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Biomedical subjects

J Kozlowski

Publications and source records attributed to J Kozlowski.

At least 19 recordsLinked to original sources
PubMed2001

Facilitation of acetylcholine release and improvement in cognition by a selective M2 muscarinic antagonist, SCH 72788.

Current treatment of Alzheimer's Disease (AD) requires acetylcholinesterase inhibition to increase acetylcholine (ACh) concentrations in the synaptic cleft. Another mechanism by which ACh levels can be increased is blockade of presynaptic M2 muscarinic autoreceptors that regulate ACh release. An antagonist designed for this purpose must be highly selective for M2 receptors to avoid blocking postsynaptic M1 receptors, which mediate the cognitive effects of ACh. Structure-activity studies of substituted methylpiperadines led to the synthesis of 4-[4-[1(S)-[4-[(1,3-benzodioxol-5-yl)sulfonyl]phenyl]ethyl]-3(R)-methyl-1-piperazinyl]-4-methyl-1-(propylsulfonyl)piperidine. This compound, SCH 72788, binds to cloned human M2 receptors expressed in CHO cells with an affinity of 0.5 nM, and its affinity at M1 receptors is 84-fold lower. SCH 72788 is a functional M2 antagonist that competitively inhibits the ability of the agonist oxotremorine-M to inhibit adenylyl cyclase activity. In an in vivo microdialysis paradigm, SCH 72788 increases ACh release from the striatum of conscious rats. The compound is also active in a rodent model of cognition, the young rat passive avoidance response paradigm. The effects of SCH 72788 suggest that M2 receptor antagonists may be useful for treating the cognitive decline observed in AD and other dementias.

Acetylcholine↗
PubMed2001

Muscarinic agonists and antagonists in the treatment of Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by cognitive impairment and personality changes. The development of drugs for the treatment of the cognitive deficits of AD has focused on agents which counteract loss in cholinergic activity. Although symptoms of AD have been successfully treated with acetylcholinesterase inhibitors (tacrine, donepezil. rivastigmine, galanthamine), limited success has been achieved with direct M1 agonists, probably due to their lack of selectivity versus other muscarinic receptor subtypes. Muscarinic M2 antagonists have been reported to increase synaptic levels of acetylcholine after oral administration to rats (e.g. BIBN-99, SCH-57790), but their selectivity versus other muscarinic receptor subtypes is modest. Exploration of a series of piperidinylpiperidines has yielded the potent and selective M2 antagonist SCH-217443. This antagonist has excellent bioavailability in rats and dogs and shows activity in a rat model of cognition.

Alzheimer Disease↗
PubMed2000

Proliferation of intimal smooth muscle cells. Attenuation of basic fibroblast growth factor 2-stimulated proliferation is associated with increased expression of cell cycle inhibitors.

Basic fibroblast growth factor (FGF2) is a potent mitogen for medial smooth muscle cells and is necessary for their proliferation after balloon catheter injury; however, intimal smooth muscle cells do not require FGF2 for their proliferation, and they respond only weakly to exogenous FGF2. The present study examined the activation of extracellular signal-regulated kinase (ERK) signaling as well as the expression and activity of cell cycle proteins in FGF2-stimulated intimal smooth muscle cells. FGF2 activates ERKs 1 and 2, and Western blot analysis showed that cyclin D, cyclin E, and cyclin-dependent kinase (CDKs) 2 and 4 were expressed in intimal smooth muscle cells after FGF2 infusion. FGF2 stimulation, however, did not lead to phosphorylation of the retinoblastoma protein (Rb), CDK 2 activation, or expression of cyclin A. Western blot analysis showed that intimal smooth muscle cells express elevated levels of the cell cycle inhibitors p15(INK4b) and p27(Kip1), compared with medial smooth muscle cells, and that FGF2 stimulation does not reduce the level of these inhibitors. These studies suggest that despite activation of ERKs 1 and 2 and expression of the cell cycle activators, cyclin D and cyclin E, high levels of cell cycle inhibitors may inhibit cell cycle transit in FGF2-stimulated intimal smooth muscle cells.

Animals↗
PubMed1999

SCH 57790: a novel M2 receptor selective antagonist.

As a decrease in cholinergic neurons has been observed in Alzheimer's Disease (AD), therapeutic approaches to AD include inhibition of acetylcholinesterase to increase acetylcholine levels. Evidence suggests that acetylcholine release in the CNS is modulated by negative feedback via presynaptic M2 receptors, blockade of which should provide another means of increasing acetylcholine release. Structure-activity studies of [4-(phenylsulfonyl)phenyl]methylpiperazines led to the synthesis of 4-cyclohexyl-alpha-[4-[[4-methoxyphenyl]sulfinyl]-phenyl]-1-piperazin eacetonitrile. This compound, SCH 57790, binds to cloned human M2 receptors expressed in CHO cells with an affinity of 2.78 nM; the affinity at M1 receptors is 40-fold lower. SCH 57790 is an antagonist at M2 receptors expressed in CHO cells, as the compound blocks the inhibition of adenylyl cyclase activity mediated by the muscarinic agonist oxotremorine. This compound should be useful in assessing the potential of M2 receptor blockade for enhancement of cognition.

Acetylcholine↗
PubMed1999

Resting sestamibi imaging for the prognosis of low-risk chest pain.

OBJECTIVE: To assess the prognostic value of resting Tc-99m sestamibi scanning for adverse cardiac events (ACEs) in ED chest pain patients with a low probability of acute cardiac ischemia (ACI). METHODS: Sixty-nine consenting, hemodynamically stable patients with chest pain and a nondiagnostic electrocardiogram received an injection of 25 mCi of sestamibi during or within two hours of active pain. Scans were interpreted locally by a nuclear cardiologist or radiologist. Interrater reliability was assessed. ACEs of myocardial infarction (MI), death, or revascularization were assessed during the index hospitalization and over a one-year follow-up period. RESULTS: For ACEs, rest scanning with sestamibi had a sensitivity of 71% (95% CI = 0.33 to 0.97), a specificity of 92% (95% CI = 0.82 to 0.97), and an accuracy of 90% (95% CI = 0.87 to 0.99). The positive predictive value was 50% (95% CI = 0.19 to 0.82) and the negative predictive value was 97% (95% CI = 0.87 to 0.98). Sestamibi scanning was highly discriminating, with 62% of patients with positive scans but only 3% with negative scans having ACEs (p<0.001, log rank test). CONCLUSION: In patients with low-risk chest pain, sestamibi scanning has good specificity and moderate sensitivity for ACEs over a 12-month period.

Chest Pain↗
PubMed1999

Response to inhaled nitric oxide in acute lung injury depends on distribution of pulmonary blood flow prior to its administration.

Responses to inhaled nitric oxide (iNO) in acute lung injury (ALI), as evidenced by improvements in oxygenation, are variable. We hypothesized that the effect of iNO may be related to the pre-iNO distribution of pulmonary blood flow (PBF). In the present study we evaluated the effect of iNO on PBF in normal healthy dogs and in a canine model of ALI induced by oleic acid (OA). In Group "OA only" (n = 5), ALI was induced by central venous injection of 0.08 ml/kg OA. In Group "E+OA" (n = 5), hypoxic pulmonary vasoconstriction after ALI was blocked with low-dose endotoxin (15 microg/kg of Escherichia coli endotoxin) administered 30 min before giving the same dose of OA. Measurements of regional PBF and lung water concentration (LWC) using positron emission tomography (PET) and H215O were performed before and after OA or placebo, and then again at concentrations of 10, 40, and 0 ppm iNO. One hundred twenty minutes after OA injury, PaO2/FIO2 fell significantly in Group OA only, from 567 +/- 32 to 437 +/- 67 mm Hg. In these animals, PBF redistributed from the dorsal edematous regions of the lungs to the nondependent zones, thus partially preserving normal ventilation/ perfusion relationships. As in the normal animals, in Group OA only, iNO did not significantly change either PBF or oxygenation. In Group E+OA, the administration of low-dose endotoxin eliminated perfusion redistribution from the dorsal edematous lung regions. As a result, PaO2/FIO2 fell from 558 +/- 70 to 119 +/- 53 mm Hg, a decrease that was significantly greater than that in Group OA only. In Group E+OA, administration of iNO restored perfusion redistribution to a similar level as in Group OA only, which was associated with a significant improvement in PaO2/FIO2, from 119 +/- 53 to 251 +/- 159 (10 ppm iNO), and 259 +/- 165 mm Hg (40 ppm iNO). We conclude that the effect of iNO on oxygenation after ALI depends on the pre-iNO perfusion pattern, which may help explain the variable response to iNO often observed in patients with acute respiratory distress syndrome.

6-Ketoprostaglandin F1 alpha↗
PubMed1998

Synergistic hemodynamic effects of low-dose endotoxin and acute lung injury.

We evaluated the effects of low-dose endotoxin (15 microg/kg) on the pulmonary and systemic responses to oleic acid (OA)-induced acute lung injury in dogs. Animals given endotoxin alone (n = 5) showed a modest decrease in arterial blood pressure, but no effects on pulmonary hemodynamics, blood gases, cardiac output, or lung water accumulation. Animals (n = 6) given only OA (0.08 ml/kg) showed the expected development of mild-moderate pulmonary hypertension, a comparable reduction in arterial blood pressure, hypoxemia, increased lung water concentration, and an altered intrapulmonary perfusion pattern, as assessed by positron emission tomography. Animals (n = 7) given the same dose of endotoxin, followed 30 min later by the same dose of OA, developed a similar increase in lung water concentration as the group given OA alone, but failed to develop pulmonary hypertension or to redistribute pulmonary blood flow away from the edematous lung regions. In addition, arterial blood pressure fell significantly more than in the other groups. These responses were associated with a 30-fold increase in circulating prostacyclin (assayed as 6-keto prostaglandin F1 alpha [PGF1alpha]). The effects on systemic blood pressure, intrapulmonary blood flow redistribution, and eicosanoid production were eliminated by pretreating (n = 5) animals with meclofenamate (2 mg/kg). The results are consistent with a "priming" effect of low-dose endotoxin on the pulmonary endothelium, with exaggerated prostacyclin production in response to a subsequent lung injury. This interaction leads to altered intrapulmonary hemodynamics that exacerbate the development of hypoxemia, and to significant decreases in systemic blood pressure. To the extent that the lung is the most likely source of the increased prostacyclin production, the synergistic effects of low-dose endotoxin and lung injury may produce a kind of "lung shock."

6-Ketoprostaglandin F1 alpha↗
PubMed1998

Adaptation of the bioprogressive philosophy to use brackets with .022" slots.

The Bioprogressive orthodontic treatment philosophy is traditionally associated with the use of brackets that have .018" slots. Proponents of the Bioprogressive philosophy suggest this slot configuration largely because they believe that lighter wires provide force levels that are within the biological limits of the periodontal support system. At the same time, the principles of orthodontic anchorage advocated by the Bioprogressive philosophy depend on careful torque control of both molar and anterior teeth. It is possible and sometimes advisable to use wires designed for use in brackets with .018" slots, in brackets with .022" slots. Under these circumstances, the thinner wires may not provide sufficient control over torque moments to develop the required degree of molar anchorage. This article suggests that with the use of certain wires, and with minor modifications to the shapes of arches, that the use of brackets with .022" slots need not conflict with many of the important principles of orthodontic treatment advocated in the Bioprogressive philosophy.

Chromium Alloys↗
PubMed1998

NCCN urothelial cancer practice guidelines. National Comprehensive Cancer Network.

Urothelial tumors represent a spectrum of diseases with a range of prognoses. Once a diagnosis is established at any point on the urothelial tract, the patient remains at risk for developing a new lesion at a different or the same location, at a similar or more advanced stage. Continued monitoring for recurrence is an essential part of management, as most recurrences are superficial and can be managed by endoscopic means. Within each category of disease, more refined methods to determine prognosis and guide management, based on molecular staging, are under development. These methods are aimed at optimizing the individual patient's likelihood of cure and chance for organ preservation. For patients with more extensive disease, newer treatments typically involve combined-modality approaches using recently developed surgical procedures, or three-dimensional treatment planning for more precise delivery of radiation therapy. While these are not appropriate in all cases, they do offer the promise of an improved quality of life and prolonged survival. Finally, within the category of metastatic disease, a number of new agents have been identified that appear to be superior to those currently considered to be standard therapies. It is thought, therefore, that the treatment of urothelial tumors will evolve rapidly over the next few years, with improved outcomes for patients with all stages of disease.

Humans↗
PubMed1993

A phase II study of continuous infusion 5-fluorouracil in advanced hormone refractory prostate cancer. An Illinois Cancer Center Study.

BACKGROUND: 5-Fluorouracil (5-FU) has been previously associated with therapeutic benefit in hormone refractory prostate cancer. However, no previous study has administered 5-FU as a prolonged continuous infusion, which may be the optimal schedule for this cell-cycle specific agent. METHODS: Therefore, 25 patients were treated with 5-FU administered as a continuous intravenous infusion at a dose of 1000 mg/m2/day for 5 days every 28 days. Eligibility required disease defined by bidimensionally measurable lesions or evaluable lesions on bone scan or radiograph with elevated serum levels of prostate-specific antigen (PSA), no severe cytopenias, and an Eastern Cooperative Oncology Group performance status less than 3. Prior chemotherapy was not allowed. Dose modifications were specified for mucositis and hematologic toxicity. RESULTS: Eighteen of 22 patients were evaluable for response and toxicity, whereas 4 were evaluable for toxicity alone. Toxicity was significant using this dose and schedule and included episodes of sudden death (one patient), paroxysmal supraventricular tachycardia (one patient), and congestive heart failure (one patient). Other Grade 3 toxicities included stomatitis (two patients) and diarrhea (one patient). Significant myelosuppression did not occur. Objective responses were not observed, but 12 patients experienced stable disease with a median duration of 4 months. CONCLUSIONS: Infusional 5-FU can not be recommended for the treatment of advanced hormone refractory prostate cancer.

Aged↗
PubMed1988

Risks associated with intraaortic balloon pumping in patients with and without diabetes mellitus.

Between 1967 and 1982, intraaortic balloon pumping (IABP) was attempted in 733 patients. Of these, 132 were diabetic: 51 patients were managed with diet alone, 46 patients took oral hypoglycemic agents and 35 patients required insulin. Vascular complications associated with IABP occurred in 34% of the insulin-dependent diabetics, in 18% of other diabetics and in 14% of nondiabetic patients. Infectious complications were 37, 22 and 25%, respectively. Seventy-five diabetic patients (57%) were discharged alive from the hospital after balloon pumping, essentially the same proportion as among nondiabetic patients (58%). It is concluded that although diabetics incur a higher complication rate, IABP is not contraindicated.

Adult↗
PubMed1986

Studies of Doppler aortic flow velocity during supine bicycle exercise.

Although Doppler echocardiography is useful in the assessment of left ventricular function at rest, little information is available on the application of this technique during exercise. Consequently, Doppler aortic flow studies were performed in 17 young normal subjects during and after supine bicycle exercise. The purposes of the study were to determine the feasibility of recording Doppler aortic flow velocity with a suprasternal notch transducer during exercise and to assess the changes in normal aortic flow velocity parameters during exercise and early recovery. Each subject exercised until fatigue; mean duration of exercise was 10 minutes. Heart rate increased from a mean of 69 beats/min at control to 159 beats/min at peak exercise. On average, aortic peak flow velocity increased by 45% from control, reaching its maximum at 2 minutes after exercise. Ejection time decreased by 34% during exercise, being shortest at peak exercise. Heart rate, peak flow velocity and ejection time had not returned to normal by 10 minutes after exercise. Aortic flow velocity integral (a relative measure of stroke volume) decreased by 10% at peak exercise (p less than 0.05) compared with control, but had returned to control at 2 minutes after exercise. Despite mild aliasing, increased spectral dispersion, faster heart rates and increased respiratory rate during maximal exercise, aortic flow velocity measurements could be recorded using the suprasternal technique. These baseline Doppler exercise data should be useful in further studies of exercise hemodynamic changes in patients with heart disease.

Adolescent↗