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Therapeutic delivery of carbon monoxide

A carbonate and carbonate compound technology, applied in the direction of organic active ingredients, non-central analgesics, active ingredients of boron compounds, etc., can solve problems such as unsuitable for commercial radiopharmaceutical use

Inactive Publication Date: 2006-12-13
HEMOCORM +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, relying on the gaseous carbon monoxide of [ 99m Tc(OH 2 ) 3 -(CO) 3 ] + disclosed formulations, not suitable for use in commercial radiopharmaceutical "kits"

Method used

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  • Therapeutic delivery of carbon monoxide
  • Therapeutic delivery of carbon monoxide
  • Therapeutic delivery of carbon monoxide

Examples

Experimental program
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Effect test

Embodiment 1 to 8

[0063] Reagent

[0064] Chloro(glycinato)ruthenium(II) tricarbonyl ([Ru(CO) 3 Cl (glycine ester)] or CORM-3) 24 . Borane carbonate disodium salt (Na 2 [H 3 BCO 2 ], here indicated as "CORM-A1") 31 . Sodium borohydride (NaBH 4 ) and all other reagents were from Sigma Chemicals (Poole, Dorset).

[0065] Preparation of blunt CORM-A1 and its use as a negative control

[0066] The chemistry of borane carbonate in aqueous solution has been described previously 31 . This compound is relatively stable in distilled water at basic pH. When the pH approaches more physiological conditions (pH = 7.4), the compound starts to release CO, and the rate of CO release is very fast at acidic pH. Based on this fact, we generated the inactive form of CORM-A1 (iCORM-A1) by reacting the compound with acid. Specifically, a small aliquot (10 μl) of concentrated hydrochloric acid (10 M) was added to 1 ml of CORM-A1 in water (100 mM final concentration). The reaction caused a rapid evolutio...

Embodiment 1

[0071] Example 1. Conversion of myoglobin (Mb) to carbon monoxide myoglobin by CO gas

[0072] Myoglobin (Mb) in its reduced state exhibits a characteristic spectrum with a maximum absorption peak at 555 nm (see figure 1 ,dotted line). Rapid conversion of carbon monoxide myoglobin (MbCO) was observed when Mb solution (50 μΜ) was bubbled with CO gas (1%) for 1 min. Such as figure 1 As shown, MbCO displays a characteristic spectrum (solid line) with two maximum absorption peaks at 540 and 576 nm, respectively. This method has been studied previously to monitor and detect CO release from CO-RMs 23 , and can be used to examine how various conditions such as different pH and temperature affect the kinetics of CO release (see Example 4).

Embodiment 2

[0073] Example 2. Conversion of myoglobin (Mb) to carbon monoxide myoglobin by CORM-A1

[0074] Addition of CORM-A1 (60 μΜ) to a solution containing reduced Mb (pH = 7.4, temperature = 37°C) resulted in the gradual generation of MbCO over time. Such as figure 2 As shown, after 210 min of incubation, the standard spectrum of reduced Mb (solid squares) was transformed into a characteristic spectrum (empty inverted triangles). Traces containing asterisks represent MbCO spectra when Mb was saturated with CO gas (positive control) as described in Materials and Methods.

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Abstract

Boranocarbonates are described for administration to a human or other mammal for delivery of carbon monoxide. The boranocarbonate is a compound or ion adapted to make CO available for physiological effect, and may be administered with a guanylate cyclase stimulant or stabilizer. The physiological effect may be stimulation of neurotransmission, vasodilation or smooth muscle relaxation.

Description

field of invention [0001] The present invention relates to pharmaceutical compositions and compounds for the therapeutic delivery of carbon monoxide to humans and other mammals. Another use of the compositions and compounds is for organ perfusion. Background of the invention [0002] Mammalian cells through constitutive (HO-2) and inducible (HO-1) heme oxygenase 1，2 The endogenous degradation of heme caused by the family of hemoglobins often produces carbon monoxide (CO) gas. CO was originally described as a putative neural messenger 3 , is now recognized as a multipotent signaling molecule with essential regulatory roles in various physiological and pathophysiological processes occurring in the cardiovascular, nervous and immune systems. Indeed, CO generated in the vessel wall by heme oxygenase has vasodilatory properties and has been shown to inhibit vasoconstriction as well as suppress acute and chronic hypertension through stimulation of soluble guanylate cyclase 4-1...

Claims

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Application Information

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IPC IPC(8): A01N1/02A61K31/416A61K31/69A61K45/06A61P7/04A61P9/04A61P9/10A61P9/12A61P11/00A61P29/00A61P31/00A61P35/00A61P41/00
CPCA01N1/0226A61K31/69A61K45/06A61K31/416A61K31/506
Inventor R·A·莫特利尼R·A·阿尔伯托
Owner HEMOCORM
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