H. Verhaegen

pharmacological and Hemodynamic Profile of Nebivolol, * a Chemically Novel, Potent, and Selective β1-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.

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

Abstract 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-1 β , interleukin-6, interleukin-10, interleukin-12, soluble interleukin-2 receptor, interferon- γ , tumor necrosis factor- α 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.

Restoration of host defense mechanisms in man by levamisole.

Abstract Levamisole, a broad-spectrum anthelmintic, increased the delayed hypersensitivity skin reaction to tuberculin and to DNCB in about one third of the patients. Levamisole and the racemate tetramisole temporarily increased serum antibody titres in response to vaccination against influenza.

The Antihypertensive Effects of a Pure and Selective Serotonin-Receptor Blocking Agent (R 41 468) in Elderly Patients

In a first experiment, an acute intravenous administration of 10 mg R 41 468, a pure serotonin-receptor blocking agent with high selectivity for blood vessels and thrombocytes and devoid of central effects, dramatically reduced systolic and diastolic blood pressure in 23 elderly hypertensive patients. Heart rate and cardiac output remained virtually unchanged. In a second double-blind placebo-controlled cross-over study a highly significant decrease of systolic and diastolic blood pressure was obtained in 14 elderly hypertensive patients during an 8-day oral treatment with 40 mg t.i.d. of R 41 468. No serious side-effects were observed. An oral maintenance therapy with R 41 468 for 3 weeks showed a further reduction of blood pressure, resulting in a normalization of blood pressure, taking into account the advanced age of the patients. R 41 468 most probably acts by decreasing the venous capacitance bed constriction. Essential hypertension might be causally related to an impair ment of venous function, in which serotonin might be an important pressor factor.

The Rheological Effects of Cinnarizine and Flunarizine in Normal and Pathologic Conditions

From the Clinical Research Unit, St. Bartholomeus, Antwerp, Belgium. Cinnarizine and its difluoro derivative, flunarizine, are long-lasting polyvalent antagonists of vasoconstrictive agents.’ They selectively inhibit the calcium transfer to the depolarized vascular smooth muscle.2~3 Both drugs improve exercise tolerance in patients with peripheral obliterative disease’ and enhance blood flow of the lower limbs in both healthy subjects’ and patients with vascular disease. 6-9

PLACEBO-CONTROLLED DOUBLE-BLIND TRIAL OF KETANSERIN IN TREATMENT OF INTERMITTENT CLAUDICATION

Ketanserin, a selective serotonin (5-HT) antagonist at 5-HT2 receptors, was investigated in a 3-month, double-blind, placebo-controlled study in twenty patients with intermittent claudication. Blood-pressure ratio (thigh/arm), reactive hyperaemia measured with an ECG-triggered venous occlusion plethysmograph, blood filterability, and claudication distance on a treadmill progressively and significantly improved during ketanserin therapy, whereas no such changes occurred in the placebo group. Mean claudication distance improved by 140%; four of the eleven patients on ketanserin were able to keep walking beyond the time limit of the exercise test. The beneficial effect of ketanserin suggests that 5-HT may be involved in the pathogenesis of peripheral arterial obstructive diseases. In an experiment comparing blood-pressure ratio measured by doppler velocimetry and by plethysmography, the plethysmographic values rose during ketanserin therapy only at thigh level, which suggests an improvement in the collateral circulation.

Increase of serum complement levels in cancer patients with progressing tumors.

Complement levels (CH50, C3, C4 and C1q) were determined in sera of 90 healthy subjects and 200 cancer patients. Complement levels of cancer patients were significantly higher than those of the healthy subjects, but there was a stage‐linked increase of complement levels. Patients in remission had nearly normal complement levels, but patients with local tumor had increased complement levels, and a further increase was observed in patients with distant metastases. Treatment of these patients with radiotherapy or cytostatic drugs lowered the complement levels. At the terminal phase of the disease we also noted a drop in complement levels.

Histamine receptor-bearing peripheral T lymphocytes in patients with allergies

The effect of histamine on the capacity of T lymphocytes to form E rosettes was tested in 10 healthy subjects and in 13 patients with allergies. Histamine had no effect on the capacity of T lymphocytes to form E rosettes in healthy subjects, but significantly inhibited the E rosette formation of T lymphocytes in patients with allergies.

Purine nucleoside phosphorylase, a possible histochemical marker for T-cells in man

A procedure is described for the histochemical detection of purine nucleoside phosphorylase (PNP) activity in circulating lymphocytes of man. The number of PNP-positive cells, as evaluated on smears of Ficoll--Hypaque purified cells, correlated well with the number of E-rosette-forming cells of the same blood samples of healthy and diseased people with normal or abnormal numbers of E-rosettes. In healthy people, the number of PNP-positive cells was within the range of 70-80% of the total lymphocyte population, whilst the corresponding E-rosette-forming cells were scored between 60-75%. Patients with unusually low or high E-rosettes had equally low or high numbers of PNP-reactive cells. More substantial evidence for the presence of PNP activity in T-cells and not in B cells was gathered from experiments in which PNP activity and surface membrane immunoglobulins (SMIg) were simultaneously demonstrated on the same preparation. These results showed, on the one hand, that the bulk of lymphocytes that are reactive for PNP do not reveal SMIg and, on the other hand, that most Ig-bearing cells were unreactive for PNP.

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 (LVET c), an indirect measure of left ventricular performance, tended to increase with atenolol and propranolol and remained unchanged with pindolol. PEP c/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 β1-selective adrenergic antagonist with an unusual hemodynamic profile, probably improving left ventricular compliance.