CDP571, a humanized antibody to human tumor necrosis factor-alpha: safety, pharmacokinetics, immune response, and influence of the antibody on cytokine concentrations in patients with septic shock. CPD571 Sepsis Study Group.

OBJECTIVES: To determine the safety of a "humanized" antibody to human anti-tumor necrosis factor-alpha (TNF-alpha) in patients with septic shock, and to examine the pharmacokinetics, immune response, and influence of the antibody on cytokine concentrations in this patient group. DESIGN: Prospective, randomized, placebo-controlled, phase II multicenter clinical trial, with escalating doses of a fully humanized anti-TNF-alpha antibody (CDP571). SETTING: Seven academic intensive care units in Europe. PATIENTS: Forty-two patients with rapidly evolving septic shock who received CDP571 in addition to standard supportive care. INTERVENTIONS: Patients received intravenously either placebo or one of four single doses of CDP571: 0.1, 0.3, 1.0, or 3.0 mg/kg. MEASUREMENTS AND MAIN RESULTS: The humanized anti-TNF-alpha antibody was well tolerated. The overall all-cause 28-day mortality rate was 62%. Mortality rate was similar in the placebo and treatment groups, except that all six patients who received 0.3 mg/kg of CDP571 died within 7 days. This outcome, which was not dose-related, is consistent with the poorer prognostic characteristics of this group at baseline. The peak CDP571 concentrations and area under the curve increased proportionately with the dose. The low level of the immune response detected had little effect on the ability of circulating CDP571 to bind TNF-alpha and on the pharmacokinetics of the antibody. An abrupt reduction in circulating TNF-alpha concentration was observed 30 mins after CDP571 administration at all active dosage levels. While interleukin-1 beta and interleukin-6 plasma concentrations decreased with time in all dosage groups, these cytokine concentrations decreased more rapidly during the initial 24 hrs in the treatment groups than in the placebo group. CONCLUSIONS: The humanized anti-TNF-alpha antibody, CDP571, is well tolerated and able to cause a dose-dependent reduction in circulating TNF-alpha concentrations in patients with septic shock. Further studies are needed to determine the efficacy of this antibody to improve the survival rates of critically ill patients with severe sepsis.

The effect of a peptide aldehyde reversible inhibitor of elastase on a human leucocyte elastase-induced model of emphysema in the hamster.

The peptide aldehyde Ro 31-3537, N alpha-(1-adamantanesulphonyl)-N epsilon-(4-carboxybenzoyl)-L-lysyl-L-alanyl-L- valinal, is a reversible competitive, hydrophilic, specific inhibitor of elastase. Its Ki against human leucocyte elastase is 6 x 10(-8) M. The effect of this compound has been studied on a model of emphysema in the hamster induced by multiple sequential intratracheal doses of human leucocyte elastase. Concomitant intratracheal dosing of 200 micrograms of inhibitor with the enzyme significantly reduces lung damage as measured by quasi-static lung compliance and by histological assessment of the emphysema.

Anti-inflammatory effects of synthetic retinoids may be related to their immunomodulatory action.

The effects of retinoids have been studied in a model of delayed-type hypersensitivity using the T-cell-dependent antigen, methylated bovine serum albumin to elicit inflammation in the hind paws of mice. A number of synthetic retinoids, including etretinate and arotinoids, showed a marked anti-inflammatory action in this model. Using differential dosing schedules, the anti-inflammatory effect of retinoids was clearly distinguished from conventional cyclooxygenase inhibitors. By screening a number of synthetic retinoids, structure-activity relationships for this effect can be deduced.

Ketotifen: current views on its mechanism of action and their therapeutic implications.

The mechanism of action of ketotifen in the prevention of bronchial asthma is discussed, the pathogenesis of the disease itself being taken as a starting point. The following biological effects of ketotifen may be relevant to its therapeutic activity: the inhibition of release of myotonic mediators, leukotrienes in particular, the inhibition of slow reacting substances-induced bronchoconstriction in vivo, calcium antagonistic properties, and the prevention or reversal of decreased beta-adrenoceptor sensitivity. In asthmatic patients the prevention of bronchospasm due to mediator release and a progressive reduction of bronchial hyperreactivity are the major consequences of these properties.

Propranolol-induced airway hyperreactivity in guinea-pigs.

In anaesthetized, spontaneously breathing guinea-pigs, enhanced bronchoconstrictor responses (increases RL) to histamine were measured following intravenous injection of practolol, (+/-)-propranolol, (+)- and (-)-propranolol. Propranolol enhanced not only histamine- but 5-hydroxytryptamine (5-HT)-induced bronchoconstrictions and its effects lasted up to 2 h. This increased airway sensitivity was not due to beta-adrenoceptor blockade because: (a) similar effects were produced by racemic propranolol and its two isomers (+)- and (-)-propranolol and (b) whilst equal doses of (+/-)- and (+)-propranolol produced the same potentiation of histamine bronchoconstriction, only (+/-)-propranolol also caused a measurable beta-adrenoceptor blockade in the airways. The enhanced histamine- and 5-HT-induced bronchoconstrictions were antagonized by the leukotriene antagonist FPL 55712 and by the lipoxygenase/cyclo-oxygenase inhibitor BW755c. The results demonstrate that endogenously released leukotrienes can produce not only a direct bronchospasm but may enhance the effects of other bronchoconstrictor agents. The relevance of this leukotriene-mediated hyperreactivity to the non-specific airway hyperreactivity seen in asthmatics is discussed.

beta-Adrenergic tachyphylaxis in the rat and its reversal and prevention by ketotifen.

A strong, long-lasting and reproducible tachyphylaxis was produced in rats by implantation of osmotic minipumps delivering isoprenaline continuously. The degree of tachyphylaxis was determined by measuring the inhibitory effect of isoprenaline on the passive cutaneous anaphylaxis (PCA). One dose of ketotifen given 1 h before the PCA test reversed this in vivo tachyphylaxis, as did dexamethasone given 24 h earlier. Implantation of a second minipump containing ketotifen prevented the development of tachyphylaxis. Weak tachyphylaxis was induced in guinea-pig trachea in vitro by incubation with a high concentration of isoprenaline, the effect being estimated by measuring the relaxation of carbachol-contracted trachea. Ketotifen partially restored the sensitivity of the trachea but this was considered to be a direct potentiation of isoprenaline effects rather than a reversal of tachyphylaxis since the same effect was seen in non-pretreated trachea. It is thought that the reversal of experimental beta-adrenergic tachyphylaxis by ketotifen could have implications for its use in the prophylactic treatment of asthma.

A comparison of the bronchoconstrictor and beta-adrenoceptor blocking activity of propranolol and acebutolol.

The bronchoconstrictor and beta-adrenoceptor blocking activity of (+/-)-propranolol, acebutolol and two of its analogues were compared in a group of littermate rats. Whilst the analogues of acebutolol had similar bronchoconstrictor potency to propranolol, acebutolol had considerably less activity. No correlation could be found between the degree of bronchoconstriction produced by the four drugs and their beta-adrenoceptor blocking activity in the airway smooth muscle. Acebutolol and its analogues show a wide properties could be related to the production of bronchospasm.

Investigation of the mechanism of propranolol-induced bronchoconstriction.

1 Dose-related increases in airways resistance (Raw) and decreases in dynamic lung compliance (Cdyn) were recorded in guinea-pigs and rats following intravenous injection of propranolol and of the cardioselective beta-adrenoceptor blocking drugs, atenolol and practolol. 2 The bronchoconstriction reached a peak in 2 to 4 min and subsided within 15 min. Repeated injections caused identical responses in the airways. 3 The isomer (+)-propranolol, which has only weak beta-adrenoceptor blocking activity, produced identical responses when given alone or when given after a dose of the racemate, sufficient to cause measurable beta-adrenoceptor blockade in the lungs. 4 After the initial bronchospasm had subsided, the beta-adrenoceptor blocking drugs and the isomer, (+)-propranolol, produced potentiation of the bronchoconstrictor effects of 5-hydroxytryptamine and histamine. 5 Both the bronchospasm and the potentiation occurred in adrenal demedullated rats. 6 The results indicate that the bronchoconstrictor effects of these drugs are unrelated to beta-adrenoceptor blockade in the airway smooth muscle.