Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
2001-10-05
2002-08-06
Reamer, James H. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
Reexamination Certificate
active
06429230
ABSTRACT:
The present invention relates to an improved therapeutic method for the treatment of chronic uremic patients undergoing periodical dialysis.
BACKGROUND OF THE INVENTION
It is well known that patients affected by chronic uraemia, undergoing periodic dialysis, frequently develop a clinical picture characterized by marked muscular asthenia and a sensation of torpor, particularly evident immediately following dialysis and which may often last even for several hours making difficult, if not impossible, to resume working activity until these conditions subside. Clinical experts recognize this problem as “post-dialytic syndrome”.
These conditions have been sometimes attributed to the loss of carnitine during dialysis.
A method for treating the post-dialytic syndrome by compensating for the loss of carnitine occurring during the dialysis session is disclosed in U.S. Pat. No. 4,272,549. This patent describes a method for alleviating asthenia and muscle weakness in a chronic uremic patient under regular dialysis treatment by administering to the patient a polysaline dialytic solution which contains a quantity of carnitine (this refers to L-carnitine throughout the present specification), or a pharmaceutically acceptable salt of it, sufficient to adjust the molar concentration of carnitine in the dialysis solution at least equal to the molar concentration of carnitine in the patient's plasma. Preferably, the concentration of carnitine in the dialytic solution is substantially equimolar to the concentration of carnitine in the patient's plasma, but a certain excess of carnitine is also provided, for example between 50 and 100 &mgr;mole per liter of solution. A specific illustration includes administration of from 3 to 6 grams of carnitine or an equivalent amount of a pharmaceutically acceptable salt thereof. The carnitine may be administered orally, preferably on days between haemodialysis in amounts ranging from 3 to 6 grams of carnitine per day.
This oral treatment is coupled with a rather complex treatment regimen with carnitine during the dialytic session, in which carnitine is administered by slow infusion. On the days of dialysis, carnitine may also be administered partly by the oral route and partly by slow infusion. In this case, the overall quantity of carnitine administered shall not exceed approximately 10 g per day. “Slow infusion” means an infusion in which the solution containing carnitine, or any of its pharmaceutically acceptable salts, is administered at the rate of 20 to 40 drops per minute. Particularly favourable therapeutic results are said to be achieved by orally administering carnitine to the patient receiving dialysis treatment only on those days during which the patient does not receive dialysis, while during the actual dialytic session, a dialyzing liquid containing carnitine is used.
A preferred regimen for treating chronic uremic patients undergoing haemodialysis, includes the following steps:
1) on the days between one haemodialytic session and the next, oral administration to these patients of 3 to 6 g per day of carnitine or any of its pharmaceutically acceptable salts;
2) on the days of haemodialytic session, dialyzing these patients using, as dialyzing liquid, a solution containing a quantity of carnitine or of any of its pharmaceutically acceptable salts, sufficient to adjust the molar concentration of carnitine in the dialysis solution at least equal to the molar concentration of the plasma carnitine of the patient receiving dialytic treatment.
Using this procedure, it is possible to avoid the loss of plasma carnitine which otherwise takes place during a haemodialytic session; that is, the concentration of plasma carnitine remains practically unchanged during the dialytic session. In this manner, it is possible to avoid tissue carnitine depletion, which is the long-term consequence of repeated losses of carnitine the patient undergoes during successive dialytic sessions over a prolonged period of time, for example a month or longer.
Although the desired objective is achieved using a hemodialysis solution equimolar in carnitine with respect to the patient's blood, it is preferred to operate with a slightly more concentrated solution. In practice, the haemodialysis solution contains 50 to 100, preferably 60-80 &mgr;moles/liter of carnitine or of any of its pharmaceutically acceptable salts. On the days of haemodialysis, carnitine may also be administered partly by the oral route and partly by slow infusion. In this case, the overall quantity of carnitine administered shall not exceed approximately 10 g per day.
The procedures in U.S. Pat. No. 4,272,549 are effective in treating “post-dialysis syndrome”, but present a cumbersome schedule of treatment. This fact leads to problems. Patient compliance, whose quality of life is already heavily affected, is a concern as patients are apt to overlook the oral self-administration of a prescribed dosage of carnitine between the dialytic sessions. There is also the problem of carnitine bioavailability through the oral route, which is subject to saturation mechanism and to some restrictions as to the absorption sites (Harper at al. Eur. J. Clin. Pharmacol. 1988; 35(5):555-62 and Matsuda et al. Biol. Pharm. Bull July, 1998, 21 (7):752-5). Also, oral administration of carnitine to a chronic uremic patient may give rise to the accumulation of toxic metabolites.
A recent article by Sloan et al. (Am. J. Kidney Dis. August, 1998, 32(2):265-72) demonstrated that oral supplementation of carnitine is effective in improving the quality of life of patients in the early stage of treatment, but the perceived effect was not sustained through long term treatment (six months).
Other than the fact that carnitine deficiency may be connected with post-dialytic syndrome, this deficiency is a disturbance of the homeostasis of such an important inborn substance, that the medical community recognizes the necessity to treat carnitine deficiency per se.
SUMMARY OF THE INVENTION
Disclosed is a method for treating chronic uremic patients undergoing periodical dialysis. This method prevents and treats carnitine deficiency in patients with end stage renal disease who are undergoing dialysis. The method comprises administering to the dialysis patient an effective dose of carnitine intravenously into the venous return line at the conclusion of each dialysis session. Dialysis session as used herein means both haemodialysis and peritoneal dialysis.
The method of the present invention provides a surprising improvement over the procedures described in U.S. Pat. No. 4,272,549 and eliminates the need for oral treatment, without affecting the maintenance or correction of carnitine deficiency obtained by the administration of carnitine through intravenous route.
Ahmad S. et al (Kidney International, Vol. 36, Suppl. 27 (1989), S-243-S-246) report a study on the administration of L-carnitine in hemodialysis patients investigating the effect on fatty acid abnormalities in the patients' serum. Carnitine was given intravenously for the first six months at the dosage of 20 mg/kg and subsequently was reduced to 10 mg/kg. The administration was performed via the blood line after each dialysis session during the rinse back cycle. Patients treated with carnitine had a partial correction of the abnormal fatty acid profile noted in untreated dialysis patients. The authors found difficult to explain the persistence of some abnormalities in lipid profiles and made no effort to correlate plasma levels with possible clinical manifestations of fatty acid deficiency. This study is not related to the general picture of carnitine deficiency.
In two subsequent articles, Ahmad, Golper et al. (Kidney International, Vol. 38 (1990), 904-911 and 912-918) report a multicenter trial of carnitine in maintenance hemodialysis patients. The administration of carnitine was performed as described in the 1989 article, but, as a clinically significant study, the carnitine dose was kept constant at 20 mg/kg. In the first paper, the authors still investigate on the effect
Nixon & Vanderhye
Reamer James H.
Sigma-Tau Industrie Farmaceutiche Riunite S.p.A.
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