Single-isomer beta-agonists.

A new generation of bronchodilators is being developed for acute asthma management-single-isomer beta-agonists. These drugs consist only of the active bronchodilatory isomer (eutomer); they do not have the inactive and potentially harmful isomer (distomer) that is present in marketed racemic beta-agonists. Clinical studies comparing the effectiveness of (R)-albuterol (levalbuterol) with racemic albuterol established a strong rationale for using single-isomer beta-agonists in place of the racemic mixture: reduced dosages provide equivalent bronchodilatory effects with fewer beta-mediated side effects. Higher dosages achieve superior bronchodilation in episodes of severe asthma and may reduce costs of emergency department treatment.

Dose-response evaluation of levalbuterol versus racemic albuterol in patients with asthma.

Albuterol, in all marketed forms, is sold as a racemate, composed of a 50:50 mixture of (R)- and (S)-isomers. Racemic albuterol and the single isomer version (R)-albuterol (levalbuterol) were compared in a randomized, double-blind, dose-ranging five-way crossover study in patients (n = 20) with mild persistent to moderate persistent asthma. Placebo, racemic albuterol (2.50 mg), or levalbuterol (0.31, 0.63, or 1.25 mg) were delivered as single, nebulized doses to 5 male and 15 female nonsmoking patients with asthma aged 18-50 years. Serial pulmonary function was assessed at 15-min intervals and mean time to onset of activity and duration of improvement of forced expiratory volume in 1 sec (FEV1) were measured. In addition, blood chemistries, electrocardiogram (ECG) readings, and patient subjective assessment of adverse symptoms were recorded. Levalbuterol was found to provide significant bronchodilatory activity and was well tolerated. Levalbuterol 1.25 mg provided the greatest increase and duration in FEV1 improvement, whereas racemic albuterol (2.50 mg) and levalbuterol 0.63 mg provided comparable effects. The lower doses of levalbuterol were associated with a less marked effect on heart rate and potassium than racemic albuterol or high-dose levalbuterol. These data suggest that 0.63 mg levalbuterol provides bronchodilation equivalent to 2.50 mg racemic albuterol with less beta-mediated side effects.

New millennium bronchodilators for asthma: single-isomer beta agonists.

Racemic beta2 agonists are composed of a 50:50 mixture of R and S isomers. The R isomer exhibits virtually all the bronchodilation, whereas the S isomers are generally considered inert. However, (S)-albuterol was shown to enhance bronchial reactivity to methacholine, eosinophil activation, and histamine-induced influx of fluid, proteins, and neutrophils into the airspaces. Actions such as these may compress the potency and foreshorten the duration of (R)-albuterol. Accordingly, pure (R)-albuterol provides bronchodilation at lower doses than racemate, allowing for fewer beta-adrenergic-mediated side effects. In addition, differential metabolism may allow for the progressive accumulation of (S)-albuterol. This logic is applicable to long-acting beta2 agonists: the therapeutically active (R,R)-formoterol is currently being developed in the United States, and preliminary results suggest rapid improvements in FEV1 with up to 24-hour duration of action. These combined observations with the R isomers of beta2 agonists suggest that potential improvements in therapeutic indices can be achieved with isomerically pure versions of existing racemic drugs.

Effects of S-salbutamol on human isolated bronchus.

A range of stimuli have been used to determine the effect of S-salbutamol on contractile responses of human isolated bronchus. Significant augmentation of contraction was evident during responses to histamine or LTC4 but responses to EFS, methacholine, bradykinin and capsaicin were not influenced and allergic bronchospasm was significantly impaired by prior exposure to S-salbutamol. Since R-salbutamol relaxes human isolated bronchus, the capacity of S-salbutamol to enhance contractile responses to histamine or LTC4 cannot be attributed to activation of beta2-adrenoceptors. It is concluded, therefore, that these effects of S-salbutamol represent distinct pharmacological actions of the distomer. It is also suggested that the capacity of S-salbutamol to augment contraction of airway smooth muscle may contribute to hyperreactivity towards spasmogens when racemic salbutamol is used for symptom relief in asthma and chronic obstructive pulmonary disease (COPD).

Clinical endoscopic evaluation of the gastroduodenal tolerance to (R)- ketoprofen, (R)- flurbiprofen, racemic ketoprofen, and paracetamol: a randomized, single-blind, placebo-controlled trial.

Ketoprofen, a nonsteroidal anti-inflammatory drug (NSAID) of the 2-arylpropionic acid class, causes gastroduodenal hemorrhages and erosions in 10-15% of patients. The (S)- enantiomer exhibits most of the anti-inflammatory properties, with concomitant gastrointestinal toxicity. The (R)- enantiomer, however, was recently found to have analgesic properties independent of prostaglandin inhibition. Seventy-two healthy male volunteers not receiving NSAIDs, alcohol, or anti-ulcer drugs, were enrolled in a randomized, investigator-blind, placebo-controlled trial to evaluate the gastroduodenal tolerance of (R)- ketoprofen 100 mg b.i.d., (R)- flurbiprofen 100 mg b.i.d., racemic ketoprofen 100 mg b.i.d., and paracetamol 1,000 mg b.i.d. Gastroduodenal endoscopies at baseline and after 2.5 days of dosing were used to detect newly occurring hemorrhages and erosions. Adverse events were also recorded. The incidence of submucosal hemorrhages was 4/16 in the (R)- ketoprofen group, 5/16 in the (R)- flurbiprofen group, 12/16 in the racemic ketoprofen group, 1/16 in the paracetamol group, and 1/8 in the placebo group. The incidence of erosions was 2/16 in the (R)- ketoprofen group, 4/16 in the (R)- flurbiprofen group, 10/16 in the racemic ketoprofen group, 0/16 in the paracetamol group, and 2/8 in the placebo group. The differences in hemorrhages and erosions among treatments were statistically significant (gastric hemorrhages P = 0.0008; duodenal hemorrhages P = 0.00062; gastric erosions P = 0.0004; duodenal erosions P = 0.0062, Kruskal-Wallis test). At 100 mg b.i.d., (R)- ketoprofen caused fewer gastroduodenal hemorrhages and erosions than racemic ketoprofen (P = 0.019, P = 0.0112, P = 0.0097, P = 0.0139 for gastric, duodenal hemorrhages and gastric, duodenal erosions, respectively). The difference between 100 mg b.i.d. (R)- ketoprofen and 100 mg b.i.d. (R)- flurbiprofen was not statistically significant. The dissociation between analgesic and anti-inflammatory properties for (R)- ketoprofen suggests that it may represent a unique analgesic with a favorable safety profile.

Preclinical enantioselective pharmacology of (R)- and (S)- ketorolac.

Many of the nonsteroidal anti-inflammatory drugs (NSAIDs) are marketed as racemic mixtures, composed of (R)- and (S)- enantiomers. Racemic NSAIDs are potent cyclooxygenase (COX) inhibitors only through the action of the (S)- enantiomers, as the (R)- enantiomers do not exhibit COX inhibition. However, the (R)- enantiomer of ketoprofen exhibits potent analgesic activity and minimal ulcerogenic potential. To extend these observations, we examined the (R)- and (S)- enantiomers of RS- ketorolac, (S)- ketorolac exhibited potent COX1 and COX2 enzyme inhibition, whereas (R)- ketorolac was > 100-fold less active on both COX subtypes. Both enantiomers did not affect norepinephrine or serotonin uptake sites, and nitric oxidase or lipoxygenase activities, nor did they demonstrate any affinity for opioid receptors (mu, delta, or kappa). In experimental models, (S)- ketorolac exhibited about 10-fold greater activity than (R)- ketorolac in the murine phenylquinone writhing model. In this model, morphine sulfate was effective at much lower doses, however, and neither (R)- nor (S)- ketorolac showed any morphine-sparing effect. In the rat gait test for analgesia in the foot paw after injection of brewers yeast suspension, neither (R)- nor (S)- ketorolac affected paw volume. However, both provoked changes in gait scores, the (S)- enantiomer being 30-fold more potent than the (R)- enantiomer. A similar reduction was observed with respect to ulcerogenic potential, measured by direct microscopic changes after test conclusion. These findings suggest that (R)- ketorolac may possess analgesic activity that is independent of COX inhibition and may be associated with reduced ulcerogenic potential compared to effects exhibited by (S)- ketorolac.

Sympathomimetic enantiomers and asthma.

Airways of asthma patients can become hyperresponsive to airway spasmogens following regular use of isoprenaline or beta 2-selective sympathomimetics. Hyper-reactivity that results from acute exposure of animals to these drugs is pre-empted by vagal section (a procedure which does not influence spasmolytic efficacy of sympathomimetics), is not diminished by antagonism of beta 2-adrenoceptors and is not associated with loss of responsivity of beta 2-adrenoceptors in the airways. Since activation, modulation, or blockade of beta 2-adrenoceptors does not determine this form of hyperreactivity, the possibility that distomers may induce hyperreactivity must be considered. Ocular and vascular responses to distomers of sympathomimetics have long been recognised and, more recently, comparable observations have been made for the airways. Thus, reactivity of guinea-pig airways to spasmogens was increased following exposure to S-isoprenaline, S-salbutamol, or S-terbutaline and exposure to S-isoprenaline or S-salbutamol can intensify symptoms in asthmatics. Regular exposure to the racemate, especially during or following an allergic reaction, predisposes to expression of hyper-reactivity, which is nullified, acutely, by the eutomer. These observations imply that biological effects of sympathomimetic distomers may contribute to morbidity and mortality in asthma patients.

The pursuit of precision pharmaceuticals: divergent effects of beta2 agonist isomers.

Beta2 agonists are the most commonly used treatment for acute bronchoconstriction. However, during regular use there is a progressive decline of protective efficacy of bronchodilators. This progressive decline has long been considered anomalous because with short-acting beta agonists, there is no corresponding change in bronchodilator efficacy. Airway hyper-responsiveness is itself a feature of asthma and there maybe however, there may be an increase in airway hyper-responsiveness following regular use of beta2 agonist. Airway hyperresponsiveness could diminish the capacity of beta agonists to protect from or result in paradoxical bronchospasm and there effects of racemic salbutamol. There have been reports of increased morbidity and mortality associated with excessive use of beta(2) agonists. As all beta agonists used clinically are racemates composed of 1:1 mixtures of R and S isomers, conducted on the possible involvement of the isomers in hyper-responsiveness. Hyper-responsiveness cannot be attributed to the R isomer, whose capacity to activate beta adrenoceptors will nullify this effect. In contrast, extensive evidence indicated that the S isomer might cause hyper-responsiveness and potential airway inflammation. Further, the S isomer shows a propensity to activate human eosinophils and alter muscarinic M(2) receptor functions. The S isomer, which makes no contribution to therapeutic efficacy and may exacerbate asthma, might therefore be excluded from asthma therapy.

Levalbuterol hydrochloride.

Racemic salbutamol (racemic albuterol) ameliorates symptoms of asthma by activating beta-adrenoceptors on nerve, smooth muscle and inflammatory cells within the airways. Racemic salbutamol comprises equal proportions of 2 isomers: (S)-salbutamol and (R)-salbutamol, with the latter being exclusively responsible for activation of beta-adrenoceptors. Accordingly, within racemic salbutamol it is (R)-salbutamol that efficiently relieves obstruction of asthmatic airways and affords highly effective protection from bronchoconstrictor stimuli, including allergens. During regular use of racemic salbutamol, there is a progressive decline of protective efficacy and a corresponding intensification of airway responsiveness. This decline is largely absent during regular use of (R)-salbutamol. Consequently, bronchodilator responses to sub-maximal doses of (R)-salbutamol exceed responses to the equivalent dose of (R)-salbutamol given as the racemate. For example, in asthmatics with baseline FEVs

Therapeutic advantages of third generation antihistamines.

A third generation of antihistamines is emerging for the treatment of allergic rhinitis and chronic urticaria. First generation antihistamines are among the most widely used drugs in the world, and provide symptomatic relief from allergies and the common cold to millions of patients, mainly in OTC combination preparations. Their full potential is limited by the sedation caused by their effects on histamine receptors in the brain. Second generation antihistamines (terfenadine, astemizole, loratadine and cetirizine), which block peripheral H1 receptors without penetrating the blood-brain barrier, were developed and introduced from 1981 onwards to provide comparable therapeutic benefit without the CNS side-effects. Although largely successful in this goal, terfenadine and astemizole were found to cause potentially serious arrhythmias when plasma concentrations became elevated subsequent to impaired metabolism. It was established that the cardiac toxicity was mainly due to the parent drugs. As active metabolites could account for most of the clinical benefit, the goal for the third generation of antihistamines became to develop therapeutically active metabolites that were devoid of cardiac toxicity. The first of these drugs, fexofenadine (the active metabolite of terfenadine), was approved in July 1996, after an unusually rapid development programme. Its introduction set a new standard of safety that led the FDA to request the withdrawal of terfenadine in 1997 on the grounds that a safer version of an equivalent drug was now available. Norastemizole and descarboethoxy loratadine, the metabolites of astemizole and loratadine, respectively, are also in clinical development. These offer comparable or superior clinical benefits.

Effect of enantiomeric forms of albuterol on stimulated secretion of granular protein from human eosinophils.

We studied the effect of R-, S- and R,S-albuterol in inhibiting the eosinophil peroxidase (EPO) secretion caused by 10(-10) to 10(-6) M formyl-met-leu-phe + 5 micrograms/ml cytochalasin B (FMLP/CB) in non-allergic and allergic subjects. Total RAST score obtained for allergic subjects was 4.12 +/- 0.21 vs 0.36 +/- 0.17 for non-allergic subjects (P < 0.0001). Stimulated EPO secretion was comparable in allergic [2,051 +/- 567 ng/10(6) eosinophils (eos)] and non-allergic subjects [2,337 +/- 488 ng/10(6) eos (P = NS)]. At all concentrations used, both R- and R,S-enantiomers caused comparable (27-32%) inhibition of FMLP/CB stimulated secretion of EPO in allergic and non-allergic subjects. Pretreatment with S-albuterol caused no augmentation of EPO secretion in either allergic (115 +/- 34.6%) or non-allergic subjects (114 +/- 23.7%) subjects, and there was no significant difference in secretion caused by FMLP/CB alone in either experimental group. Similar results were obtained for subjects stratified according to serum IgE concentration. Our data demonstrate that both R- and R,S-albuterol are equivalently effective in inhibiting stimulated secretion of EPO in both normal and allergic subjects and that there is no paradoxical augmenting effect of S-albuterol in stimulated eosinophil secretion.

Preclinical pharmacology and possible mechanism of action of the novel antitumor agent 5-(4'-piperidinomethylphenyl)-2,3-dihydroimidazo [2,1-a]isoquinoline.

SDZ 62-434 (CAS 115621-95-9, 5-(4'-piperidinomethylphenyl)-2,3-dihydroimidazo [2,1-a]isoquinoline dihydrochloride), a member of a novel class of antitumor agents, exhibited direct and macrophage-induced cytotoxicity against a variety of murine tumor cell lines. It is more effective than edelfosine in increasing survivors and reducing tumor volume in the oral mouse Meth A fibrosarcoma model. Preliminary studies suggest that an undefined cytotoxic effect, macrophage activation and possible effects on signal transduction may account for its antitumor mechanism of action. SDZ 62-434 is currently in Phase I clinical trials as a potential antitumor agent.

Experimental therapeutics and clinical studies in (re)stenosis.

Restenosis is defined functionally as loss of luminal vessel patency following various methods of interventional cardiology, but ultrastructurally, it represents a wound healing response that involves smooth muscle migration, proliferation and matrix deposition at the site of injury. Currently, despite intensive experimental and clinical studies, there are no therapeutic agents that are able to suppress pharmacologically the clinical restenosis. Ultrastructural pathology and animal modeling have played a pivotal role in defining new experimental therapies and rationales for clinical trials. However, concerns regarding the lack of suitable animal models persist and of the many compounds reported efficacious preclinically, none have demonstrated clinical benefit in preventing restenosis. Animal modeling studies now include the use of true restenosis studies, which may be more clinically relevant and pharmacologically predictive of clinical performance.

Antitumor activity of 5-aryl-2,3-dihydroimidazo[2,1-a]isoquinolines.

A series of 5-aryl-2,3-dihydroimidazo[2,1-a]isoquinolines previously reported to be platelet activating factor (PAF) receptor antagonists were evaluated for potential antitumor activity. Several compounds, such as the 5-(4'-tert-butylphenyl) (65), 5-[4'-(trimethylsilyl)phenyl] (69), and 5-(4'-cyclohexylphenyl) (71) analogs showed very good cytotoxicity against several tumor cell lines. 5-[4'-(Piperidinomethyl)phenyl]-2,3-dihydroimidazo[2,1- a]isoquinoline (SDZ 62-434, 53) was more effective on a milligram per kilogram basis than the clinical cytostatic agent edelfosine (1) in increasing survivors and decreasing tumor volume in the oral mouse Meth A fibrosarcoma assay. It was selected for further development and is currently in phase I clinical trials in cancer patients.

Antitumor activity of a piperidine phospholipid.

A piperidine phospholipid ((+/-)-2-[hydroxy] [1-octadecyloxycarbonylpiperidin-3-yl]methoxy-phosphinyl] oxy]-N,N,N, trimethylethaniminium hydroxide inner salt, SDZ 62-826) has been prepared that exhibited weak direct cytotoxicity and strong macrophage-induced cytotoxicity in vitro against a variety of murine and one human tumor cell lines. This compound was found to be as effective as ET-18-OCH3 and SRI 62-834, phospholipids with both strong direct and macrophage-induced cytotoxicity, in increasing survivors and reducing tumor volume when given either orally or intravenously in the mouse MethA fibrosarcoma model. These findings suggest that the macrophage-induced cytotoxicity exhibited by ET-18-OCH3 and other phospholipids may play an important role in this tumor model.