Unchanged levels of interleukins, neopterin, interferon-gamma and tumor necrosis factor-alpha in cerebrospinal fluid of patients with dementia of the Alzheimer type.

Several histopathological studies suggest that amyloidogenesis in dementia of the Alzheimer type is accompanied by activated glia and glia-derived cytokines, leading to chronic, self-propagating, cytokine-mediated molecular and cellular reactions. As studies regarding inflammatory changes in cerebrospinal fluid of patients with dementia of the Alzheimer type has been inconclusive, we set up a prospective study to assess cerebrospinal fluid levels of interleukin-1beta, interleukin-6, interleukin-10, interleukin-12, soluble interleukin-2 receptor, interferon-gamma, tumor necrosis factor-alpha and neopterin in 20 patients with dementia of the Alzheimer type and 20 age- and sex-matched controls. Comparing both groups, no significant differences in concentrations and specific activities could be revealed. An additional 22 patients were included to enlarge the study population. No statistically significant differences were shown comparing patients (n=42) with the control group (n=20). We conclude that the immune-mediated inflammatory changes found in histopathological studies are not reflected in cerebrospinal fluid of patients with dementia of the Alzheimer type. Probably, cytokine production appears very localized in the central nervous system, not allowing representative detection in cerebrospinal fluid. Further studies assessing cytokine levels in various regions of central nervous system of patients with dementia of the Alzheimer type will be of interest to confirm this hypothesis.

A simple and rapid flow cytometric method to measure lymphocyte activation in HIV+ subjects. Diminished response to pokeweed mitogen in early disease.

It was our objective to investigate the effect of asymptomatic infection with HIV on the expression of lymphocyte activation markers after stimulation with mitogens. Whole blood cultures were made of HIV+ and HIV- subjects (29 asymptomatic HIV-1-infected subjects and 33 apparently healthy normal volunteers). At various times after stimulation with concanavalin A (Con A), anti-CD3 and pokeweed mitogen (PWM), the expression of activation markers (CD25 and HLA-DR) and the blastogenesis were quantified by flow cytometry. The flow cytometric quantification of the expression of activation markers and blastogenesis in whole blood cultures provided an easy and safe alternative to thymidine incorporation to assess lymphocyte responses in HIV+ subjects. Activation showed a tendency to be lower in the HIV+ subjects with all three stimulants. This difference with HIV- subjects was statistically significant only for stimulation with PWM after 4 days. Further investigations should be undertaken to show whether this functional impairment is related to disease progression and whether it can be influenced by effective therapy.

Acute renal infarction and heavy marijuana smoking.

The first case of acute renal infarction in a patient with heavy marijuana smoking is described. The patient had no concomitant previous medical history. There was no evidence of a primary or secondary hypercoagulable state. Underlying neoplasm was excluded. Recovery was associated with normalization of transaminases and lactic dehydrogenase but with a persistent triangular hypoechogenic area in the right kidney. The combination of marijuana-associated alterations in systemic blood pressure due to peripheral vasodilation, functional anemia and an adrenergic effect might have been the cause of the arteria renalis thrombosis in our patient, but the real underlying pathophysiological mechanism still remains unresolved.

Anticholinergic intoxication with commercially available thorn apple tea.

Two adolescents were admitted to the hospital with acute psychosis and peripheral signs of anticholinergic intoxication. Atropine intoxication due to drinking tea made from thorn apple (Datura stramonium) was diagnosed. After conservative treatment recovery was complete.

Orthodeoxia and platypnea in liver cirrhosis: effects of propranolol.

Chronic liver disease is well known to be associated with pulmonary abnormalities. Hypoxemia, clubbing, cyanosis and hyperventilation are common. The hypoxemia in cirrhotic patients has several causes: diffuse shunts due to intrapulmonary arteriolar vasodilatation, impaired hypoxic vasoconstriction, impaired matching of ventilation to perfusion, pleural effusions and diaphragmatic dysfunction. Because of gravity, shifting of blood to the dilated precapillary beds of the lung bases results in an increased hypoxemic dyspnea when the patient is in the upright position, also known as orthodeoxia and platypnea. It has only been described in 5% of the cirrhotic patients and has not been described in a Belgian refereed journal (Medline literature search 1983-Aug 1993). It should be considered in the initial differential diagnosis of hypoxemia in patients with liver cirrhosis and dyspnea. Measuring arterial blood gases in the lying and upright position can prevent further invasive investigations, and whole body nuclide scan with technetium-99m macroaggregated albumin can confirm the diagnosis. Standard therapy with spironolactone (Aldactone) can worsen the condition and we found no additional benefit of beta-antagonists (propranolol/Inderal) in the reduction of the shunt fraction, probably because the main reason for the shunting is precapillary vasodilatation. Since there are no anatomical porto-pulmonary shunts, surgery is also inappropriate. The only therapy consists of oxygen supplements and low dose diuretics in patients with edema.

The effect of a combined administration of ridogrel and ketanserin in patients with intermittent claudication.

After a 1-month placebo run-in phase, 27 patients with proven peripheral arterial obstructive disease participated in a double blind placebo controlled study and were divided in 3 groups, receiving either placebo, ridogrel 300 mg b.i.d. (a combined thromboxane synthase and receptor blocking agent) or a combination of ridogrel 300 mg b.i.d. and ketanserin 20 mg t.i.d. (a 5-HT2 serotonergic receptor antagonist) for a period of 1 month. In both active treatment groups, serum levels of thromboxane B2 decreased significantly to 3% of baseline. The levels of 6-keto-prostaglandin F1 alpha and prostaglandin F2 alpha increased two- to three-fold and levels of prostaglandin E2 6 times. Platelet aggregation induced by collagen and by U 46619, a thromboxane A2 mimetic, were significantly inhibited by both treatment regimen. Template bleeding times were significantly prolonged but plasma fibrinogen levels and the activated partial thromboplastin time were not affected with the active treatments. No such changes were seen with placebo. An inhibition of the serotonin-induced platelet aggregation was only seen in the ketanserin-treated group. In a 3-month open follow-up period during combined treatment with ridogrel and ketanserin in 22 patients, the effects on platelet function and prostanoids were maintained. The total duration of the walking distance on a treadmill improved significantly from 323 +/- 53 seconds to 399 +/- 48 seconds and the onset of claudication pain improved significantly from 121 +/- 29 seconds to 212 +/- 44 seconds, whereas the maximal drop of the post-exercise ankle/arm pressure gradient markedly and significantly improved from a control value of 0.38 +/- 0.05 to 0.51 +/- 0.05. These findings suggest that a combination of ridogrel and ketanserin may be of therapeutic value in the treatment of intermittent claudication.

The antihypertensive and cardiac hemodynamic effects of nebivolol.

Acute, subacute, and chronic treatment with nebivolol, a novel beta 1-selective adrenergic antagonist, significantly lowered systolic and diastolic blood pressure and heart rate in patients with essential hypertension. No orthostatism and bradycardia were reported. A comparison between a normal control group and 23 hypertensive patients revealed that the ratio between the preejection period (PEP) and the left ventricular ejection time (LVET) of the systolic time intervals (STI) was significantly increased in the hypertensive patients, owing to a prolongation of the PEPc (PEP corrected for heart rate). Treatment with nebivolol 5 mg once a day significantly improved the PEP/LVET, in acute conditions from 0.42 +/- 0.023 to 0.39 +/- 0.018, after one month of treatment from 0.40 +/- 0.013 to 0.36 +/- 0.013 and after one year of treatment from 0.41 +/- 0.012 to 0.36 +/- 0.010, owing to a significant shortening of the PEPc. There was no correlation between changes of blood pressure and changes of STI. Diastolic dysfunction is an early finding in hypertension and may well be reflected in the prolongation of the PEPc. The improvement of left ventricular performance, as measured with STI, suggests that treatment with nebivolol may favorably influence the underlying diastolic dysfunction and be of therapeutic value for hypertensive patients with left ventricular damage.

Comparative cardiac haemodynamics of bisoprolol, celiprolol, carvedilol and nebivolol in normal volunteers.

Nebivolol is a novel selective beta 1-adrenergic antagonist with an unusual haemodynamic profile. It improves left ventricular function in normals and in patients with a damaged left ventricle. We compared the cardiac effects of a 14-day treatment period with 10 mg o.d. of bisoprolol, 400 mg o.d. of celiprolol, 25 mg o.d. of carvedilol and 5 mg o.d. of nebivolol in a placebo-controlled crossover study in 7 volunteers with a mean age of 39 (range 30-53) years. Cardiac haemodynamics were assessed serially by means of systolic time intervals. The ratio of the preejection period to the left ventricular ejection time (PEP/LVET) was used as a indirect measure of left ventricular performance. The results show that the PEP/LVET is a very sensitive and reproducible index of left ventricular function. During treatment with placebo and bisoprolol no changes occurred; during treatment with celiprolol and carvedilol a significant but transient decrease of PEP/LVET occurred, and only during treatment with nebivolol a long-lasting and significant decrease of PEP/LVET occurred. With bisoprolol an increase of PEP and QS2c (total electromechanical systole) was observed, indicative of a negative inotropic effect. In conclusion, nebivolol, in contrast with both classical and vasodilating beta-blocking agents, substantially improves left ventricular function, possibly due to an improvement of diastolic function and left ventricular compliance, which may be of therapeutical value in the treatment of congestive heart failure.

Levamisole in the treatment of cancer: anything new? (Review).

Recently, levamisole combined with 5-FU was shown definitively to increase the survival of patients after surgery for colon cancer (9, 10). In the light of these findings the experimental and clinical findings with levamisole in the field of oncology are reviewed. The conclusion is reached that levamisole has proven activity, although its mechanism of action remains elusive. The progress that has been made in our understanding of immunology in general, the remarkable advance in experimental and diagnostic tools and the recent emergence of new indications of levamisole's interaction with immunosuppressive factors and interleukins all together warrant sufficient optimism to engage in a renewed clinical and experimental research effort. The outcome may be rewarding not only in terms of optimised treatment of patients with levamisole but also a more rational search for more potent successors may become feasible.

The effects of short-term treatment with levamisole on cytokines in volunteers and cancer-patients.

In search for clues to the potential immunomodulating mechanism of action of levamisole which might be used as monitoring parameters, we have determined a variety of cytokines in the peripheral blood of volunteers and carcinoma patients before and after a single or a 3-day-treatment with 150 mg/day. In cancer patients no changes could be detected 4 days after a 3-day-treatment course in the levels of TNF-alpha, IL-1beta, IL-2 or IL-6. In a placebo-controlled volunteer study the same treatment did not affect the levels of beta2-microglobulin, IL-1beta, IL-1alpha, IL-2 or IL-6. However, 24hr after the last treatment the concentration of neopterin was slightly but significantly increased and the concentration of soluble IL-2 receptors decreased. A single treatment failed to produce such an effect. It is suggested that the measurement of neopterin and soluble IL-2 receptors may provide useful information in future trials.

Comparison of the subacute hemodynamic effects of atenolol, propranolol, pindolol, and nebivolol.

In an observer-blind four-way crossover study, 7 healthy volunteers received in random sequence, one month apart, atenolol 100 mg od, propranolol (slow release) 160 mg od, pindolol 5 mg tid, and nebivolol 5 mg od for a period of seven days, followed by a single-blind placebo washout period of seven days. The decrease of peak exercise heart rate and systolic blood pressure was significant (p = 0.02) and comparable for the four drugs studied and varied between 15% and 23% for heart rate and between 15% and 20% for systolic blood pressure. Although no statistically significant difference was observed among the four drug regimens, the decrease of peak exercise heart rate was less pronounced with nebivolol than with the three reference beta-blocking agents. The ratio of the preejection period (PEPc) to the left ventricular ejection time (LVETc), an indirect measure of left ventricular performance, tended to increase with atenolol and propranolol and remained unchanged with pindolol. PEPc/LVETc progressively and significantly improved with nebivolol from a control value of 0.37 +/- 0.012 to 0.31 +/- 0.009 (p = 0.03) after seven days of treatment, owing to a decrease in PEPc and an increase in LVETc, suggestive of a combined effect both on preload and afterload. Postexercise LVETc, an index of the intrinsic positive inotropy of exercise, was significantly suppressed by atenolol, propranolol, and pindolol, but not during treating with nebivolol. These data suggest that nebivolol is a beta 1-selective adrenergic antagonist with an unusual hemodynamic profile, probably improving left ventricular compliance.

Hemodynamic effects of nebivolol in men: comparison of radionuclide angiocardiography with systolic time intervals.

In a subacute experiment the authors studied the effects of a fourteen -day treatment with nebivolol, 5 mg once a day, in 10 healthy male volunteers with a mean age of thirty-one, twenty-five to thirty-nine years, by comparing the results of the resting ratio of the preejection period (PEP) to the left ventricular ejection time (LVET), as measured by systolic time intervals (STI), with the results obtained by equilibrium radionuclide angiocardiography (ERNA), using technetium 99m-labeled autologous red blood cells as a marker. A submaximal treadmill exercise test performed before and during treatment demonstrated that nebivolol significantly (p less than 0.01) reduced peak exercise heart rate and systolic blood pressure from a mean value of 158 +/- 5.4 bpm to 131 +/- 4.3 bpm and from 171 +/- 4.9 mmHg to 144 +/- 4.5 mmHg respectively. The data from the STI and ERNA were calculated and analyzed independently by two observers. A highly significant (r = 0.8182, p = 0.0038) correlation was found between the changes of stroke volume (SV) and PEPc/LVETc during treatment with nebivolol. Furthermore end-diastolic volume significantly(p = 0.03) increased from a mean value of 177 +/- 10.1 ml to 198 +/- 6 ml and stroke volume significantly (p = 0.01) increased from 120 +/- 6.8 ml to 136 +/- 6.3 ml. Systemic vascular resistance tended to decrease from a mean value of 11.4 +/- 1.28 units to 10.6 +/- 1.10 units. No changes could be observed either in ejection fraction or in cardiac output.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacological and hemodynamic profile of nebivolol, a chemically novel, potent, and selective beta 1-adrenergic antagonist.

The pharmacological profile of nebivolol (N), a chemically novel beta-adrenergic antagonist, was assessed in investigations on isolated tissues, awake spontaneously hypertensive rats (SHR), closed-chest anesthetized dogs, and humans. In vitro, N was found to be a potent antagonist of beta 1-adrenergic receptors (A2 value, 5.8 X 10(-9) M) and only a weak beta 2-adrenergic antagonist (A2 value, 1.7 X 10(-6) M). The selectivity for the beta 1-adrenergic receptor was higher for N than for any of the reference compounds. In dogs--similarly with atenolol--N was more potent in blocking the isoprenaline (I)-induced increases in left ventricular performance than the I-induced decrease in arterial pressure. In dogs, as compared with propranolol, N (0.025 and 0.01 mg.kg-1 i.v.) increased cardiac output and stroke volume, lowered systemic vascular resistance, and had no significant effect on the variables related to left ventricular contraction. In contrast to other beta-adrenergic antagonists, N acutely lowered arterial blood pressure in SHR (1.25 mg.kg-1 i.p.) and in hypertensive patients (1 oral dose of 5 mg) for several hours. In healthy volunteers N (5 mg) lowered systemic vascular resistance during daily oral treatment and did not negatively affect left ventricular function. In conclusion, N is a potent and selective beta 1-adrenergic blocking agent with an interesting hemodynamic profile. In hypertensive subjects and SHR, a single dose lowers arterial blood pressure for substantial periods of time.

Subacute hemodynamic effects of nebivolol in man at rest and during exercise.

In a subacute experiment 7 apparently healthy volunteers received a daily oral dose of 5 mg nebivolol for seven days, followed by a seven-day washout period with placebo. From the first day during treatment with nebivolol, peak exercise heart rate and systolic blood pressure, as measured during a standardized submaximal treadmill exercise, significantly decreased by 15% and 19% respectively. A prolonged treatment for one week did not further increase the response of exercise heart rate and systolic blood pressure to nebivolol. However, the ratio of preejection period (PEPc) to left ventricular ejection time (LVETc), an indirect and valuable measure of left ventricular performance, progressively and significantly decreased during the seven-day treatment period with nebivolol from a mean value of 0.37 +/- 0.012 to 0.31 +/- 0.009. The improvement of systolic time intervals resulted from a shortening of the PEPc and a lengthening of the LVETc. At rest, heart rate did not change significantly with nebivolol, whereas both systolic and diastolic blood pressure gradually and significantly lowered. The postexercise LVETc significantly shortened during treatment with nebivolol, and this shortening was more pronounced after seven days of treatment. After discontinuation of treatment with nebivolol, all these effects persisted for more than thirty hours after the last intake and gradually returned to pretreatment values thereafter. From these data it appears that nebivolol effectively reduces blood pressure at rest and during exercise in healthy volunteers, beneficially influencing preload and afterload, as measured by systolic time intervals.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of ketanserin, a 5-HT2-receptor antagonist, on 5-hydroxytryptamine-induced irreversible platelet aggregation in patients with cardiovascular diseases.

Platelet aggregation in response to 5-hydroxytryptamine was investigated in 40 normal subjects, in 45 patients with acute myocardial infarction, and in 65 patients with peripheral arterial obstructive disease. It was found that of the 110 patients with cardiovascular disease, 40% had a biphasic irreversible platelet aggregation, whereas this phenomenon occurred in only 7.5% of the normal population. A double-blind placebo-controlled study further showed that a subacute treatment with ketanserin, a selective 5-HT2-receptor antagonist both on platelets and on vascular tissue, efficiently abolished the irreversible platelet aggregation in patients hyperreactive to 5-hydroxytryptamine. In an additional open study, including 10 patients with peripheral arterial obstructive disease, a chronic treatment with ketanserin 40 mg t.i.d. for a period of 3 months significantly suppressed the primary platelet aggregation to 5-HT at 2 X 10(-5) M and at 2 X 10(-6) M and significantly lowered the plasma beta thromboglobulin levels. Since 5-HT is a potent mediator of vasospasm, treatment with ketanserin might be of therapeutic value in atherosclerotic diseases, where platelet activation is thought to be involved.

Effect of ketanserin on the hyperreactivity of platelets to 5-hydroxytryptamine in patients with cardiovascular diseases.

Platelet aggregation in response to 5-hydroxytryptamine (5-HT) was investigated in 110 patients with cardiovascular diseases and in 40 age-matched control subjects. It was found that 40% of those patients had a biphasic irreversible platelet aggregation in response to 5-HT, whereas 92.5% of the control subjects responded with a weak reversible aggregation. A double-blind, placebo-controlled study, including 41 patients, showed that a subacute treatment with ketanserin significantly abolished platelet aggregation in patients hyperreactive to 5-HT. In an additional open study, including 10 patients with peripheral arterial obstructive disease, chronic treatment with ketanserin for a period of 3 months significantly suppressed the primary platelet aggregation to 5-HT at 2 X 10(-5) M and at 2 X 10(-6) M and significantly lowered the plasma beta-thromboglobulin levels.

Ketanserin and red blood cell sodium content in hypertension.

The sodium content of erythrocytes from patients with essential hypertension is increased. In a double-blind, placebo-controlled study, a 5-day treatment with ketanserin, a serotonergic antagonist lowered significantly the sodium content of the red blood cells (RBC). Ouabain induces an increase of sodium content of the RBC, which is paralleled by a decrease in RBC deformability. The ouabain-dependent fraction of RBC deformability is significantly reduced after a single oral dose of ketanserin. In vitro, serotonin (5-HT) decreases RBC deformability; this effect could be antagonized by ketanserin. These data might suggest a regulating role of 5-HT in transmembrane ion fluxes.