Reduction of side-effects from ultrarush immunotherapy with honeybee venom by pretreatment with fexofenadine: a double-blind, placebo-controlled trial

BACKGROUND: Immunotherapy with Hymenoptera venoms is highly effective but causes allergic side-effects frequently, especially when honeybee venom is used. Therefore, our objective was to investigate the effect of pretreatment with the antihistamine fexofenadine on the incidence of allergic side-effects during ultrarush immunotherapy with bee venom. METHODS: In a double-blind, placebo-controlled trial, 57 patients with a history of systemic allergic reactions to honeybee stings and positive diagnostic tests (skin tests, serum specific IgE to honeybee venom) were investigated. Bee venom immunotherapy was started with an ultrarush protocol and patients were randomized to pretreatment with either fexofenadine 180 mg or placebo on days 1, 8, 22, and 50 of the protocol. Local and systemic allergic side-effects were registered. RESULTS: Fifty-four patients completed the study, 28 on fexofenadine and 26 on placebo pretreatment. On day 1, large local reactions were significantly reduced in both extension and duration by fexofenadine pretreatment (P<0.025). Systemic allergic side-effects on the whole were not reduced. However, the symptoms pruritus, urticaria, and angioedema occurred less frequently with fexofenadine (P<0.05). CONCLUSIONS: Pretreatment with fexofenadine during venom immunotherapy reduces local allergic reactions and generalized symptoms of the urticaria and angioedema type.     

Hemodynamic Conditions Alter Axial and Circumferential Remodeling of Arteries Engineered <Emphasis Type="Italic">Ex Vivo</Emphasis>

We previously demonstrated that growth and remodeling was stimulated in arteries elongated ex vivo using step increases in axial strain. Viability and vasoactivity were similar to fresh arteries, however there was a substantial decrease in the ultimate circumferential stress. To test the hypothesis that the subphysiological perfusion conditions (i.e., low pressure and flow) previously used caused the reduction, arteries were subjected to the identical elongation protocol (50% increase over 9 days) while being perfused with physiological levels of flow, viscosity and pulsatile pressure. A significant increase in unloaded length was achieved by elongation under both perfusion conditions, although the increase was less under physiological (7 ± 1%) than under subphysiological conditions (19 ± 2%, p < 0.005). When length at physiological stress was estimated using mechanical testing data the values were similar. The ultimate circumferential stress of arteries elongated under physiological conditions was increased (33%), whereas the ultimate axial stress was decreased (50%) as compared with arteries elongated under subphysiological conditions. Elongated arteries under both perfusion conditions showed significant increases in proliferation and collagen mass, and similar viability and appearance to fresh arteries. These data suggest that there is substantial cross-talk between perfusion conditions and axial strain that modulates arterial remodeling and length.     

Modulation of Event-Related Potentials by Word Repetition: The Effects of Inter-Item Lag

The modulation of event-related potentials by word repetition was investigated in two experiments. In both experiments, subjects responded to occasional nonwords interspersed among a series of words. A proportion of the words were repetitions of previously presented items. Words were repeated after 0 or 6 intervening items in Experiment 1 and after 6 or 19 items in Experiment 2. Event-related potentials to repeated words were characterised by a sustained, widespread positive-going shift with an onset of approximately 300 ms. This effect did not vary significantly as a function of lag in either experiment. When words were repeated immediately, this repetition-evoked positive shift was preceded by a transient negative deflection (onset ca. 200 ms) which was absent in event-related potentials to words repeated at longer lags. These results suggest that the modulation of event-related potentials by word repetition is influenced by at least two processes. One of these processes acts relatively early during the processing of a repeated word, but subsides rapidly as inter-item lag between first and second presentations increases. The second process occurs later in time, but is considerably more robust over variations in inter-item lag.     

Influence of food on the intravenous and oral dose kinetics of propranolol in the dog

The intravenous and oral dose kinetics of propranolol were studied in the dog both in a fasted state and immediately after a meal consisting of 100 g of cooked beef liver. Fifty Ci of³H-propranolol was administered intravenously simultaneously with a 40-mg oral dose of unlabeled propranolol. Plasma³H-propranolol was measured by specific extraction and liquid scintillation spectrometry, and unlabeled plasma propranolol was determined by gas chromatography-mass spectrometry. Feeding significantly reduced (25%) the elimination half-life and increased (52%) the systemic clearance of intravenous propranolol. The increase in the systemic clearance of propranolol after feeding was mostly due to an increase (60%) in apparent hepatic blood flow, which appeared to remain elevated for 5–7 hr. The meal had no influence on the apparent volume of distribution or plasma binding. Feeding did not affect the area under the concentration-time curve of oral propranolol, but significantly delayed the rate of oral propranolol absorption, shifting the time to reach peak plasma levels from 60 to 158 min. The results of this study suggest that feeding alters the disposition of propranolol in the dog by producing a sustained increase in hepatic blood flow.This work was supported by National Institute of Health grants GM 07534, GM 20387, and HL 29566.     

The temperature dependence of derivative ultraviolet absorption spectra

The effects of variation of temperature in the range 0 degrees -40 degrees C on the zero and second derivative ultraviolet absorption spectra of ten compounds have been investigated. When the temperature of the solutions was increased, most of the substances showed a linear reduction of maximum absorbance (A(max)), with temperature coefficients of -0.07 +/- 0.03% per degree. The second derivative amplitudes of all the substances were reduced, with temperature coefficients (-0.1 to -0.5% per degree) that bore no significant relationship to those of the corresponding A(max) values. These effects on the extrema of the derivative spectra are explained by the small reduction in curvature at the corresponding wavelengths of the fundamental spectra, that occurs with increasing temperature. The precise and accurate assay of substances by derivative UV spectrophotometry requires that the temperatures of the standard and sample solutions are identical at the time of measurement.     

Acute systemic and renal haemodynamic effects and long-term antihypertensive action of cadralazine in patients pretreated with β-blockers and diuretics

Summary The antihypertensive effects of the hydralazine-related compound cadralazine (2-{3-[6-(2-hydroxypropyl)ethylamino]pyridazinyl}ethyl carbazate, ISF 2469), were investigated in 16 patients with primary hypertension concurrently treated with -blockers and diuretics. The protocol included a double-blind placebo controlled haemodynamic evaluation after the first tablet and two 4-week double-blind placebo controlled cross-over periods followed by an open evaluation during 2 months. Cadralazine induced a moderate, prolonged fall in blood pressure that was associated with vasodilatation and slight increases in cardiac output (dye-dilution) and heart rate. Renal plasma flow (PAH) and glomerular filtration rate (⁵¹Cr-EDTA) were not significantly influenced, but the filtration fraction was reduced. Plasma concentrations of noradrenaline and adrenaline rose, whereas plasma renin activity was unchanged. The haemodynamic parameters were not correlated with the plasma concentrations of cadralazine. During chronic cadralazine treatment the supine blood pressure was significantly lower than during the double-blind placebo phase (160/93 vs 174/102 mmHg). The compound was generally well tolerated but the body weight increased slightly (1.1 kg), probably because of fluid retention. Several patients who had previously experienced side effects with hydralazine, including one with hydralazine-syndrome, tolerated cadralazine well. This suggests that cadralazine does not cross-react with hydralazine.     

Pharmacokinetics and effects on blood pressure of a single oral dose of milrinone in healthy subjects and in patients with renal impairment

Summary Milrinone, a new, nonglycosidic inotropic agent with peripheral vasodilating properties, was given as a single oral 5 mg dose to 7 healthy subjects, 7 patients with moderate renal impairment (CRI I, creatinine clearance 30–63 ml/min) and 7 patients with severe renal impairment (CRI II, creatinine clearance 9–29 ml/min). All except one of the patients with renal impairment had hypertension. The mean urinary recovery of milrinone was 82% in healthy subjects, the renal clearance was 288 ml/min and the plasma half-life (t_1/2) was 0.94 h. In CRI the mean plasma t_1/2 was prolonged (CRI I 1.78 h, CRI II 3.24 h). There was a significant linear relationship between creatinine clearance and the elimination rate constant, and between creatinine clearance and the renal clearance of milrinone. During the study day there was a tendency to a decrease in supine BP from 1 to 6–8 h after dosing, with the maximal decrease at 2–3 h (healthy subjects 118/71107/56, CRI 159/95136/79 mmHg). The same degree of change was seen in standing BP. A slight rise in standing HR was seen from 2–6 h after dosing. Changes in BP and HR are difficult to evaluate since the study was not placebo-controlled.The plasma elimination rate of milrinone was decreased in CRI and dose adjustment may be necessary. Placebo-controlled studies of milrinone in hypertensive patients would be required to validate its possible antihypertensive effect.     

The β2-adrenoceptor antagonist CGP 20712 A unmasks β2-adrenoceptors activated by (−)-adrenaline in rat sinoatrial node

Summary The role of sinoatrial ₁- and ₂-adrenoceptors mediating positive chronotropic effects of (–)-adrenaline and (–)-noradrenaline was investigated in rat right atria. Concentration effect curves for (–)-adrenaline, but not for (–)-noradrenaline, became biphasic in the presence of the ₁-adrenoceptors antagonist CGP 20712 A. The curves for (–)-adrenaline in the presence of 300 nmol/l CGP 20712 A (equivalent to 1,000 times its K _B, K _B=0.3 nmol/l for ₁-adrenoceptors) comprise a high-sensitivity component that saturates at 1/4 of maximum effect, and a low sensitivity component. The high-sensitivity component is blocked by the ₂-adrenoceptor-selective antagonist ICI 118,551. These results are consistent with an involvement in the rat of both ₁-adrenoceptors (to a major extent) and ₂-adrenoceptors [only at high (–)-adrenaline concentrations] in the positive chronotropic effects of (–)-adrenaline. (–)-Noradrenaline appears to activate mostly rat sinoatrial ₁-adrenoceptors.     

Dose-dependent impairment in the performance of a go-no go successive discrimination by chlordiazepoxide

After learning a light-cued, go-no go successive discrimination to criterion, male Sprague-Dawley rats received 0, 5, or 10 mg/kg chlordiazepoxide on six performance sessions, followed by two drug-recovery (saline) sessions. Chlordiazepoxide impaired discrimination performance in a dose-dependent manner, with animals in the 5 mg/kg dose condition demonstrating tolerance to the drug after two performance sessions. The degree of discrimination impairment in both drug dose conditions paralleled an increase in responding during no-go phases of the performance task. These findings are consistent with a disinhibitory hypothesis of performance impairment and suggest that CDP-drugged animals have difficulty in withholding incorrect responses.These data were presented at the Annual Meeting of the Psychonomic Society, San Antonio, Texas, 1984     

Stretched attend posture,a non-social form of ambivalence,is sensitive to a conflict-reducing drug action

Based upon the ethological element stretched attend to a conspecific, which reflects ambivalence between approach and avoidance in a social context, a simple, non-social behavioral method for studying conflict behavior in mice was investigated. Thus, stretched attend posture (SAP) and other behavioral acts were measured in untreated or drug-treated mice which were individually placed on a perforated platform previously rubbed with foreign male urine and boluses. In naive, untreated mice, the occurrence of SAP was partly housing- and lighting-dependent. After repeated exposure to the test situation, untreated mice showed less SAP, whereas static behavior (immobility and activity at rest) was increased. After single oral treatment with diazepam, clobazam or phenobarbital, SAP was reduced, whereas static behavior or going forwards in SAP was increased. Chlorpromazine and imipramine did not influence SAP. In naive mice, single IP injection of pentylenetetrazol did not significantly increase SAP. The similarity in the behavioral response between experienced, untreated mice and naive animals treated with diazepam, clobazam, or phenobarbital suggests that drug-treated mice behaved as if they were already familiar with the test situation. The latter drug-induced changes are consistent with data obtained in animal models which are based upon the measurement of behavioral inhibition. Under the present test conditions, pentylenetetrazol did not show anxiogenic properties. Nevertheless, the SAP test, based primarily on the measurement of the ambivalence element, offers a simple procedure for examining the conflict-reducing properties of drugs, dispensing with the need of noxious stimuli or prior training.Some of these results were presented at the 15th Annual USGEB/USSBE Meeting in Fribourg, Switzerland (17–18 March 1983) and, published in abstract form in Experientia (1983) 39(6):681–682