X-Message-Number: 7478
Date: 10 Jan 97 17:03:19 EST
From: "Steven B. Harris" <>
Subject: Cryopreservation Premedication, prt 6

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 VI 
by Michael Darwin 


	ALCAR (Acetyl-l-Carnitine) 500 mg t.i.d. with meals. 
	Several mitochondrial enzyme systems such as adenine  
nucleotide translocase and those involved in oxidative  
phosphorylation are damaged in ischemia. As a consequence, there  
is a marked accumulation of free fatty acids, long-chain acyl  
CoA, and long-chain acyl carnitines. 
 
	Many of the metabolic derangements known to occur in cerebral  
ischemia are apparently a result of the accumulation of acyl CoA  
which is known to damage many different enzyme systems. Acyl  
carnitine analogs such as acetyl-l-carnitine can penetrate the  
blood brain barrier, the cell membrane and the mitochondrial  
membrane. They are readily metabolized and appear to normalize  
mitochondrial metabolism by removing long chain acyl groups from  
a variety of mitochondrial CoAs. ALCAR has been shown to greatly  
reduce neurological injury in a canine model following 10 minutes  
of normothermic global cerebral ischemia. 
 
	ALCAR improves cognitive function in organic brain syndrome  
secondary to Alzheimers, atherosclerosis-related cerebrovascular  
insufficiency, and advanced age (i.e., nonspecific dementia).  
ALCAR's absorption will be decreased if taken at meals. ALCAR is  
not a medication which is central to cerebroprotective  
premedication. 
 
	Twinlab Daily One Multivitamin capsule p.o. with the evening  
meal. The ingredients of the Daily One multi-vitamin are  
reproduced below. Daily One is a good micronutrient supplement  
which will improve the patient's energy level and sense of well  
being in wasting disease. Micronutrient deficiency occurs early  
in terminal illness and is usually acute during the agonal  
period. Micronutrient deficiency can be expected to exacerbate  
ischemic injury. 
 
Twinlab Daily-One Multi-vitamin ingredients: 
 
Each hard gelatin capsule supplies: 
 
Beta-Carotene (pro-vitamin A)	10,000 I.U. 
Vitamin D 	400 I.U. 
Vitamin C	150 mg 
Natural vitamin E (succinate)	100 I.U. 
Vitamin B-1 (thiamine)	25 mg 
Vitamin B-2 (riboflavin)	25 mg 
Vitamin B-6 (pyroxidine)	25 mg 
Vitamin B-12 (cobalamin conc.)	100 mcg 
Niacinamide	100 mg 
Pantothenic acid 	50 mg 
Biotin	300 mcg 
Folic acid	400 mcg 
PABA (para-aminobenzoic acid)	25 mg 
Choline bitartate 	25 mg 
Inositol	25 mg 
Calcium (from calcium citrate and calcium carbonate)	25 mg 
Magnesium (from magnesium aspartate and magnesium oxide)	7.2  
mg 
Potassium (from potassium aspartate and potassium citrate)	5 mg 
Zinc (from zinc picolinate)	15 mg 
Copper (from copper gluconate)	2 mg 
Manganese (from manganese gluconate)	5 mg 
Iodine (from potassium iodide)	150 mcg 
Selenium (from selenomethionine and  
     selenate - 50/50 mixture)	200 mcg 
Chromium (GTP)	200 mcg 
Molybdenum (natural molybdate)	150 mcg 
 
 
 
Category 2 Drugs 
 
	Naproxen sodium (Naprosyn, Aleve, Anaprox) 125 mg b.i.d.  
with morning and evening meals. Aleve is an OTC nonsteroidal  
anti-inflammatory drug which is an inhibitor of cyclooxygenase,  
arachadonic acid, and leukotrienes. The mechanism of action of  
naproxen is not fully understood, however much of its anti- 
inflammatory activity is undoubtedly a result of its activity as  
a cyclooxygenase inhibitor. Related nonsteroidal anti- 
inflammatory drugs (NSAIDs) such as ibuprofen are  
cerebroprotective in normothermic global ischemia and head  
injury. Aleve was selected for use in cryopatient premedication  
because of its long serum half-life (13 hours), its rapid and  
complete absorption from the GI tract, and its relatively  
favorable (for NSAIDs) GI side-effect profile. 
 
	Despite the fact that naproxen is available as an OTC drug,  
it must be understood that it has the potential for serious and  
even life-threatening adverse effects. Like all other NSAIDs,  
naproxen has hematologic effects including prolonged bleeding and  
increased risk of GI or other bleeding in terminal illness. Other  
side effects of the drug as well as drug interactions are  
reviewed by system (the side effects that are most commonly  
encountered are italicized). 
 
CNS: headache, drowsiness, dizziness, tinnitus, cognitive  
dysfunction, and aseptic meningitis. 
CV (Cardiovascular): peripheral edema, palpitations and digital  
vasculitis. 
EENT: visual disturbances, tinnitus. 
GI: epigastric distress, occult blood loss, nausea, peptic  
ulceration. 
GU: Increased BUN and creatinine, nephrotoxicity 
Hematologic: prolonged bleeding time, agranulocytosis,  
neutropenia. 
Hepatic: elevated liver enzymes, jaundice 
Respiratory: dyspnea. 
Skin: pruritis, rash, urticaria. 
Metabolic: hyperkalemia. 
 
Drug Interactions: 
 
	Naproxen decreases the effectiveness of diuretics and  
antihypertensives and increases risk of GI bleeding with aspirin,  
alcohol and corticosteroids. It also increases methotrexate  
toxicity (a common anticancer drug) and increases toxicity of  
oral anticoagulants, sulfonylureas, Dilantin, and other drugs  
that are protein bound. 
 
	Patients should take naproxen only with meals and should be  
advised that naproxen (as is the case with other NSAIDs) can mask  
signs of infection and gastric perforation. Patients should be  
carefully instructed on how to determine if they are experiencing  
silent GI bleeding by cautioning them to examine bowel movements  
for a tarry black appearance and emesis for coffee grounds  
appearance or the presence of frank blood. 
 
	Naproxen should be used with great caution in patients with  
renal or liver impairment as naproxen, like all NSAIDs, decreases  
renal blood flow by inhibiting the formation of renal  
prostaglandins.   
 
	Patients in the final weeks of their illness should have  
gastric protection in the form of concomitant misoprostol and  
sucraflate administration as necessary. If continuous  
administration of naproxen becomes problematic, and it is not  
otherwise contraindicated, IM or IV ketorlac tromethamine  
(Toradol) may be given at the start of the agonal phase (see  
below) and most of the cerebroprotective benefit of NSAIDs  
administration will result.  
 
	Aspirin (acetylsalycilic acid) 30 mg p.o. or by suppository  
every day or every other day (as tolerated) with the evening  
meal. Aspirin is an anti-inflammatory prostaglandin synthesis  
inhibitor and an antiplatelet agent as well as being a centrally  
acting (hypothalamic) antipyretic. It has diverse pharmacologic  
actions more of which are uncovered. The mechanism of action as a  
cerebroprotective in premedication of cryopatients is its  
antiplatelet activity. The doses of aspirin used for this purpose  
are sufficiently low that GI and other side effects and drug  
interactions (including its interaction with naproxen; it  
decreases Naproxen's effectiveness) will be minimal. Indeed, it  
is important not to give aspirin in doses greater than 80 mg/day  
in order to avoid side effects. The sole purpose of aspirin is to  
acetylate platelets. 
 
 
  
 
 
Figure 7:1 
 
 
	Possible adverse reactions at this dose are prolonged  
bleeding, GI distress, peptic ulceration, skin rash and bruising. 
 
	A variety of enteric coated low-dose aspirin products are  
available OTC. 
 
	Pepcid (famotidine) 20-40 mg p.o. b.i.d. or p.r.n. for  
stomach upset or epigastric discomfort or NSAID or agonal GI  
bleed prophylaxis  May be used to decrease risk of GI distress  
and bleeding with NSAID 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, greatly simplifying dosing.   
 
	Famotidine has no significant drug interactions.   
 
Adverse reactions: 
 
CNS: headache, dizziness, hallucinations. 
GI: diarrhea, constipation, nausea, flatulence. 
GU: elevated BUN and creatinine. 
Hematologic: thromobocytopenia (very rare). 
Skin: acne pruritis, rash. 
 
	Famotidine may be given IV as a Category 4 drug during the  
agonal period to minimize the risk of GI bleed during shock and  
reperfusion following cardiac arrest. 

End of Part VI 
To be continued. 
 
BioPreservation, Inc. 
10743 Civic Center Drive 
Rancho Cucamonga, California 91730 
(909)987-3883 


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