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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