Chemistry: analytical and immunological testing – Composition for standardization – calibration – simulation,... – Preparation composition
Reexamination Certificate
2000-05-16
2001-09-04
Krass, Frederick (Department: 1614)
Chemistry: analytical and immunological testing
Composition for standardization, calibration, simulation,...
Preparation composition
C436S062000, C436S063000, C600S562000
Reexamination Certificate
active
06284542
ABSTRACT:
The present invention relates to oxidative metabolism in smooth muscle cells and to methods and materials relating thereto.
In particular, the present invention relates to methods and materials relating, for example, to
(i) diagnosis of the existence or onset of chronic vasospasm/vasoconstriction
(ii) monitoring treatment of chronic vasospasm/vasoconstriction
(iii) identifying new drugs effective in the treatment of chronic vasospasm/vasoconstriction
(iv) the elucidation of agents (“spasminogens”) causing chronic vasospasm/vasoconstriction.
Vasospasm/vasoconstriction represents a significantly preventable cause of morbidity and death. Vascular smooth muscle (VSM) is able to maintain tension for extended periods at low energy cost (the phenomena is known as “latch”). This is essential for the autonomous and continuous regulation of blood flow to the organs etc. However in vasospasm/vasoconstriction, there is an abnormal contraction of the blood vessels to a vascular bed combined with the blood vessels having a diminished ability to relax. This restricts the blood flow and in consequence the oxygen supply. A variety of vascular beds including eg cardiac, mesenteric, placental, uterine and cerebral may be affected with consequent serious clinical implications such as organ damage, stroke, death or miscarriage (Rajani, R. M., B. V. Dalvi, S. A. D'Silva, Y. Y. Lokhandwali and P. A. Kale (1991)
Postgrad. Medical Journal
67 (783) 78-80 and Gewertz B. L. and C. K. Zarins (1991)
J. Vasc. Surg.
14 382-385.)
The term “vasospasm” is generally used in relation to contraction of the blood vessels particularly associated with the brain. In contrast, the term “vasoconstriction” is generally used in relation to constrictions of the blood vessels associated with organs other than the brain. Hereafter, where the term vasospasm is used it should not be interpreted solely as a reference to a vascular spasm associated with the brain unless the context otherwise demands such interpretation.
The invention of the present application is disclosed with reference to a number of clinical conditions linked with abnormal metabolism associated with vasospasm/vasoconstriction, namely: cerebral vasospasm in consequence of sub-arachnoid haemorrhage; pre-eclampsia and Alzheimer's disease. Conditions other than those specifically named will be known to those skilled in the art as being associated with chronic spasm/constriction of smooth muscle cells, such as chronic vasospasm/vasoconstriction.
Cerebral vasospasm occurs as a result of a sub-arachnoid haemorrhage. The haemorrhage strikes without warning, mostly in young adults and affects about 16 in every 100,000 people each year. The condition accounts for about 10% of all cerebrovascular disease.
The arachnoid layer lies between the pia meter (which wraps the brain and closely follows its contours) and the outermost dural layer. It comprises two arachnoid membranes separated by the sub-arachnoid space which is a cerebral spinal fluid (CSF) filled cavity containing blood vessels which supply oxygen to the brain. Thus, these blood vessels supplying the brain are bathed in CSF. A sub-arachnoid haemorrhage occurs when a blood vessel in the sub-arachnoid space ruptures. Typically the rupture results from an aneurysm. Blood leaks from the vessel into the sub-arachnoid space where it mixes with the CSF.
In 30% of sub-arachnoid haemorrhage patients, the rupture to the blood vessel results in death before the patient reaches the hospital. The remaining 70% survive the initial damage to the blood vessel and are admitted to hospital. In these admitted patients, the damaged vessel constricts to prevent excess blood loss and blood flow is reduced. This initial constriction in the acute phase of the condition is known as a vasoconstriction and is a part of the normal vessel repair response process. With the constriction, the repair of the rupture commences with the formation of a clot. In some patients (about 60% of those admitted) the vessel eventually re-dilates following occlusion of the rupture and blood flow returns to normal with consequent good clinical outcome and return to good health. Unfortunately, and despite considerable clinical efforts, other patients (the remaining 40% of those admitted) deteriorate. The deterioration may be the result of a vessel re-bleed or hydrocephalus (excess CSF in the cranial vault) and in such circumstances the patient can be treated by surgery and stands a relatively good chance of survival. Alternatively, the deterioration may be due to the delayed onset of prolonged and irreversible vasospasm (hereafter referred to chronic vasospasm). Unless the condition is diagnosed prior to its onset and effectively treated by drug therapy or surgery, it can lead to stroke, brain oedema or death.
In order to prevent the onset of chronic vasospasm in sub-arachnoid haemorrhage patients, one needs to be able to accurately diagnose those patients who are likely to undergo the condition. The presently available diagnostic methods do not allow one to predict the likely onset of chronic vasospasm in sub-arachnoid haemorrhage patients. It is only possible to diagnose the actual presence of chronic vasospasm and this is determined by performing an angiogram in order to determine the cause of the bleed and also to look for evidence of vascular constrictions.
Of the 70% of patients who survive the initial bleed and undergo an angiogram, 60% show evidence of vasospasm. Only 40% of these will actually develop neurological deterioration. However, some patients can develop a delayed neurological deterioration without evidence of angiographic vasospasm, but with reduced blood flow. Therefore, in this group of patients the data suggests that an angiogram is not an accurate method of diagnosing the onset of chronic vasospasm.
There is also a time window for performing successful surgery, as if surgery is performed between 3 and 14 days after sub-arachnoid haemorrhage, the risk of chronic vasospasm actually increases. The results from angiograms are not sufficiently predictive of the optimal time for undertaking surgery.
Thus there is a need for a method which allows one to predict as soon as possible those patients likely to go into chronic vasospasm, such that appropriate and/or required intervention can be initiated within the first three days following the cerebral haemorrhage.
In addition to the absence of suitable diagnostic methods, there is not at present an effective treatment for chronic cerebral vasospasm. To date, the condition is treated by angioplasty to the narrowed artery and by use of the Ca
2+
antagonist, Nimodipine (Nimotop*, Bayer). However, results have shown that although treatment with Nimodipine produces a small (20%), but significant improvement in clinical outcome for patients, it does not alter the vessel lumen size and therefore does not reverse the constrictive effects of the cerebral vasospasm (Pickard, J. D., G. D. Murray and R. Illingworth (1989)
Brit. Med. Journal
298 636-642).
Indeed it is possible that the use of calcium antagonists may be counterproductive. The prior art to date indicates that cerebral vasospasm is the result of metabolic failure of the VSM cells and that breakdown products of red blood cells within CSF can alter the energy metabolism of VSM as evidenced by decreases in phosphocreatine and ATP (Kim, P., J. Jones and T. M. Sundt (1992)
J. Neurosurg.
76 991-996) and an increase in ADP. ADP has been shown to inhibit VSM cross-bridges (Clark J. F., Z. Khuchua, A. V. Kuznetsov, A. E. Boehm and R. Ventura-Clapier (1994)
J. Musc. Res. Cell motil.
15 432-439 and Clark J. F., G. J. Kemp and G. K. Radda (1995)
J. Theor. Biol.
173 207-211) and therefore elevated ADP may lead to an inability of vascular smooth muscle (VSM) to relax. This suggestion fits with the observation that a Ca
2+
antagonist such as (Nimodipine) cannot change the contractile state, as ADP maintained tension is independent of Ca
2+
(Clark et al., (1994) supra). Therefore the use of anything which results in an e
Cadoux-Hudson Thomas A. D.
Clark Joseph F.
Krass Frederick
Medical Research Council
Nixon & Vanderhye P.C.
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