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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