Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Patients with a motor deficit due to ischaemic stroke usually develop muscular spasticity, but in some cases they may remain with a prolonged muscular flaccidity which impairs their recovery. Little is known about the causes of these two different functional outcomes. We correlated CT/MRI and 99mTc HM-PAO SPECT with clinical findings in 42 patients at a mean time interval of 3 months after stroke. The patients were divided into two cohorts with either flaccid (prolonged muscular flaccidity) or spastic (muscular spasticity) hemiparesis. Although patients with prolonged muscular flaccidity had a greater motor deficit, the mean structural volume of the ischaemic lesion was similar to that of the muscular spasticity cohort. There was a significantly higher prevalence of structural involvement of the lentiform nucleus in prolonged muscular flaccidity cases. Relative perfusion in the lentiform nucleus, thalamus and contralateral cerebellar hemisphere was significantly lower in prolonged muscular flaccidity than in muscular spasticity patients. A subgroup with only subcortical structural lesions also showed significantly lower relative perfusion in the ipsilateral frontal association areas. A primary involvement of the lentiform nucleus by the structural lesion seems to be crucial for the persistence of flaccidity after stroke. However, cerebral blood flow (CBF) changes in other structurally intact regions indicate their additional role. It is likely that both subcortical-cortical loops involved in motor control, i.e. cortex-basal ganglia-thalamus-cortex and cortex-pons-cerebellum-thalamus-cortex, are more widely and more severely affected in patients with prolonged muscular flaccidity.
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PMID:Prolonged muscular flaccidity after stroke. Morphological and functional brain alterations. 749 90

To evaluate the cerebral pharmacokinetics of 99mTc-ethyl cysteinate dimer (99mTc-ECD) at blood flow levels beyond the normal range, we investigated "luxury perfusion" in subacute stroke, ictal hyperperfusion in epilepsy and post-decompressive hyperemia in head trauma. All 7 patients showed a hyperactive area on SPECT studies using 99mTc-HM-PAO. 99mTc-ECD static image demonstrated a hyperactive area in both epilepsy and head trauma, and a hypoactive area in "luxury perfusion." On the dynamic SPECT of 99mTc-ECD in both epilepsy and head trauma, brain distribution of the tracer was determined within 2 min. postinjection and remained stable for up to 1 hour; however, "luxury perfusion" area showed a change from initial hyperactivity to late hypoactivity with the passage of time. The time activity curve in "luxury perfusion" area demonstrated a steep decrease of counts/pixel for up to 4-5 minutes postinjection, and a moderate decrease in the following phase. The early wash-out mechanism of 99mTc-ECD from "luxury perfusion" area can be described by a biexponential function including an initial steep decrease representing the rapid loss of the lipophilic complexes which were not metabolized in injured brain tissue.
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PMID:[99mTc-ECD dynamic SPECT in "luxury perfusion" of subacute stroke]. 855 92

The effect of enalapril on cerebral blood flow (CBF) was studied in 11 patients with chronic heart failure (NYHA II or III, dilated cardiomyopathy in 6 and old myocardial infarction in 5). CBF was evaluated by analyzing the Patlak-Plot curve obtained from radionuclide angiography with technetium-99m hexamethylpropylene amine oxime (99mTC-HM-PAO). Cardiac index (CI) and stroke volume (SV) were simultaneously measured by impedance cardiography. These measurements were performed before and at four weeks after daily administration of 5 mg enalapril. The stroke volume, cardiac index, and heart rate were not significantly changed after four weeks of enalapril administration. However, CBF was increased by 6.5% from 36.72 +/- 4.66 to 39.13 +/- 5.65 mL/100g/min (P < 0.05). These results suggest that enalapril increased cerebral blood flow, which was not related to increased cardiac output in congestive heart failure. Patlak-Plot analysis of radionuclide angiography using 99mTC-HM-PAO may be available for quantitative assessment of brain perfusion.
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PMID:Effect of enalapril maleate on cerebral blood flow in patients with chronic heart failure. 926 40

SPECT (single photon emission computed tomography) using iomazenil (IMZ) as a ligand for benzodiazepine receptors has recently been developed. Feasibility of the technique for detecting neuronal damage in the cerebral cortex was evaluated in 17 patients with cerebral infarction, specifically, patients with internal carotid artery (ICA) thrombosis (n = 6), middle cerebral artery (MCA) thrombosis (n = 5) and embolism (n = 6). IMZ SPECT was performed 5 to 17 days after stroke. Following the injection of 123I-IMZ 167 or 222 MBq intravenously, images were obtained at 15 minutes (early image) and 180 minutes (late image). In 11 cases, 99mTc-HM-PAO (hexamethyl-propylamine oxime) SPECT was also performed to measure cerebral blood flow (CBF). MRI was performed in all cases to elucidate areas of infarct. Early images from IMZ SPECT correlated well with those from HM-PAO, suggesting that early scans using IMZ SPECT reflect mainly CBF. In late images from IMZ SPECT, observed lesions were consistent with infarcted areas on MRI in most cases. However, in 3 cases of ICA thrombosis, 1 case of MCA thrombosis and 1 case of embolism, late IMZ SPECT imaging showed that the affected area was wider than apparent infarcts on MRI, indicating that the cerebral cortex, which was intact on MRI, was also involved. In these patients, clinical signs of cortical involvement were observed as well. These results suggest that moderately reduced CBF may affect cortical neurons without inducing apparent infarct, and such damage can be detected with IMZ SPECT.
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PMID:Changes in benzodiazepine receptor binding detected with SPECT in patients with cerebral infarction. 978 63

Alfimeprase, a fibrolase derivative with thrombolytic activity produced by recombinant DNA technology, was discovered by Amgen and was in development with Nuvelo for the treatment of stroke and catheter occlusion. However, development has been discontinued. Fibrolase is a zinc-containing metalloendopeptidase that was first isolated from the venom of the Southern copperhead snake, Agkistrodon contortrix contortrix. Alfimeprase directly degrades fibrin to break down clots. Alfimeprase is infused directly into the thrombus (side-hole catheter pushed through the entire clot) via multiple manual pulsed infusions. Alfimeprase degrades fibrin directly and entrapped blood cells are freed. Excess alfimeprase is rapidly inactivated by alpha-2 macroglobulin through an irreversible, covalent interaction. Phase III development of alfimeprase for peripheral arterial occlusion was discontinued based on poor results from the NAPA-2 and SONOMA-2 trials; however, Nuvelo resumed development of alfimeprase in 2007 for stroke and catheter occlusion.Alfimeprase's thrombolytic activity appears to be localized to the site of delivery because it is rapidly inactivated by alpha-2 macroglobulin, a naturally occurring protein in the blood, as it moves away from the site of delivery and into general blood circulation. In January 2002, Amgen and Hyseq Pharmaceuticals (now Nuvelo) entered into a collaboration to develop and commercialize alfimeprase. Nuvelo is to develop the product through clinical trials and Amgen was to be responsible for its manufacture. Both companies were to participate in commercial activities; Amgen was to have the option to lead these. Full financial terms were not disclosed. Further to this agreement, in November 2004 Amgen granted Nuvelo worldwide rights to develop and commercialize alfimeprase in exchange for milestone and royalty payments. In August 2007, Nuvelo decided to focus on core development programmes that it believed would produce the nearest-term proof-of-concept data. As a result of this realignment of organizational expenses, Nuvelo decided to continue to pursue the development of alfimeprase. In February 2003, Hyseq Pharmaceuticals merged with Variagenics Inc. to form Nuvelo Inc. In January 2006, Nuvelo and Bayer HealthCare entered a collaboration to develop and commercialize alfimeprase. Bayer was to commercialize the drug in all territories outside the US, whilst Nuvelo retains full US rights. Nuvelo was to receive other territory royalties and milestone payments to a total of $US385 million. A $US50 million upfront payment will be made to Nuvelo, while Bayer was to be responsible for 40% of the commercialization cost for global development. This partnership was to also develop stroke and deep vein thrombosis therapies. Data from the SONOMA-3 trial fell short of the company's expectations and so Nuvelo has decided to discontinue further development of alfimeprase. Nuvelo previously had decided to resume development of alfimeprase for the treatment of multiple coagulation-related disorders, including acute ischaemic stroke, catheter occlusion (CO) and acute peripheral arterial occlusion.Previously, results from the NAPA-2 (Novel Arterial Perfusion with Alfimeprase-2) trial and SONOMA-2 (Speedy Opening of Non-functional and Occluded catheters with Mini-dose Alfimeprase) phase III trial of alfimeprase in patients with acute peripheral arterial occlusion and catheter occlusion did not meet their primary endpoints. The primary endpoint of the NAPA-2 trial was the avoidance of surgery within 30 days of treatment with alfimeprase, whilst the SONOMA-2 trial's endpoint was the restoration of function at 15 minutes after dosing. In addition, these trials did not meet their secondary endpoints. As a result, Nuvelo and Bayer suspended enrolment in the NAPA-3 and SONOMA-3 phase III trials until additional analysis was complete; the SONOMA-3 trial was re-initiated. Nuvelo concluded that the delivery method for alfimeprase in the treatment of peripheral arterial occlusive disorders was suboptimal. The company closed the suspended NAPA-3 trial and planned to initiate preclinical studies focused on identifying optimized delivery methods in acute PAO in the second half of 2007. Data from the NAPA-2 trial suggested that efficacy could potentially be enhanced by maintaining alfimeprase longer at the site of the thrombus. Nuvelo's multinational phase III programme for peripheral arterial occlusion consisted of the NAPA-2 and NAPA-3 trials. Both trials were randomized, double-blind studies comparing 0.3 mg/kg of alfimeprase with placebo in a total of 600 patients in 100 centres. The primary endpoint of the NAPA-2 trial was the avoidance of surgery within 30 days of treatment; secondary endpoints included safety and pharmacoeconomics such as length of hospital and intensive care unit stay. Results from both trials have been presented. The phase II trial (NAPA-1) was completed in June 2004. This open-label, dose-escalation trial assessed the safety and efficacy of alfimeprase in 115 patients with acute peripheral arterial occlusion and was conducted in centres across the US, Europe and South Africa. Full data from the trial have been presented, which indicated that the 0.3 mg/kg dose appeared to be the optimal dose for investigation in phase III trials. In March 2003, Nuvelo announced the positive results of a phase I trial initiated in the US in July 2002; an IND was transferred from Amgen to Nuvelo in January 2002. In the SONOMA-2 trial, alfimeprase restored catheter function in patients with occluded catheters within 15 minutes with a p-value of 0.022. However, it did not meet the company's target product profile for commercial success with a p-value < 0.00125. Data from a phase II trial were presented at the 46th Annual Meeting of the American Society of Hematology held in December 2004. The study was closed in July 2004 with 55 patients enrolled. Initially the phase II study was to compare three doses of alfimeprase with the approved dose of alteplase in over 90 patients in the US. Nuvelo initiated the phase II CARNEROS-1 (Catheter Directed Alfimeprase for Restoration of Neurologic Function and Rapid Opening of Arteries in Stroke) study of alfimeprase in the treatment of acute ischaemic stroke in June 2007. CARNEROS-1 was a multicentre, open-label, dose-escalation study beginning with doses of 1, 5 and 10 mg of alfimeprase in 100 patients within 3-9 hours of stroke onset. The primary endpoints were recanalization (unblocking) of the occlusive lesion within 120 minutes of treatment, and symptomatic intracerebral haemorrhage. The first patient was dosed in December 2007; enrolment was taking place in the US and Canada. In the US, three patents have been issued relating to alfimeprase; US Patent Nos 6 261 820 (alfimeprase protein sequence), 6 440 414 (formulation of alfimeprase with a zinc stabilizer) and 6 455 269 (methods for localized administration of alfimeprase).
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PMID:Alfimeprase. 1845 71

The increased incidence of ventilator-associated complications in patients with chronic obstructive pulmonary disease (COPD) necessitates rapid weaning and extubation. The presence of secondary polycythemia in this subgroup increases the incidence of stroke and myocardial infarction due to hyperviscosity and tissue hypoxia. We present a 58-year-old male patient of COPD with secondary polycythemia (hematocrit 64%) who had possible hyperviscosity-related complications leading to cardiac arrest after a minor surgical procedure. The patient developed ventilator dependence after recovery. Phlebotomy was done to remove 10% of total blood volume. Symptomatic improvement was dramatic. Improvement in weaning indices like rapid shallow breathing index and PaO(2)/PAO(2) was observed facilitating rapid weaning and early extubation. Monitored, acute phlebotomy is safe and cost-effective. It decreases blood volume and viscosity, increases cardiac output and improves exercise tolerance in patients.
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PMID:Phlebotomy for rapid weaning and extubation in COPD patient with secondary polycythemia and respiratory failure. 2053 67

Diagnostic and therapeutic guidelines of peripheral arterial disease of extremities recommanded by five scientific societies of Slovak Medical Association (Slovak Angiological Society, Slovak Society for Vascular Surgery, Slovak Cardiologic Society, Slovak Internal Society and Slovak Radiologic Society) are discussed in this article. Peripheral arterial disease (PAO) of extremities is an important manifestation of systemic atherosclerosis The lower the ankle-brachial pressure index, the greater the risk of serious cardiovascular events (e.g. myocardial infarction, stroke). Nevertheless, patients with PAO are undertreated with regard to use of antiplatelet drugs or lipid-lowering drugs, as compared with patients with coronary artery disease.
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PMID:[Peripheral arterial disease of extremities--guidelines for diagnostic and treatment]. 2368 12


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