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Methods and preparations for curing clinically ill patients

Methods and preparations for curing clinically ill patients description/claims

This application is a continuation of U.S. application Ser. No. 09/853,193 filed May 11, 2001 (allowed May 22, 2008) which is a continuation of International Application No. PCT/DK01/00287 filed Apr. 30, 2001 and claims priority under 35 U.S.C. 119 of Danish Application No. PA 2001 00604 filed Apr. 15, 2001; Pa 2001 00605 filed Apr. 16, 2001 and British Application No. 0010856.3 filed May 5, 2000, the contents of which are fully incorporated herein by reference.

The present invention relates to a novel the use of blood glucose regulators, and a novel method of treating a clinically ill patient. Furthermore, the present invention relates to advertising media and material and information media and material like giving information about the novel utilities, indications and actions of these medicaments and to a method of selling these medicaments by giving information about their novel utilities, indications and actions.

A specific type of polyneuropathy develops in patients that are treated within an intensive care unit (hereinafter also designated ICU) for several days to weeks and this for a variety of primary injuries or illnesses. This polyneuropathy, known as “Critical Illness Polyneuropathy” (hereinafter also designated CIPNP) occurs in about 70% of patients who have the systemic inflammatory response syndrome (SIRS) (Zochodne D W et al. 1987 Polyneuropathy associated with critical illness: a complication of sepsis and multiple organ failure. Brain, 110: 819-842); (Leijten F S S & De Weerdt A W 1994 Critical illness polyneuropathy: a review of the literature, definition and pathophysiology. Clinical Neurology and Neurosurgery, 96: 10-19). However, clinical signs are often absent and it remains an occult problem in many ICUs worldwide. Nonetheless, it is an important clinical entity as it (is) a frequent cause of difficulty to wean patients from the ventilator and it leads to problems with rehabilitation after the acute illness has been treated and cured.

When CIPNP is severe enough, it causes limb weakness and reduced tendon reflexes. Sensory impairment follows but is difficult to test in ICU patients. Electrophysiological examination (EMG) is necessary to establish the diagnosis (Bolton C F. 1999 Acute Weakness. In: Oxford Textbook of Critical Care; Eds. Webb A R, Shapiro M J, Singer M, Suter P M; Oxford Medical Publications, Oxford UK; pp. 490-495). This examination will reveal a primary axonal degeneration of first motor and then sensory fibers. Phrenic nerves are often involved. Acute and chronic denervation has been confirmed in muscle biopsies of this condition. If the underlying condition (sepsis or SIRS) can be successfully treated, recovery from and/or prevention of the CIPNP can be expected. This will occur in a matter of weeks in mild cases and in months in more severe cases. In other words, the presence of CIPNP can delay the weaning and rehabilitation for weeks or months.

The pathophysiology of this type of neuropathy remains unknown (Bolton C F 1996 Sepsis and the systemic inflammatory response syndrome: neuromuscular manifestations. Crit Care Med. 24: 1408-1416). It has been speculated to be directly related to sepsis and its mediators. Indeed, cytokines released in sepsis have histamine-like properties which may increase microvascular permeability. The resulting endoneural edema could induce hypoxia, resulting in severe energy deficits and hereby primary axonal degeneration. Alternatively, it has been suggested that cytokines may have a direct cytotoxic effect on the neurons. Contributing factors to disturbed microcirculation are the use of neuromuscular blocking agents and steroids. Moreover, a role for aminoglucosides in inducing toxicity and CIPNP has been suggested. However, there is still no statistical proof for any of these mechanisms in being a true causal factor in the pathogenesis of CIPNP.

Although polyneuropathy of critical illness was first described in 1985 by three different investigators, one Canadian, one American, and one French, to date there is no effective treatment to prevent or stop Critical Illness Polyneuropathy.

To date the current standard of practice of care, especially of critically ill patients, was that within the settings of good clinical ICU practice, blood glucose levels are allowed to increase as high as to 250 mg/dL or there above. The reason for this permissive attitude is the thought that high levels of blood glucose are part of the adaptive stress responses, and thus do not require treatment unless extremely elevated (Mizock B A. Am J Med 1995; 98: 75-84). Also, relative hypoglycaemia during stress is thought to be potentially deleterious for the immune system and for healing (Mizock B A. Am J Med 1995; 98: 75-84).

This invention was based in part on the discovery that critical illness in a patient and/or CIPNP can be prevented, treated or cured, at least to a certain extent, by strictly controlling glucose metabolism during said critical illness by applying intensive treatment with a blood glucose regulator, for example, insulin treatment, with clamping of blood glucose levels within a range where the lower limit can be selected to be about 60, about 70 or about 80 mg/dL and the upper limit can be selected to be about 110, about 120 or about 130 mg/dL, more specifically to the normal range (i.e., from about 80 to about 110 mg/dL). The skilled art worker, for example, the physician, will be able to decide exactly which upper and lower limits to use. Alternatively, the range is from about 60 to about 130, preferably, from about 70 to about 120, more preferred, from about 80 to about 110 mg/dL.

This invention demonstrates that clamping of blood glucose levels within the above range, for example, within normal limits (about 80 to about 110 mg/dL) in a critically ill patient or in a chronic ill patient can be used to significantly reduce the incidence of critical illness in a patient and/or CIPNP and to lengthen the time free of critical illness in a patient and/or CIPNP in a patient that do develop this problem.

In the illustrative embodiments of present invention, blood glucose levels were controlled by insulin treatment. However after this invention, it will be clear for the man skilled in the art that also active insulin derivatives and its physiologically tolerated salts and other blood glucose regulators can be used to obtain the same outcome.

Furthermore, it will be clear for the man skilled in the art, that compounds of the group of biologically active substances having insulin releasing action can be used to treat critical illness in a patient and/or Critical Illness Polyneuropathy or to manufacture a medicine to treat critical illness in a patient and/or Critical Illness Polyneuropathy. Such compound with an activity of promoting the secretion of insulin were already well disclosed before the moment of this invention such as the Islets-Activating Proteins (Ui; Michio et al. U.S. Pat. No. 5,000,953, 19 Mar. 1991) and the glucagon-like peptides (Habener; Joel F. Newton Highlands, Mass. U.S. Pat. No. 5,614,492, 25 Mar. 1997).

Furthermore, it will be clear for the man skilled in the art, that compounds of the group of compounds that stimulate signal transduction mediated by an insulin receptor type tyrosine kinase in a cell can be used to treat or to manufacture a medicine to treat critical illness in a patient and/or Critical Illness Polyneuropathy. It was well known before the date of this invention that insulin binding to the insulin receptor triggers a variety of metabolic and growth promoting effects. Metabolic effects include glucose transport, biosynthesis of glycogen and fats, inhibition of triglyceride breakdown, and growth promoting effects include DNA synthesis, cell division and differentiation. It is known that some of these biological effects of insulin can be mimicked by vanadium salts such as vanadates and pervanadates. However, this class of compounds appears to inhibit phosphotyrosine phosphatases generally, and are potentially toxic because they contain heavy metal (U.S. Pat. No. 5,155,031; Fantus et al., 1989, Biochem., 28:8864-71; Swarup et al., 1982, Biochem. Biophys. Res. Commun. 107:1104-9). Moreover, it had been already demonstrated (LAMMERS REINER et al. 19 Jan. 1999, U.S. Pat. No. 5,861,266 & WO 9523217) that certain protein-tyrosine phosphatases (PTP's), in particular, RPTP.alpha. and RPTP.epsilon., specifically regulate the insulin receptor signalling pathway. Compounds that specifically modulate the activity of the controlling RPTP, thereby prolonging or enhancing signal transduction mediated by the insulin receptor can thus be used to treat critical illness in a patient and/or Critical Illness Polyneuropathy or to manufacture a medicine to treat critical illness in a patient and/or Critical Illness Polyneuropathy. Such compounds have low toxicity since they are specific for the PTPs associated with insulin receptor activity, and do not significantly affect the activity of other PTPs that are non-specific.

One object of the present invention is to increase the survival rate of a critically ill patient and/or a CIPNP patient.

Another object of the present invention is to find a life saving drug for a critically ill patient and/or a CIPNP patient.

A further object of the present invention is to find a life saving treatment of critically ill patients and/or a CIPNP patient.

A still further object of the present invention is to reduce the time a critically ill patient and/or a CIPNP patient, stays within an ICU.

Another object of the present invention is to shorten the time a critically ill patient and/or a CIPNP patient, stays at the hospital.

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