Chemistry: molecular biology and microbiology – Differentiated tissue or organ other than blood – per se – or...
Reexamination Certificate
2000-08-25
2003-02-25
Low, Christopher S. F. (Department: 1653)
Chemistry: molecular biology and microbiology
Differentiated tissue or organ other than blood, per se, or...
C435S001200, C514S046000, C514S047000, C562S560000, C562S563000, C536S026100
Reexamination Certificate
active
06524785
ABSTRACT:
The invention has as its object a solution for perfusion and/or preservation and/or re-perfusion during organ transplant, especially of the heart.
The preservation period of human hearts is at present 4 hours and a certain number of rejections are still due to deterioration in the condition of the transplanted organ between the time of removal and the moment of implantation in the recipient.
Short-term myocardiac preservation (4 hours) is currently provided by cold storage after cardioplegic arrest. A variety of processes exist however differing by the composition of the solution used, the preservation temperature and the administration protocol. Different solutions for arresting and preserving the heart have been developed to protect the myocardium in cardiac surgery.
The St Thomas solution [Ledingham, S. J. M., Braimbridge, M. V., Hearse, D. J. The St Thomas' Hospital cardioplegic solution: a comparison of the efficacy of two formulations. J. Thorac. Cardiovasc. Surg. (1987)
93: 240-246] has in particular been much used.
Solutions similar to the St Thomas solution have been developed like the Broussais solution [Fabiani, J. N., Ponzio, O., Jebara, V. Myocardiac protection; encycl. Méd. Chir. (Paris, France), Techniques chirurgicales, Thorax, 42511, 10-1989].
More recently experiments have been carried out with the University of Wisconsin (UW) solution [Ledingham, S. J . M., Katayama, O., Lachno, D. R., Yacoub, M. H. Prolonged cardiac preservation. Evaluation of the University of Wisconsin preservation solution by comparison with the St Thomas' solution in the rat.
Circulation
(1990) 82 (Part 2): IV351-8] currently used for other organs (liver, kidney). The use of the UW solution has allowed impressive progress in the preservation of the transplanted organ in renal and hepatic transplantation by significantly increasing the duration of cold ischemia before transplantation.
Certain teams have already reported favourable results by applying the UW solution to the preservation of the cardiac transplant. This solution comprises different protective elements; glutathion and allopurinol, inhibitors of the formation of free radicals from oxygen, water resistant agents (lactobionate and raffinose) and adenosine, a precursor of ATP.
Different solutions directly derived from the UW solution have been developed, yet others take only certain elements of the UW solution (Celsior solution) [Ménasché, P., Termignon, J L., Pradier, F., Grousset, C., Mouas, C. Experimental evaluation of Celsior, a new heart preservation solution.
Eur J. Cardio. Thorac. Surg
. (1994) 8: 207-213].
It has been shown that the University of Wisconsin solution (UW) made it possible to increase the duration of myocardium preservation. This solution comprises different protective elements, glutathion and allopurinol, inhibitors of the formation of free radicals from oxygen, water resistant agents, (lactobionate, raffinose), a precursor of ATP (adenosine). However, this solution has not been specifically developed for the heart and presents various features which are not optimal if not harmful for the heart: 1) the UW solution is characterised for example by a strong concentration in K
+
(125 mM) damaging to the cells as it leads to contracture, 2) inorganic phosphate (Pi) is equally present in a strong concentration or it is an inhibitor of numerous ATPases (Na
+
/K
+
ATPase, Ca
2+
ATPases) and can thus increase the accumulation in poisonous Na
+
and Ca
2+
in the course of ischemia, 3) it does not comprise any Ca
2+
and because of this induces a massive influx of Ca
2+
during re-perfusion, 4) adenosine has numerous effects on the heart and its concentration is not optimised in the solution, 5) the UW solution does not include a certain number of elements whose protective action has been able to be shown in the heart.
Several years ago a cardioplegic solution (solution B20) was developed for short periods of ischemia (2 to 3 hours) [Monique Bernard et al. J Thorac. Cadiovasc Surg 90: 235-242, 1985].
If the needs expressed by the surgeons are considered, only the option of an extension of the duration of preservation to 12 hours or 6 months or more presents any importance. A passage of 4 to 12 hours of preservation in effect corresponds much more to a marginal increase in the duration of ischemia. It presents several advantages; (1) an extension of the geographical area in which the collection of the transplanted organs takes place and thus an increase in the chances of transplantation for a given patient by offering him the possibility to use a removed transplant, from geographically further away, (2) to be able to envisage transplanting by HLA compatibility freeing the necessary time to carry out the best possible donor-recipient matching (such transplants have already shown much better results in terms of survival of the transplant in renal transplantation, than the simple ABO matching currently used for heart transplants), (3) finally, the passage of 4 to 12 hours would leave at least 1 hour for the global non invasive evaluation of the metabolic state of the transplant by magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI) without breach of the chain of sterility inasmuch as the study can be carried out in the preservation bag. Moreover, to date, no known solution allows preservation of the heart for a period longer than 4 hours, and all the more so during a period of 12 hours.
One of the aims of the invention is to suggest a solution of improved quality, used to arrest the heart then preserve it for a duration longer than 4 hours, with a view to transplantation.
One of the other aspects of the invention is to suggest a solution for arrest and preservation of the organ, especially the heart, making it possible to maintain cellular and metabolic integrity of the organs after ischemia.
Another aspect of the invention is to suggest a solution for organ preservation, especially the heart, allowing post-ischemic functional recovery.
The invention concerns a solution for perfusion and/or preservation and/or re-perfusion during organ transplant, especially the heart, characterised in that it contains the following elements:
K
+
at a rate of about 4 to about 7 mM,
especially about 4 mM
Ca
2+
at a rate of about 0.2 to about 0.3 mM,
especially about 0.25 mM
Mg
2+
at a rate of about 13 to about 16 mM,
especially about 13 mM
glutamate
at a rate of 18 to about 22 mM,
especially about 20 mM
arginine
at a rate of about 2 to about 4 mM,
especially about 3 mM
adenosine
at a rate of about 0.5 to about 1 mM,
especially about 0.5 mM
The solution developed within the framework of the present invention for the arrest and the preservation of hearts for long term ischemia is such that it induces cardiac arrest with a strong concentration of magnesium rather than potassium. It comprises moreover glutamate (metabolic substrate of ATP in anaerobic) and is characterised by a non zero concentration in Ca
2+
and a concentration in extracellular type Na
+
. Different protective agents, (lactobionate, raffinose, glutathion -reduced form-, allopurinol and adenosine) have been added to this solution. As far as certain components (adenosine, butanedione-2,3-monoxime) are concerned, research on the optimal concentration has been carried out. Recent work has underlined the importance of endothelial dysfunction in the damage linked to the ischemia-re-perfusion sequence. Because of this fact, L-arginine was included, precursor of NO, in the preservation solution.
By solution for re-perfusion during organ transplantation, is designated a solution useable during the transplant of an organ, to make the transplanted organ go from an ischemic state to the cardioplegic state.
According to an advantageous method of implementation, the solution of the invention does not contain butanedione 2.3-monoxime.
According to an advantageous method of implementation, the invention solution contains at least one
Bernard Monique
Cozzone Patrick
Centre National de la Recherche Scientifique
Gupta Anish
Low Christopher S. F.
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