X-Message-Number: 7464 Date: 09 Jan 97 02:28:35 EST From: "Steven B. Harris" <> Subject: Cryopreservation Premedication, prt 4 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 IV by Michael Darwin Formulating a Program Generalities Once a complete evaluation of the patient is done, including Pantox testing, it is time to meet with the patient and his family to determine if premedication is an option that they wish to pursue and whether it is one which is practically open to them. In other words do they have not just the will but also the financial and logistic ability. Can they afford the medication? Will their physician object? Are there family members or other key players who might create serious problems? And finally, does the patient really want to do this? This last consideration may seem a given but it is not. Dying people are remarkably refractory to taking medication. This is particularly true of oral medication. Lack of appetite and psychological withdrawal are normal elements of dying. As the patient deteriorates physically his threshold for any kind of inconvenience or discomfort will decrease dramatically. As energy for important daily activities disappears the patient will most often become extremely protective of how that energy is used. Even the simplest acts such as bathing, eating a meal or swallowing pills on a schedule can become an unacceptable burden. Add to this normal alteration in physiology and psychology the presence of GI dysfunction, nausea or malaise and you have the perfect recipe for noncompliance. Thus, it is important to go over in considerable detail with the patient what is involved in premedication. It is also important to negotiate with the patient in advance for how much pressure should be brought to bear on the patient by caretakers to maintain compliance. Patients considering premedication need to know that very few patients remain committed to this course of action till the end. They need to understand that those around them will allow them to stop premedication when it is no longer psychologically or physically possible for the patient to continue. And, just as importantly, the patient needs to know that benefits of premedication will likely extend well beyond the time it is stopped. This is particularly true of fat soluble drugs such as vitamin E, co-enzyme Q10 (CoQ10), PBN and melatonin. If appropriate (i.e., they are long term cryonicists using alternative parenteral medications), the use of parenteral premedications can be generally discussed. It is not recommended that Standby personnel or cryonics organizations provide or recommend unapproved parenteral medications, however, if this is something the patient is aware of and intends to pursue, information may be given about how to avoid complications and injury as a result of inappropriate use of injectable drugs. Similarly, determining dosages on parenteral products to achieve the desired serum and tissue levels is something that can be addressed on a case-by-case basis carefully, and without advocacy. Once the general kind of premedication program is determined, the next step is to determine the specific elements of the program. If the program is a multi-drug one which includes water soluble drugs with short half-lives then it is very important to keep dosing simple, uniform and an integral part of the normal daily routine. The best way to achieve this is by specifying that all medications be taken with meals or with two meals and at bedtime. This has two added advantages in that it is likely to decrease GI side effects of the medication (heartburn, nausea, diarrhea) and increase the length of time which the program can be followed. It is almost never acceptable to have the patient taking any medication more than three times a day or at times other than mealtime or bedtime. If the patient is inclined he should be encouraged to note side effects, problems or questions so they can be addressed and rectified (say sleepiness during the day or stomach discomfort with bedtime medicine). In any event, and this is very important, the patient's medication intake should be charted or, if that is not possible, a day-by-day pillbox set up so that medicines taken or not taken can be reliably determined by looking at the container at the end of the day, end of the week, etc. Pantox levels should be run, if financially possible, at least three times during the course of premedication: at two weeks after the start, at the estimated "mid-point" of the patient's terminal course, and during the agonal period. Specifics An Exposition of Putative Cerebroprotective Drugs and Their Pharmacology A discussion of the comprehensive pharmacology of each of the cerebroprotective premedications discussed below would consume a full volume. The approach used here will be to divide the medications by category type and give a brief account of the drug's pharmacology both as it relates to its traditional use and to its use as a putative premedication for ischemia-reperfusion injury. Category 1 Drugs 400 IU d-alpha tocopherol (vitamin E) p.o., t.i.d. Vitamin E is a naturally occurring lipid soluble free radical scavenger and antioxidant which has been shown to be cerebroprotective in a variety of experimental models of cerebral ischemia and in spinal cord injury and head trauma. The cerebroprotective effects of vitamin E are greatest when given as a premedication where it becomes incorporated into cell membrane lipids before the ischemic insult occurs. Vitamin E comes in a variety of dosage forms as an over the counter product. The packaging, chemical formula and source all affect its bioavailability and activity. Several chemical forms of vitamin E are marketed: natural mixed tocopherols, d-alpha tocopherol (synthetic) and esterified tocopherols. The esterified versions of the tocopherols (usually the succinate or the acetate) are resistant to auto-oxidation and may be safely stored at room temperature. This is by far the most common way vitamin E is sold in the United States whether it is packaged dissolved in oil in gelcaps, as a powder in capsules, or as an emulsion in chewable tablets or elixirs. In a healthy individual the vitamin E is de-esterified in the liver (and to a lesser extent in other tissues) and becomes fully biologically active only 7-10 days after ingestion. The likelihood of impaired hepatic metabolism and the need for immediate protection (terminal patients often die far earlier than expected) make the use of esterified vitamin E problematic. At this time it is recommended that nonesterified d-alpha tocopherol obtained fresh from a reliable supplier be used for vitamin E premedication. In addition to its antioxidant and neuroprotective effects, vitamin E is an essential nutrient which is involved in immunity, wound healing, and cardiovascular health. Vitamin E has antiplatelet activity and is a moderate antagonist of vitamin K1 and thus has coumadin-like effects in doses much about 40 IU. At doses of 400 IU and above the coumadin-like effects of vitamin E can cause potentially serious bleeding in a patient with gastrointestinal ulceration. High dose vitamin E can also interact with coumadin (Warfarin) and related anticoagulants to potentiate their effects, thereby increasing the risk of hemorrhage into joints or bleeding in the CNS. The antagonistic effect of vitamin E on vitamin K1 can be reversed by vitamin K1 supplementation using vitamin K1 obtained from health food stores. Ascorbic acid (Vitamin C) CAUTION: Do not administer to patients with iron overload! 1 g p.o., t.i.d. Ascorbic acid is a water soluble antioxidant which is distributed throughout the tissues of the body and is accumulated in the CNS. Approximately 80% of the total body ascorbate load is in the brain. Ascorbic acid reacts directly with hydroxyl and peroxyl radicals as well as superoxide radicals and singlet oxygen. Of significance to this protocol, ascorbic acid is important to the regeneration of oxidized d-alpha tocopherol to the reduced form. The use of ascorbic acid as a cerebroprotective agent is an empirical one. While ascorbic acid is important in regenerating vitamin E and glutathione (two critical ischemia protective antioxidants), it is also one of the most effective hydroxyl radical generators present in the brain in high concentrations. Ascorbic acid participates in hydroxyl radical generation by its central participation as a reductant in the Fenton reaction. The Fenton reaction is driven in the CSF and interstitial fluid of the brain by the massive release of ascorbate as a result of the exchange of intracellular ascorbate for extracellular glutamate as one of the first physiochemical events of ischemia. The other critical ingredient in the Fenton reaction is iron. Approximately 10% of the population has a defect in iron metabolism or a blood dyscrasia that results in hemochromatosis (iron overload). In a normal person the total body iron stores (including hemoglobin) amount to about 5 grams. In hemochromatosis, total body iron is in the range of 50 grams. To normalize such massive iron overload would require therapeutic phlebotomy of 1 unit of blood (450 cc) every 6 weeks for five years! Administration of ascorbic acid to patients with hemochromatosis can result in massive free radical injury resulting in serious morbidity or death. A primary target of injury is the CNS with seizures and cardiorespiratory arrest as the proximate cause of death. Serious injury to the lungs and the liver is also likely. Thus, it is critical to evaluate the patient's free iron levels and total iron binding capacity before supplementing with ascorbic acid. There is some empirical evidence that ascorbic acid provides neuronal protection in ischemia by improving regional blood flow and oxygen consumption in the injured spinal cord and by protecting cultured cortical neurons from NMDA-mediated toxicity in vitro. Ascorbic acid has been repeatedly shown to be cerebroprotective when given in advance of ischemia. Much like vitamin E, ascorbic acid is provided in a bewildering array of dosage forms, packaging and chemistries. Vitamin C has been esterified, made fat soluble by reacting it with palmitate, and delivered to the stomach and intestines as almost every salt imaginable in capsules, tablets, time-released granules, and flavored elixirs. The plain sodium salt or calcium salt (as the patient's medical condition dictates) delivered in simple gelatin capsules is the preferred form of ascorbic acid for premedication. In addition to driving the Fenton reaction, ascorbic acid (as either the acid or the salt) causes stomach upset in some people. Taking it with a meal almost always eliminates this side effect. In patients with diminished urine output, ascorbic acid can precipitate out of the urine and form stones or painful crystals. Dosage should be adjusted in patients with renal failure or in patients who are dehydrated. An occasional patient is intolerant to significant doses of ascorbic acid due to either GI side effects (including diarrhea) or due to back or flank pain. End of Part IV To be continued. BioPreservation, Inc. 10743 Civic Center Drive Rancho Cucamonga, California 91730 (909)987-3883 Rate This Message: http://www.cryonet.org/cgi-bin/rate.cgi?msg=7464