is 10-12 hours. 
 
	Cytotek (misoprostol) 200 micrograms t.i.d. with meals.  
Misoprostol is a synthetic prostaglandin E1 analog that replaces  
endogenous gastric prostaglandins depleted by NSAID  
administration and the hypoperfusion of agonal shock. Misoprostol  
also appears to decrease basal hydrochloric acid secretion and  
increase gastric mucus and bicarbonate production. Unfortunately,  
misoprostol is not available in a parenteral form, but may be  
administered to the hemmoroidal plexus by suppository  
(suppositories of misoprostol may be made by crushing a tablet  
and mixing it into a regular suppository (such as an APAP  
suppository). 
 
Adverse Reactions: 
 
CNS: headache. 
GI: nausea, diarrhea, abdominal pain, flatulence, dyspepsia,  
vomiting and constipation. 
 
	Dilantin (phenytoin) 100-300 mg p.o. with the evening meal.  
Dilantin (use only Parke-Davis Dilantin, do not use generic  
phenytoin) is discussed here as a cerebroprotective premedication  
largely because it is cerebroprotective when given before global  
cerebral ischemia (but not when administered after the insult)  
and it is a medication that patients dying from malignancies  
(with brain metastasis or primary brain tumor), HIV or other  
disease which involves the CNS will frequently already be taking.  
It is not generally recommended that Dilantin be used a primary  
cerebroprotective drug except perhaps administered IV during the  
agonal period because of its unfavorable adverse reaction  
profile. Adverse reactions are common and in some patients fatal  
hepatocellular necrosis occurs as a consequence of the  
administration of the first few doses. 
 
 
	Deferoxamine HCl (Desferal) 2 g, dissolved in 100-200 cc of  
normal saline given IV or dissolved in 10 ml of sterile water  
given IM. Desferal can be given during agonal shock to scavenge  
free iron and reduce ischemia- induced free radical damage.  
(Note: Higher doses may be needed in patients with high serum  
ferritins or transferrin: iron overload). 
 
	The neurons of the CA1 area of the hippocampus have long  
been known to be selectively vulnerable to ischemic injury, both  
global and regional. These neurons are also known to have high  
endogenous iron levels and low SOD and glutathione peroxidase  
levels. A large number of studies have shown that these neurons  
selectively accumulate lipid peroxidation products associated  
with the iron-driven Fenton reaction. 
 
	Desferal is a selective chelator of free iron which has been  
shown in a wide range of experimental ischemia-reperfusion models  
to reduce iron-catalyzed biochemistry and to improve  
electrophysiology and neurological outcome. 
 
	Desferal chelates iron by forming a stable non-reactive  
compound and it is highly effective at chelating free (ferrous)  
iron but will not combine with iron in cytochromes, transferrin  
and hemoglobin. It is known that iron is delocalized from  
cytochromes, erythrocytes (hemoglobin) and perhaps other tissue  
iron stores during ischemia.   
 
	Deferoxamine mesylate (N-[5-{3-[(5-aminopentyl)- 
hydroxycarbamoyl]propionamido]-pentyl]-3-[[5-(N-hydroxy- 
acetamido)pentyl]carbamoyl] propionhydroxamic acid  
methansulfonate (salt) is an off-white powder which is freely  
soluble in water. It is used clinically to treat iron overload  
and acute iron intoxication. Desferal has a long plasma half life  
and its metabolism in the context of cryopreservation transport  
is not a concern. 
 
	Desferal is a sterile lyophilized powder which is  
reconstituted with water for injection prior to administration. 
 
 
	Methylprednisolone Sodium Succinate (Solu-Medrol), 1 g  IM  
or dissolved in a minimum of 100 cc of normal saline or other  
appropriate vehicle given by IV administration over a minimum of  
30 minutes. Methylprednisolone may be given during agonal shock  
to provide membrane stabilization, reduce cold agglutination, and  
protect against cold ischemic injury46.  
 
	Methylprednisolone is a potent synthetic anti-inflammatory  
steroid which acts to stabilize cell and intracellular  
(lysosomal) membranes during shock, ischemia, and hypothermia.  
Methylprednisolone reduces the margination of leukocytes and  
stabilizes leukocyte membranes. Administered before experimental  
shock or ischemia it greatly reduces sticking and degranulation  
of leukocytes in the lungs and heart. Metyhylprednisolone must be  
administered slowly, over a period of 3 to 5 minutes to avoid  
hypotension. Solu-Medrol is a white to off-white powder which is  
extremely soluble in water in sharp contrast to most other  
steroids. Its onset of action is rapid and its duration of action  
is 2-4 days after IM or IV administration. 
 
	Deprenyl (l-deprenyl) 10 mg p.o. b.i.d. with meals. Deprenyl  
is an antiparkinsonian agent which is a nonselective inhibitor of  
MAO at doses great than 5 mg/day. It is known to protect the CNS  
against toxic, free radical inducing compounds such as 6- 
hydroxydopamine and it up-regulates the levels of superoxide  
dismutase and catalase in the selectively vulnerable neurons of  
the hippocampus and striatum. It is also cerebroprotective in  
hypoxia and ischemia. 
 
	The degree of effectiveness of deprenyl in premedication for  
cryopatients is very uncertain. Few studies have been documenting  
its effectiveness in animal models of ischemia, however on  
theoretical grounds it is an attractive agent. Further, it is  
well tolerated by most patients and generally results in an  
improvement in energy level and well being when administered in  
the context of terminal illness with malnutrition and wasting. 
 
Adverse Reactions: 
 
CNS: dizziness, restlessness, behavioral changes, headache,  
fatigue. 
CV: orthostatic hypotension, hypertension, arrhythmias, increased  
anginal pain, peripheral edema, syncope (all uncommon). 
EENT: blepharospasm. 
GI: dry mouth, nausea, vomiting, constipation, diarrhea,  
heartburn, dysphagia. 
Skin: rash, hair loss. 
Other: malaise, diaphoresis. 
 
	Deprenyl is not recommended as a mainstay of premedication  
but rather is included here as a drug which may be used at the  
patient's and physician's discretion.  At the doses suggested  
here it may exert an antidepressant effect which may be of  
benefit to the patient who is depressed as a result of illness. 
 
Category 4 Drugs 
 
	Piracetam (Nootropil) 800 mg p.o. t.i.d. with meals.   
Piracetam is a nootropic drug used primarily to treat attention  
deficit disorder in children and adults. It is a stimulant with  
properties similar to those of caffeine. Piracetam is protective  
in hypoxia and cerebral ischemia48.  It is widely available  
through life extension buyers clubs and is available in Mexico  
inexpensively as tablets under the brand name Dinagen.   
 
	Adverse effects of piracetam are insomnia, restlessness,  
dyspepsia and skin rash.  adverse reactions are rare and the drug  
is well tolerated by both healthy and ill patients 
 
	Zileuton 400 mg p.o. with any meal of the day.  Zileuton is  
a novel lipoxygenase inhibitor which inhibits 5-lipoxygenase and  
prevents the release of arachadonic acid and the production of  
leukotrienes in vivo49. Zileuton also inhibits the production of  
PAF and inhibits CoA-IT, a major mediator of the early phases of  
the immune-inflammatory cascade. Zileuton is currently being  
introduced in Europe as an anti-inflammatory and antiasthmatic  
compound. It is not known when or if it will be available.  
Discussion of adverse reactions and other aspects of Zileuton's  
pharmacology is deferred. 
 
 
Category 5 Drugs 
 
	PBN (N-t-butyl-alpha-phenylnitrone) 10 mg/kg, p.o. with the  
largest meal of the day. PBN is a spin trapping free radical  
quencher which is available through buyers clubs and as a reagent  
chemical. There is no, repeat no pharmaceutical experience with  
this drug. Its pharmacology and potential adverse reactions .are  
completely unknown. 
 
	N-t-butyl-alpha-phenylnitrone (PBN) is a spin trapping agent  
that combines with a wide range of free radicals to form stable  
nitroxide radical adducts. In vitro PBN protects neurons against  
glutamate (NMDA) mediated toxicity. In vivo PBN has proven  
effective in reducing infarct size in global ischemia, middle  
cerebral artery occlusion, and a variety of local ischemic  
insults. The structure of PBN bears some resemblance to melatonin  
in that both agents posses an electron rich aromatic ring. (See  
discussion of melatonin below.) PBN and melatonin also have in  
common free radical buffering through the formation of a nitrogen  
centered radical intermediate and resonance stabilized mesomery. 
 
	PBN is white, granular powder with a faintly pleasant  
chemical odor. PBN is sparingly soluble in water. To be taken  
orally PBN is placed in 00 or 000 gelatin capsules using a  
CapMQuick or similar device. 
 
 
 
Category 6 Drugs 
 
	GHB (gamma hydroxy butyric acid, sodium salt) 100 mg/kg IV  
push to inhibit CNS excitotoxicity and reduce cerebral  
metabolism. 
 
	Gamma hydroxy butyric acid (GHB) is a neurotransmitter  
associated with sleep and the regulation of cerebral metabolism.  
It was introduced into anesthesiology in 1960 but was abandoned  
due to its prolonged action. GHB rapidly crosses the blood brain  
barrier and produces sedation and Plane II-III anesthesia without  
respiratory or cardiac depression. GHB acts by binding to sites  
which actively synthesize, accumulate and release GHB. GHB does  
not interact significantly with GABA receptors.   
 
	GHB causes a profound decrease in cerebral metabolism  
(roughly comparable to that seen with barbiturates) and is a  
moderately effective free radical scavenger. GHB is markedly  
protective in in-house models of murine blunt force head injury  
and has been demonstrated in in-house studies to inhibit  
increased spectral edge frequency and other EEG manifestations of  
excitotoxicity during reperfusion in dogs following 12 minutes of  
normothermic cardiac arrest. GHB, in conjunction with other  
cerebroprotective drugs, has allowed for recovery of dogs from 12  
minutes of normothermic circulatory arrest without adverse  
neurological sequelae. GHB has also been used clinically with  
good results as a sedative in head trauma and it increases  
neuronal protein synthesis following ischemia. Interestingly, GHB  
is known to cause absence seizure-like disorders in animals and  
man, and it may act as an excitatory neurotransmitter for some  
neurons (auditory hallucinations are reported in some users).  
Presumably any excitatory/toxic effect GHB may have in the  
context of this protocol is inhibited by kyneurinine (see above). 

	GHB was freely available in U.S. health-food stores 
until 1990, when the FDA restricted its sale, but not 
its possession (FDA has no power to do the latter).  
GHB is NOT a federal "controlled substance" (i.e., possession 
restricted) as of January 1997, but due to the sales 
restriction, is presently available for human use chiefly as 
an underground drug and as a street drug.  Some GHB has slipped into
the country in private pharmaceutical shipments from countries where 
GHB is a pharmaceutical, and still fully legal.  GHB may be used by 
some cryopatients for sedation and for immunomodulation (as a growth 
hormone releaser agent) in the treatment of malignant disease.  
For these reasons this semi-legal substance is included in 
this text. 

End of Part VII
End of Article 
 
BioPreservation, Inc. 
10743 Civic Center Drive 
Rancho Cucamonga, California 91730 
(909)987-3883 


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