Salbutamol misuse or abuse with fatal outcome: A case-report

Salbutamol is a short-acting agonist of the β2 adrenergic receptors sometimes misused or abused, which can result in various cardiovascular adverse effects. We report one case of fatal salbutamol misuse or abuse in a 36-year-old poorly controlled female asthmatic patient with a past medical history of alcoholism and a recent smoking cessation. She died shortly after hospital admission following acute dyspnea and sudden collapse at home. Toxicological analyses evidenced salbutamol overdose, and necropsy showed acute lung edema and marked dysplasia of the right ventricle and revealed the patient was pregnant. The involvement of an initial disorder of the ventricular rhythm leading to cardiac failure is suggested by the presence of several combined pro-arrhythmogenic factors, such as arrhythmogenic right ventricle dysplasia, hypoxemia related to bronchospasm and salbutamol overdose.

Immunogenicity, toxicology, pharmacokinetics and pharmacodynamics of growth hormone ligand–receptor fusions

A fundamental concern for all new biological therapeutics is the possibility of inducing an immune response. We have recently demonstrated that an LR-fusion (ligand–receptor fusion) of growth hormone generates a potent long-acting agonist; however, the immunogenicity and toxicity of these molecules have not been tested. To address these issues, we have designed molecules with low potential as immunogens and undertaken immunogenicity and toxicology studies in Macaca fascicularis and pharmacokinetic and pharmacodynamic studies in rats. Two variants of the LR-fusion, one with a flexible linker (GH–LRv2) and the other without (GH–LRv3), were tested. Comparison was made with native human GH (growth hormone). GH–LRv2 and GH–LRv3 demonstrated similar pharmacokinetics in rats, showing reduced clearance compared with native GH and potent agonist activity with respect to body weight gain in a hypophysectomized rat model. In M. fascicularis, a low level of antibodies to GH–LRv2 was found in one sample, but there was no other evidence of any immunogenic response to the other fusion protein. There were no toxic effects and specifically no changes in histology at injection sites after two repeated administrations. The pharmacokinetic profiles in monkeys confirmed long half-lives for both GH–LRv2 and GH–LRv3 representing exceptionally delayed clearance over rhGH (recombinant human GH). The results suggest that repeated administration of a GH LR-fusion is safe, non-toxic, and the pharmacokinetic profile suggests that two to three weekly administrations is a potential therapeutic regimen for humans.