Glass fibers covered with sol-gel glass as a new support for affinity chromatography columns: a review.

The search for mechanical supports for biochemically active compounds serving as immunochemical sensors has been the goal of many studies. A new compound in the form of gel fiberglass (GFG) membranes was recently developed as an example of such supports. In this review, these membranes were analyzed with respect to their use for cancer detection. The membranes are prepared from glass fibers covered with oxysilane to provide a sol-gel glass matrix. Derivatization of the support eliminates nonspecific adsorption. A thin layer of protein trapped in the gel glass during its preparation is deposited on the surface of a lattice of glass fibers. The major innovation of the membrane is its large area. External agents percolating through such a membrane contact a maximal number of molecules of the compounds trapped in the sol-gel glass. As a result, this membrane is highly effective. Each GFG column is built from a series of 20 to 30 membranes. The preparation of such columns is relatively simple, requiring only several hours. The capacity of GFG columns is high: the total amount of tumor-associated antigens (TAA) isolated by these columns from the blood of colon cancer patients reached 50% of the total protein and amounted to up to 9-12 mg/ml of serum. The main components of the isolated TAA were the soluble p66 and p51 proteins. A determination of their concentration by HPLC can be used for early cancer detection. Thus, the described method allows the easy and highly effective isolation of TAA and can be used for different goals, including cancer diagnosis. GFG supports have great potential for the isolation of various macromolecules utilizing specific ligands.

Management of sexual dysfunction in patients with cardiovascular disease: recommendations of the Princeton Consensus Panel.

Sexual dysfunction is highly prevalent in both sexes and adversely affects patients' quality of life and well being. Given the frequent association between sexual dysfunction and cardiovascular disease, in addition to the potential cardiac risk of sexual activity itself, a consensus panel was convened to develop recommendations for clinical management of sexual dysfunction in patients with cardiovascular disease. Based upon a review of the research and presentations by invited experts, a classification system was developed for stratification of patients into high, low, and intermediate categories of cardiac risk. The large majority of patients are in the low-risk category, which includes patients with (1) controlled hypertension; (2) mild, stable angina; (3) successful coronary revascularization; (4) a history of uncomplicated myocardial infarction (MI); (5) mild valvular disease; and (6) no symptoms and <3 cardiovascular risk factors. These patients can be safely encouraged to initiate or resume sexual activity or to receive treatment for sexual dysfunction. An important exception is the use of sildenafil in patients taking nitrates in any form. Patients in the intermediate-risk category include those with (1) moderate angina; (2) a recent MI (<6 weeks); (3) left ventricular dysfunction and/or class II congestive heart failure; (4) nonsustained low-risk arrhythmias; and (5) >/=3 risk factors for coronary artery disease. These patients should receive further cardiologic evaluation before restratification into the low- or high-risk category. Finally, patients in the high-risk category include those with (1) unstable or refractory angina; (2) uncontrolled hypertension; (3) congestive heart failure (class III or IV); (4) very recent MI (<2 weeks); (5) high-risk arrhythmias; (6) obstructive cardiomyopathies; and (7) moderate-to-severe valvular disease. These patients should be stabilized by specific treatment for their cardiac condition before resuming sexual activity or being treated for sexual dysfunction. A simple algorithm is provided for guiding physicians in the management of sexual dysfunction in patients with varying degrees of cardiac risk.

Management of sexual dysfunction in patients with cardiovascular disease: recommendations of The Princeton Consensus Panel.

Sexual dysfunction is highly prevalent in both sexes and adversely affects patients' quality of life and well being. Given the frequent association between sexual dysfunction and cardiovascular disease, in addition to the potential cardiac risk of sexual activity itself, a consensus panel was convened to develop recommendations for clinical management of sexual dysfunction in patients with cardiovascular disease. Based upon a review of the research and presentations by invited experts, a classification system was developed for stratification of patients into high, low, and intermediate categories of cardiac risk. The large majority of patients are in the low-risk category, which includes patients with (1) controlled hypertension; (2) mild, stable angina; (3) successful coronary revascularization; (4) a history of uncomplicated myocardial infarction (MI); (5) mild valvular disease; and (6) no symptoms and <3 cardiovascular risk factors. These patients can be safely encouraged to initiate or resume sexual activity or to receive treatment for sexual dysfunction. An important exception is the use of sildenafil in patients taking nitrates in any form. Patients in the intermediate-risk category include those with (1) moderate angina; (2) a recent MI (<6 weeks); (3) left ventricular dysfunction and/or class II congestive heart failure; (4) nonsustained low-risk arrhythmias; and (5) >/=3 risk factors for coronary artery disease. These patients should receive further cardiologic evaluation before restratification into the low- or high-risk category. Finally, patients in the high-risk category include those with (1) unstable or refractory angina; (2) uncontrolled hypertension; (3) congestive heart failure (class III or IV); (4) very recent MI (<2 weeks); (5) high-risk arrhythmias; (6) obstructive cardiomyopathies; and (7) moderate-to-severe valvular disease. These patients should be stabilized by specific treatment for their cardiac condition before resuming sexual activity or being treated for sexual dysfunction. A simple algorithm is provided for guiding physicians in the management of sexual dysfunction in patients with varying degrees of cardiac risk.

The role of alpha 1-blockers in combination therapy for hypertension.

Antihypertensive monotherapy provides adequate blood pressure control in less than 50% of patients with hypertension (BP > 140/90 mmHg), especially those with stage 2-3 disease. This article reviews clinical studies that demonstrate that add-on therapy with an alpha1-blocker (doxazosin, terazosin or prazosin) is an effective and well-tolerated regimen for improving blood pressure control in patients with inadequately controlled hypertension. Furthermore, alpha1-blockers have therapeutic benefits that go beyond blood pressure management. They have a small but positive effect on the serum lipid profile and they have favourable or benign effects on conditions that frequently coexist with hypertension, such as type 2 diabetes mellitus and benign prostatic hyperplasia.

Effect of sildenafil citrate on blood pressure and heart rate in men with erectile dysfunction taking concomitant antihypertensive medication. Sildenafil Study Group.

OBJECTIVES: To assess the acute effect of sildenafil citrate on blood pressure and heart rate in men with erectile dysfunction taking concomitant antihypertensive medication. DESIGN: Post-hoc subanalysis of five, 12- or 24-week, prospective, randomized, double-blind, placebo-controlled studies. SETTING: Private-practice and academic urology clinics. PATIENTS: A total of 1685 men with erectile dysfunction of > or = 6 months duration, of whom 667 (sildenafil n = 406, placebo n = 261) were taking antihypertensive medication (diuretic, beta-blocker, alpha-blocker, angiotensin converting enzyme inhibitor, and/or calcium antagonist). Of the patients taking antihypertensive medication, 608 (91%) completed the studies (374 of 406 receiving sildenafil, 234 of 261 receiving placebo). INTERVENTIONS: The last dose of oral sildenafil (25-200 mg) or placebo was taken at home on the morning of the final clinic visit. Patients taking antihypertensive medication maintained usual dosing schedules. MAIN OUTCOME MEASUREMENTS: Sitting systolic (SBP)/diastolic blood pressure (DBP) and heart rate at baseline and after dosing with sildenafil or placebo (end-of-treatment visit). RESULTS: Mean changes from baseline in SBP/DBP for men taking antihypertensive medication were -3.6/-1.9 mmHg for those receiving sildenafil and -0.8/-0.1 mmHg for those receiving placebo compared with -2.2/-2.0 mmHg and -0.1/0.4 mmHg, respectively, for men not taking antihypertensive medication. Mean changes from baseline in heart rate for men taking antihypertensive medication were -0.6 beats/min after sildenafil and 0.9 beats/min after placebo compared with 0.4 beats/min and -0.6 beats/min, respectively, for patients not taking antihypertensive medication. Differences in SBP, DBP, and heart rate between the patients taking and those not taking antihypertensive medication were small. CONCLUSIONS: The acute, short-term effects of oral sildenafil on blood pressure and heart rate in men with erectile dysfunction were small and not likely to be clinically significant in those taking concomitant antihypertensive medication.

Cardiovascular effects of sildenafil citrate and recommendations for its use.

Sildenafil citrate is the first orally active therapy proved to be effective and safe treatment for erectile dysfunction (ED). Because men with cardiovascular disease are at increased risk of developing ED, and because ED and cardiovascular disease share important risk factors, attention has focused recently on the use of sildenafil in these men. When used in combination with nitroglycerin and other nitric oxide (NO) donors, sildenafil may potentiate major drops in blood pressure. Use of nitrate antianginal agents are an absolute contraindication to sildenafil use. In normotensive men and in men receiving antihypertensive medications evaluated in Phase II/III clinical trials, sildenafil use at the recommended doses (25-100 mg 1 hour before sexual intercourse and no more than once daily) was associated with modest, transient reductions in blood pressure and negligible effects on heart rate. In a more recent study, sildenafil was well tolerated in patients receiving antihypertensive medications and was not associated with major decreases in blood pressure. From the time of its approval in the United States in March 1998 through mid-November 1998, with approximately 6 million prescriptions written, 130 deaths were reported by the US Food and Drug Administration (FDA). Seventy-seven of the men who died had documented cardiovascular events. Sixteen men took or were administered nitroglycerin or an organic nitrate; 3 others had nitroglycerin in their possession. Physician prescribing guidelines issued by the American College of Cardiology/American Heart Association (ACC/AHA) recommend caution when prescribing sildenafil to men with certain cardiovascular conditions, liver or kidney disease, and to those taking medications that may prolong sildenafil's half-life (e.g., erythromycin or cimetidine). Those with known or suspected coronary artery disease may benefit from an exercise test to determine whether resumption of sexual activity with use of sildenafil is likely to be associated with an increased risk of myocardial ischemia.

Antiplatelet therapy in the prevention of ischemic vascular events: literature review and evidence-based guidelines for drug selection.

BACKGROUND: New antiplatelet drugs are being developed and many clinical trials evaluating the benefits of antiplatelet drugs for the secondary prevention of ischemic events in patients with atherosclerotic vascular disease have been performed. HYPOTHESIS: An updated systematic review and evidence-based guidelines for the appropriate selection of antiplatelet drugs may be beneficial to physicians and healthcare organizations attempting to create or update current clinical practice guidelines or clinical pathways aimed at caring for these patients. METHODS: (1) A systematic review of the recent literature on the relative efficacy and safety of aspirin, ticlopidine, and clopidogrel was undertaken; (2) an evidence-based, expert panel approach using a modified Delphi technique to create explicit guidelines for prescribing antiplatelet therapy was instituted; and (3) the recommendations of an expert panel were summarized. RESULTS: Consensus guidelines were developed for the utilization of aspirin, ticlopidine, or clopidogrel for the prevention of ischemic events in patients with manifestations of atherosclerotic vascular disease (prior myocardial infarction, prior ischemic stroke, or established peripheral arterial disease) who are at increased risk for recurrent ischemic events. Based on efficacy and safety, clopidogrel was recommended as the drug of choice for patients with established peripheral arterial disease; aspirin or clopidogrel should be considered in patients with prior myocardial infarction (with clopidogrel favored for patients who have had a recurrent event while on aspirin or in whom aspirin is contraindicated); aspirin or clopidogrel should be considered as first-line treatment in patients with prior ischemic (nonhemorrhagic) stroke--however, clopidogrel is the favored drug in patients in whom other antiplatelet drugs are either contraindicated or who have had recurrent events while on therapy. CONCLUSIONS: Myocardial infarction, ischemic stroke, and peripheral arterial disease are all clinical manifestations of the same underlying disease process (atherosclerosis), with thrombus formation on the disrupted atherosclerotic plaque (atherothrombosis) being a common precipitating factor of ischemic events in patients suffering from these disorders. An evidence-based approach was used to develop a practice guideline, based on available published evidence, for the appropriate utilization of antiplatelet agents (aspirin, ticlopidine, or clopidogrel). These guidelines may be of use to multidisciplinary teams wishing to create or update clinical guidelines or clinical pathways which address the care of patients with atherosclerotic vascular disease. New antiplatelet agents such as clopidogrel may be more effective and associated with lower risk of selected adverse effects (such as gastrointestinal distress, gastrointestinal hemorrhage, and neutropenia) than those previously used to prevent thrombus formation in the setting of atherosclerotic arterial disease. Combination antiplatelet therapy is being evaluated as an option for those patients who experience recurrent events on a single antiplatelet agent.

Effects of nifedipine on myocardial blood flow and systolic function in humans with ischemic heart disease.

OBJECTIVE: To test the hypothesis that, in humans with ischemic heart disease, nifedipine is a primary dilator of the coronary circulation and in general exerts a net positive effect on the balance of myocardial oxygen supply and demand. METHODS: Positron-emission tomography with [13N]-ammonia was used to measure myocardial blood flow in patients at rest, and during infusion of adenosine and ingestion of nifedipine (10 mg capsule, a bite-and-chew technique). Myocardial segments were defined physiologically on the basis of blood flow to adenosine as being normal or having mild, moderate, or severe impairment of dilator reserve. Myocardial systolic function was assessed under comparable physiologic conditions using gated single-photon-emission computed tomography radionuclide ventriculography. RESULTS: Our study population consisted of 13 male patients and one female patient. Ingestion of nifedipine increased heart rate (from 63 +/- 11 to 80 +/- 16 beats/min, P < 0.001) and, as intended, lowered systolic arterial pressure (from 148 +/- 20 to 123 +/- 14 mmHg, P < 0.001) but had no effect on heart rate-pressure product (which changed from 9283 +/- 1576 to 9942 +/- 2162 mmHg/min). Myocardial blood flow in patients at rest in segments with mild, moderate, and severe reductions of dilator capacity (0.63 +/- 0.20, 0.67 +/- 0.25, and 0.58 +/- 0.27 ml/min per g, respectively) was less (P < 0.01) than normal (0.91 +/- 0.29 ml/min per g). Nevertheless, flow of blood was increased versus that at rest (P < 0.01) by infusion of adenosine (to 1.78 +/- 0.13, 1.29 +/- 0.16, and 0.75 +/- 0.22 ml/min per g) and ingestion of nifedipine (to 1.17 +/- 0.51, 1.06 +/- 0.36, 0.85 +/- 0.42 ml/min per g) in segments with mild, moderate, and severe reduction of dilator capacity as well as in normal segments (to 3.18 +/- 0.85 ml/min per g with adenosine and 1.68 +/- 0.65 ml/min per g with nifedipine). Global left ventricular systolic function remained unchanged versus baseline (ejection fraction 0.74 +/- 0.09) with nifedipine (0.76 +/- 0.10). Regional contraction expressed in normalized amplitude units also remained unchanged versus baseline in response to nifedipine. CONCLUSION: Nifedipine increases myocardial blood flow in humans with ischemic heart disease in normal segments as well as in segments with mild, moderate, and severe reductions of dilator capacity, albeit to a lesser extent with increasing impairment of dilator capacity. Both global and regional left ventricular contractile function also are not adversely affected by nifedipine. These improvements in myocardial blood flow in face of no change or a decrease in myocardial demand for oxygen reflect an overall favorable effect on the balance between the supply of and demand for myocardial oxygen.

Morphological and morphometric studies of the splenic antitumor immune response, elicited by liposome-covered soluble p53 kDa antigen, in chemically-induced rat colon cancer.

We evaluated the splenic morphometric changes in rats treated with carcinogen to study development of anti-cancer immune response. When liposome-covered soluble 53 kDa antigen (s53) was injected into these rats, significant tumor-suppression was seen and the percentage of tumor-free animals rose from 15.4% in non-vaccinated rats to 53.8%. In the spleens of carcinogen treated rats that did not develop tumors, activity of B lymphocytes increased significantly. This was manifested by the expansion of the germinal centers to 50.9% of the follicular area reflecting depletion of B cells, and the decrease of the mantle layer to 48.9% of the follicles. A similar picture was seen with T lymphocytes: the area of the marginal zone decreased to 55.2% of the T zone of the white pulp, and that of the periarterial lymph sheaths (PALS) to 33.6%. In tumor-bearing rats features of the immune decompensation were seen: the germinal centers increased to 96.5% of the follicular area, and the mantle layer and PALS decreased significantly. Vaccination prevented these effects, especially in tumor-bearing rats: the PALS occupies 30.4% of the white pulp and the marginal zone 56.1%, and the mantle layer occupied 58.1% of the follicular zone. Similar changes were found in vaccinated rats without tumors reflecting the compensatory character of the immune reaction in vaccinated rats. In conclusion, we found that treatment with carcinogen followed by vaccination with the s53-liposomes complex stimulated the activity of the splenic B, and to a lesser degree the T systems.

Overall cardiovascular profile of sildenafil citrate.

Sildenafil, a selective inhibitor of phosphodiesterase type 5 (PDE5), is the first in a new class of orally effective treatments for erectile dysfunction. During sexual stimulation, the cavernous nerves release nitric oxide (NO), which induces cyclic guanosine monophosphate (cGMP) formation and smooth muscle relaxation in the corpus cavernosum. Sildenafil facilitates the erectile process during sexual stimulation by inhibiting PDE5 and thus blocking the breakdown of cGMP. Sildenafil alone can cause mean peak reductions in systolic/diastolic blood pressure of 10/7 mm Hg that are not dose related, whereas the heart rate is unchanged. Sildenafil and nitrates both increase cGMP levels in the systemic circulation but at different points along the NO-cGMP pathway. The combination is contraindicated because they synergistically potentiate vasodilation and may cause excessive reductions in blood pressure. Erectile dysfunction is a significant medical condition that shares numerous risk factors with ischemic heart disease, and hence a substantial overlap exists between these patient groups. From extensive clinical trials, the most commonly reported cardiovascular adverse events in patients treated with sildenafil were headache (16%), flushing (10%), and dizziness (2%). The incidences of hypotension, orthostatic hypotension, and syncope and the rate of discontinuation of treatment due to adverse events were <2% and were the same in patients taking sildenafil and those taking placebo. Retrospective analysis of the concomitant use of antihypertensive medications (beta blockers, alpha blockers, diuretics, angiotensin-converting enzyme inhibitors, and calcium antagonists) in patients taking sildenafil did not indicate an increase in the reports of adverse events or significant episodes of hypotension compared with patients treated with sildenafil alone. In clinical trials, the incidence of serious cardiovascular adverse events, including stroke and myocardial infarction, was the same for patients treated with sildenafil or placebo. Concurrent disease states, such as renal or hepatic impairment, or concomitant use of inhibitors of the cytochrome P450 isozyme CYP3A4 could increase systemic exposure to sildenafil. Since the US market launch in April 1998, monitoring of spontaneous adverse event reports in association with sildenafil has demonstrated a pattern that is generally consistent with the experience observed during clinical development, with the exception of infrequent reports of priapism. In conclusion, extensive clinical testing has shown that overall treatment with sildenafil for up to 1 year is well tolerated and is associated with a low incidence of adverse events that result in discontinuation of treatment in <3% of patients.

Are there differences among angiotensin receptor blockers?

Pharmacologic effects of specific drugs are frequently attributed to their therapeutic class because all agents within a particular class have the same mechanism of action. Because "head-to-head" comparisons in trials are rare, any differentiation between drugs of the same class is usually limited to comparisons of their pharmacokinetic profiles, and it is usually assumed that most of the drugs in a therapeutic class have similar efficacies. Two recent randomized clinical trials demonstrated that the antihypertensive agents irbesartan and losartan, both angiotensin receptor blockers, are not equally effective in reducing blood pressure among patients with hypertension. In both a fixed-dose trial and a titration-protocol trial, patients treated with irbesartan achieved a greater reduction in blood pressure than did those treated with losartan. The response rate was also higher among patients treated with irbesartan. Therefore, irbesartan, used either alone or as a component of response-based combination therapy with a diuretic, is a more potent antihypertensive agent than losartan. These results and the previously published pharmacologic profiles of these drugs demonstrate that angiotensin receptor blockers are, like many other classes of antihypertensive agents, more different than alike.

The role of the soluble p53 antigen and its autoantibodies as markers for diagnosis of colon cancer: a comparative study.

The role of various serological tumor markers, p53 soluble antigen and its autoantibodies, was evaluated for the detection of colon cancer in humans. An HPLC technique was used to measure serum levels of both forms of p53 protein after their partial isolation on gel fiberglass affinity chromatography columns. Tumor-associated proteins (TAP) in the form of either antigens or autoantibodies were about 4% of the total protein isolated from the serum of colon cancer patients. The absolute amount of each of the two types of TAP was also similar: 14.69 2.88 and 18.29 3.85 mg ml-1, respectively. The amount of p53 autoantibodies was higher than those of p53 antigen, but the difference was not significant: 9.35 3.48 and 6. 19 3.87 mg/ml, respectively (p>0.05). A good correlation was found between the total amount of tumor-associated antigens (TAA) and the amount of p53 antigen (r=0.69), total amount of IgG and the amount of p53 autoantibodies (r=0.46), and between both forms of p53 protein (r=0.46). A high coefficient of regression was found between the total amount of TAA and the amount of p53 antigen (b=2.4). Relationships between Duke's stage in colon cancer and the serum levels of p53 protein were weak: 0.33 and -0.32 for p53 antigen and its autoantibodies, respectively. Serum determination of p53 autoantibodies has no advantage over the determination of p53 antigen. Both forms of p53 protein can be isolated with extremely high accuracy for the pathological diagnosis of cancer (87-93%). Specificity of the method was proved using of commercial p53 PAb OD1: the GFG columns with this antibody were able to isolate the same proteins which were isolated by GFG columns with anti-p53 IgG. Moreover, the isolation of p53 protein was performed with higher effectiveness using the GFG columns with entrapped anti-p53 IgG than those columns with commercial DO1 PAb.