Biomedical subjects

Domenico Spina

Publications and source records attributed to Domenico Spina.

21 records · Page 2Linked to original sources

PubMed2002

Pharmacokinetic and pharmacodynamic profile following oral administration of the phosphodiesterase (PDE)4 inhibitor V11294A in healthy volunteers.

AIMS: To assess the pharmacokinetic and pharmacodynamic profile of the novel PDE4 inhibitor V11294A (3-(3-cyclopentyloxy-4-methoxybenzyl)-6-ethylamino-8-isopropyl-3H purine hydrochloride) in healthy male volunteers. METHODS: This was a double-blind, single dose, randomized crossover study in eight healthy volunteers who received a single oral, fasting dose of V11294A (300 mg) or placebo. Blood samples were taken before and 0.5, 1, 2, 2.5, 3, 4, 6, 9, 12, 18 and 24 h after oral dosing for determination of plasma concentrations of V11294A. Blood samples were also taken before and 3 and 24 h after dosing for the assessment of the effect of V11294A on mononuclear cell proliferation and tumour necrosis factor (TNF) release in whole blood. RESULTS: Following a single oral dose of 300 mg V11294A, plasma concentrations of V11294A and its active metabolite V10332 reached Cmax (ng ml-1; mean +/- s.d.; 1398 +/- 298, 1000 +/- 400, respectively) after 2.63 +/- 0.79 and 5.9 +/- 2.3 h, respectively. For V11294A and V10332, t1/2 were 9.7 +/- 3.9 and 9.5 +/- 1.7 h, and AUC(0, infinity ) were 18100 +/- 6100 and 18600 +/- 8500 ng ml-1 h, respectively. At 3 h dosing, plasma concentrations of V11294A and V10332 (3-(3-cyclopentyloxy-4-methoxy-benzyl)-8-isopropyl-3H-purin-6-ylamine) were 1300 +/- 330 and 860 +/- 300 ng ml-1, 7 and 3 times their in vitro IC50s for inhibition of TNF release and proliferation, respectively. Treatment with V11294A resulted in a significant reduction of lipopolysaccharide (LPS)-induced TNF release at 3 h (P < 0.001) and at 24 h (P < 0.05) post ingestion. The amount of TNF released (pmol ml-1) in response to a submaximal concentration of LPS (4 ng ml-1) was not significantly altered following placebo treatment (before 681 +/- 68 vs 3 h postdose 773 +/- 109, P = 0.27). In contrast, there was a significant reduction in the amount of TNF released following treatment with V11294A (before 778 +/- 87 vs 3 h postdose 566 +/- 72, P = 0.02). Phytohaemagluttinin (PHA) stimulated the incorporation of [3H]-thymidine in whole blood prior to drug administration. V11294A inhibited the PHA-induced proliferation at 3 h (P < 0.05). No adverse reactions were noted following single oral administration of V11294A. CONCLUSIONS: A single oral 300 mg dose of V11294A administered to healthy volunteers results in plasma concentrations adequate to inhibit activation of inflammatory cells ex vivo, which persists for at least 24 h without any adverse reactions.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed2002

Bronchial hyperresponsiveness induced by chronic treatment with albuterol: Role of sensory nerves.

BACKGROUND: It has recently been suggested that regular treatment with racemic beta(2)-adrenoceptor agonists might result in bronchial hyperresponsiveness (BHR) to a range of spasmogens, and this might be due to adverse effects of the distomer. OBJECTIVE: We sought to determine whether BHR induced by means of continuous exposure to racemic and S-albuterol was mediated by sensory nerves. METHODS: Naive or ovalbumin-sensitized guinea pigs were treated for 10 days with RS-, R-, or S-albuterol (1 mg.kg(-1).d(-1)) through subcutaneously implanted minipumps. Lung function was then determined in response to a number of spasmogens and assessed on the basis of an increase in total airway resistance. A separate group of animals were chronically treated with capsaicin (80 mg/kg) before the albuterol treatment. RESULTS: Treatment with RS- or S-albuterol increased airway responsiveness to bradykinin, leukotriene C(4), and capsaicin in naive guinea pigs (P <.05) and to histamine and ovalbumin in immunized guinea pigs (P <.05). Chronic treatment with capsaicin prevented the development of RS- and S-albuterol-induced BHR in these models. The bronchodilator efficacy of acute intravenously administered RS-albuterol was unaffected in RS-, R-, or S-albuterol-treated guinea pigs compared with in vehicle-treated animals. CONCLUSION: We have provided evidence demonstrating that continuous exposure to RS- and S-albuterol increases bronchial responsiveness to a range of stimuli, an effect not attributed to beta-adrenoceptor occupancy or desensitization. Furthermore, capsaicin-sensitive sensory nerves mediate the development of BHR, at least in part.

Adrenergic beta-Agonists↗

PubMedDate not supplied

Beta2-agonists and bronchial hyperresponsiveness.

Bronchial hyperresponsiveness (BHR) is a characteristic feature of asthma, and individuals with this disease respond to a range of physiological and chemical insults that are otherwise innocuous to healthy subjects, suggesting that the mechanisms underlying this phenomenon are characteristic of the asthma phenotype. BHR can be increased following exposure to environmental allergens in suitably sensitized individuals, pollutants, and certain viruses and can also be exacerbated by exposure to certain drugs, including nonsteroidal anti-inflammatory agents and beta-blockers. Although beta2-agonists administered acutely remain the treatment for the symptoms of asthma, paradoxically, regular treatment with these drugs can result in an increase in BHR, and this has been suggested to contribute to the increase in asthma morbidity and mortality that has been reported by numerous investigators. This article highlights our current understanding of this phenomenon and examines the potential mechanisms responsible for this effect.

Adrenergic beta-2 Receptor Agonists↗