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Inhaled adenosine receptor agonists induce bronchoconstriction and inflammation in asthma and are used as bronchial challenge agents for the diagnosis of asthma and in respiratory drug development. Recently developed dry powder aerosols of adenosine have several advantages over nebulised adenosine 5′-monophosphate (AMP) as bronchial challenge agents. However, reverse translation of this bronchial challenge technique to pre-clinical drug development is limited by the difficulty of administering powder aerosols to animals. The aim of the current study was to develop methods for delivering powder aerosols of adenosine receptor agonists to sensitised guinea pigs (as a model of allergic asthma) and evaluate their effect as challenge agents for the measurement of airway responsiveness. The PreciseInhale system delivered micronised AMP and adenosine powders, with mass median aerodynamic diameters of 1.81 and 3.21 μm and deposition fractions of 31 and 48% in the lungs, respectively. Bronchoconstrictor responses in passively sensitised, anaesthetised, spontaneously breathing guinea pigs were compared to responses to nebulised and intravenously administered AMP and adenosine. AMP- and adenosine-induced bronchoconstriction following all routes of administration with the magnitude of response ranking intravenous > dry powder > nebulisation, probably reflecting differences in exposure to the adenosine agonists delivered by the different routes. In conclusion, the PreciseInhale system delivered AMP and adenosine dry powder aerosols accurately into the lungs, suggesting this method can be used to investigate drug effects on airway responsiveness.

Protease activated receptor‐2 (PAR2) is a seven transmembrane domain G protein coupled receptor proteolytically activated. PAR2, together with other PARs, can be also activated by peptides mimicking the sequence of the receptor tethered ligand. We have evaluated the effect of systemic administration of a peptide activating PAR2 (PAR2‐AP, SLIGRL) on histamine‐induced increase in lung resistances in the guinea‐pig.Intravenous administration of PAR2‐AP (1 mg kg−1) significantly inhibited histamine‐induced increase in lung resistance in a time‐dependent fashion that was not abolished by indomethacin or vagotomy.Bronchoprotective effect of PAR2‐AP was not reversed by the cyclo‐oxygenase inhibitor, indomethacin, the nitric oxide synthetase inhibitor, L‐NAME, nor by the non‐selective beta‐antagonist, propranolol.Indomethacin augmented the bronchoconstriction to histamine which was inhibited by PAR2‐AP. Furthermore, in vagotomized animals, the bronchial hyper‐responsiveness to histamine was significantly reduced, and in these circumstances, PAR2‐AP still retained the capacity to provide bronchoprotection against histamine.PAR2‐AP also produced a modest reduction in histamine‐induced protein leakage in trachea and upper bronchi.Our results indicated that PAR2 might have a bronchoprotective role in the guinea‐pig in vivoindependent of prostaglandin or nitric oxide release.

Abstract: Our previous studies exploring melphalan resistance in the human rhabdomyosarcoma xenograft TE-671 MR revealed elevation of DNA polymerase-α and DNA polymerase-β . The present study evaluated the alteration of melphalan activity in TE-671 (melphalan-sensitive) and TE-671 MR (melphalan-resistant) subcutaneous xenografts in nude mice after DNA polymerase-α was inhibited using aphidicolin glycinate (AG) and DNA polymerase-β was inhibited using dideoxycytidine (DDC). Administration of AG or DDC did not produce toxicity or demonstrate antineoplastic activity when given alone. AG (90 mg/m2) enhanced the activity of melphalan against TE-671, with growth delays increasing by 8.4, 15.8, and 21.2 days over the regimen with melphalan only. AG (180 mg/m2) only modestly increased melphalan activity against TE-671 MR, with the growth delays increasing from 9.6 and 12.1 days using melphalan alone to 12.1 and 14.5 days using melphalan plus AG. AG (180 mg/m2) plus melphalan (the dose lethal to 10% of animals) produced greater weight loss compared with melphalan alone, whereas DDC plus melphalan produced no additional toxicity. DDC modestly enhanced the activity of melphalan plus AG against TE-671 MR. AG plus O 6-benzylguanine did not increase the activity of 1,3-bis(2-chloroethyl)-1-nitrosourea against TE-671 or TE-671 MR. AG (90 mg/m2 and 180 mg/m2) inhibited DNA polymerase-α to 80% and 72% of control in TE-671 and 64% and 37% in TE-671 MR, and DDC inhibited DNA polymerase-β to 59% in TE-671 and 48% in TE-671 MR. These results suggest a role for AG-mediated enhancement of melphalan activity, particularly in the treatment of newly diagnosed, melphalan-sensitive tumors.

1 Protease activated receptor-2 (PAR2) is a seven transmembrane domain G protein coupled receptor proteolytically activated. PAR2, together with other PARs, can be also activated by peptides mimicking the sequence of the receptor tethered ligand. We have evaluated the effect of systemic administration of a peptide activating PAR2 (PAR2-AP, SLIGRL) on histamine-induced increase in lung resistances in the guinea-pig. 2 Intravenous administration of PAR2-AP (1 mg kg−1) significantly inhibited histamine-induced increase in lung resistance in a time-dependent fashion that was not abolished by indomethacin or vagotomy. 3 Bronchoprotective effect of PAR2-AP was not reversed by the cyclo-oxygenase inhibitor, indomethacin, the nitric oxide synthetase inhibitor, L-NAME, nor by the non-selective beta-antagonist, propranolol. 4 Indomethacin augmented the bronchoconstriction to histamine which was inhibited by PAR2-AP. Furthermore, in vagotomized animals, the bronchial hyper-responsiveness to histamine was significantly reduced, and in these circumstances, PAR2-AP still retained the capacity to provide bronchoprotection against histamine. 5 PAR2-AP also produced a modest reduction in histamine-induced protein leakage in trachea and upper bronchi. 6 Our results indicated that PAR2 might have a bronchoprotective role in the guinea-pig in vivo independent of prostaglandin or nitric oxide release. British Journal of Pharmacology (2001) 132, 1229 – 1234

A large study on 121 patients with the chronic fatigue syndrome (CFS) that examined muscle biopsy samples for enterovirus by means of polymerase chain reaction analysis was carried out. The results were compared with those obtained from 101 muscle biopsy specimens from patients with a variety of other neuromuscular disorders (OND), including neurogenic atrophies, dystrophies, and mitochondrial, metabolic, and endocrine myopathies. Thirty-two (26.4%) of the biopsy specimens from the group of patients with CFS were positive, compared with 20 (19.8%) from the group of patients with OND, a difference that was not significant. This finding is in contrast to those of our previous smaller study in which significantly more patients with CFS than control subjects (53% [32 of 60] vs. 15% [6 of 41]) had enterovirus RNA sequences in their muscle. It was concluded that it is unlikely that persistent enterovirus infection plays a pathogenetic role in CFS, although an effect in initiating the disease process cannot be excluded.