Physiochemical properties, safety and pharmacokinetics of bimosiamose disodium after intravenous administration

Meyer, Michael C.; Jilma, Bernd; Zahlten, Rainer N.; Wolff, Gerhard

doi:10.5414/cpp43463

Cited by 11 publications

(5 citation statements)

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“…In contrast to the low systemic exposure observed in the present inhalation study, a much higher C max value (7.1 µg ml −1 ) was achieved after a 15‐min intravenous infusion of 1 mg kg −1 bimosiamose disodium in healthy subjects [19]. The AUC 0–∞ = 1360 h µg ml −1 determined for the maximum single intravenous dose of 30 mg kg −1 [19] exceeds the total AUC obtained for multiple inhalations over 1 week (present study) by several orders of magnitude. The low plasma concentrations found after inhalation of bimosiamose disodium do not permit a reliable estimation of AUC after a single inhalation.…”

Section: Discussionmentioning

confidence: 75%

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Tolerability and pharmacokinetics of inhaled bimosiamose disodium in healthy males

Meyer¹,

Beeh²,

Beier³

et al. 2006

Brit J Clinical Pharma

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AimsThe aim of these first-in-human studies was to investigate the tolerability and the pharmacokinetics of bimosiamose disodium (TBC1269Z) administered by inhalation. MethodsTwo randomized, double-blind, placebo-controlled Phase I trials were per formed in healthy males. In a single-dose escalating study 48 subjects received doses of 2-140 mg bimosiamose disodium by inhalation and in a multiple-dose study 32 subjects received 8-70 mg bimosiamose disodium twice daily. In both studies 4 ml of the drug solution was administered via nebulizer over 15 min. Adverse events, vital signs, ECG, clinical laboratory parameters and forced expiratory volume in 1 s (FEV 1 ) data were recorded and nasopharyngeal examinations were per formed to address the safety and tolerability. Blood was collected for the determination of plasma concentrations of bimosiamose. ResultsAll subjects completed the study. No deaths or severe adverse events occurred. Eleven mild adverse events occurred in the dose-escalation study and 34 in the multipledose study after inhalation of bimosiamose disodium. Adverse events were more frequent at the highest dose (140 mg) of the dose-escalation study. For placebo treatment one moderate adverse event was observed in the dose-escalation study after placebo treatment, eight mild and three moderate adverse events occurred in the multiple-dose study. Bimosiamose was detected in plasma (maximum concentration 64 ng ml − 1 ) only at doses ≥ 50 mg given twice daily and 105 mg once daily. For the highest dose a median value of 5746 h ng ml − 1 was determined for the AUC over the entire period of treatment of the multiple-dose study. ConclusionThe results suggest that single and multiple inhalation of bimosiamose disodium up to 70 mg is well tolerated in healthy males. Systemic bioavailability after inhalation is low.

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Section: Discussionmentioning

confidence: 75%

“…In humans, the clinical effects and pharmacokinetics of bimosiamose disodium after intravenous administration have been described recently [19]. In addition, bimosiamose disodium is effective in attenuating the late asthmatic response in mild allergic asthmatic patients [20].…”

Section: Introductionmentioning

confidence: 99%

Tolerability and pharmacokinetics of inhaled bimosiamose disodium in healthy males

Meyer¹,

Beeh²,

Beier³

et al. 2006

Brit J Clinical Pharma

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“…Initial efficacy studies in experimental animals showed reduced reperfusion injury after myocardial infarction in rat, effects of which were attributed to inhibition of leukocyte extravasation [79]. Promising results from Phase I studies have been reported [80]. In human trials, 600 mg of bimosiamose (TBC1269) over 14 days by subcutaneous injection improved skin lesions in psoriasis patients and inhalation reduced the reaction of mild asthmatics following antigen challenge [81].…”

Section: Other Selectin Ligand Targetsmentioning

confidence: 96%

P-Selectin Antagonism in Inflammatory Disease

Woollard¹,

Chin-Dusting

2010

CPD

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Inflammation plays a fundamental role in many chronic diseases, including atherosclerosis associated cardiovascular disease. Adhesion of immune cells plays a critical role in the inflammatory response and indeed the pathophysiology of inflammatory related diseases. P-selectin is an inflammatory adhesion molecule, enabling the recruitment of leukocytes to the endothelium and to activated platelets involved with the growing thrombus. P-selectin is critical in the progression of atherosclerosis as evidenced by knockout animal models where P-selectin knockout mice crossed with apoE deficient mice exhibit significantly reduced atherosclerosis and leukocyte recruitment in the plaque. A soluble form of P-selectin also exists, which may have pro-atherogenic and pro-thrombotic effects. Thus targeting of P-selectin remains a strong clinical candidate for developing novel therapeutic strategies in inflammatory diseases. This review will discuss the role of P-selectin and describe the function of P-selectin antagonists as clinical targets.

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“…Therefore, a ligand-based approach has been employed being based on 1 , a selectin antagonist that was tested in Phase I and Phase IIa trials for the treatment of asthma and psoriasis. − Presently, further preclinical and clinical studies are ongoing. The molecule was identified as the most advanced pharmaceutical compound in the field of selectin antagonists, and it appears to be an appropriate template for a ligand-based drug design.…”

Section: Rational Drug Designmentioning

confidence: 99%

Rational Design of Novel, Potent Small Molecule Pan-Selectin Antagonists

Kranich¹,

Busemann²,

Bock³

et al. 2007

J. Med. Chem.

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This report describes the first results of a rational hit-finding strategy to design novel small molecule antiinflammatory drugs targeting selectins, a family of three cellular adhesion molecules. Based on recent progress in understanding of molecular interaction between selectins and their natural ligands as well as progress in clinical development of synthetic antagonists like 1 (bimosiamose, TBC1269), this study was initiated to discover small molecule selectin antagonists with improved pharmacological properties. Considering 1 as template structure, a ligand-based approach followed by focused chemical synthesis has been applied to yield novel synthetic small molecules (MWr < 500) with a trihydroxybenzene motif, bearing neither peptidic nor glycosidic components, with nanomolar in vitro activity. Biological evaluation involves two kinds of in vitro assays, a static molecular binding assay, and a dynamic HL-60 cell attachment assay. As compared to controls, the novel compounds showed improved biological in vitro activity both under static and dynamic conditions.

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Physiochemical properties, safety and pharmacokinetics of bimosiamose disodium after intravenous administration

Cited by 11 publications

References 0 publications

Tolerability and pharmacokinetics of inhaled bimosiamose disodium in healthy males

Tolerability and pharmacokinetics of inhaled bimosiamose disodium in healthy males

P-Selectin Antagonism in Inflammatory Disease

Rational Design of Novel, Potent Small Molecule Pan-Selectin Antagonists

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