Disease relevance of SkF94836

• 9. We conclude that SK&F 94836, as an orally active inotropic/vasodilator agent with a sustained duration in vivo, has potential utility in the treatment of congestive heart failure [1].
• The rise in IL-5 at 3 h was additionally attenuated by the PDE3 inhibitor, siguazodan, which failed to attenuate the eosinophilia at 24 h [2].

High impact information on SkF94836

• The PDE3 inhibitor, siguazodan, was ineffective in downregulating gene expression for the proinflammatory cytokines assayed; when used in combination with the PDE4 inhibitor, the PDE3 inhibitor provided no increase in efficacy over that seen with the PDE4 inhibitor alone [3].
• The inhibitors of PDE type 3 (SK&F 94836) and type 5 (zaprinast) failed to alter allergen-evoked eosinophil recruitment in rats [4].
• 4. The PDE3-selective inhibitors Org 9935 (0.02 - 10 microM) and siguazodan (0.1 - 10 microM) inhibited cyclic AMP PDE activity in the pellet but not the supernatant fractions of cell homogenates, with a maximum inhibition of about 30% [5].
• Finally, RP 73401 (IC50: 0.41 +/- 0.19 nM) inhibited anti-CD3-stimulated DNA synthesis in splenocyte preparations from M. corti-infected mice and siguazodan (10 microM) had no effect on this response, either alone or in combination with the PDE4 inhibitor [6].
• The PDE3 inhibitor, siguazodan (10 microM), had little or no effect on IL-2 release or DNA synthesis [7].

Biological context of SkF94836

• 2. In anaesthetized cats and dogs SK&F 94836 administered intravenously caused increases in left ventricular contractility and decreases in peripheral vascular resistance at similar doses, thus demonstrating the compound to be a mixed acting positive inotropic/vasodilator agent [1].
• 6. Haemodynamic studies in anaesthetized cats indicated that as a consequence of the inotropic/vasodilator actions, SK&F 94836 caused significant increases in cardiac output and stroke volume [1].
• 4. The inodilator activity of SK&F 94836 in conscious and anaesthetized animals occurred in association with minimal changes in either blood pressure or heart rate [1].
• However, when administered in combination with siguazodan (5.4 mg/kg, i.v.), rolipram (0.4-5.4 mg/kg) abolished histamine- and LTD4-induced bronchoconstriction [8].
• The type 3 phosphodiesterase inhibitor, SK&F 94836 significantly inhibited cell proliferation, but only at high concentrations [9].

Anatomical context of SkF94836

• 5. Detailed studies carried out on anaesthetized cats indicated that SK&F 94836 caused a balanced dilatation of both resistance and capacitance blood vessels [1].
• However, siguazodan produced significantly greater (P<0.05), and rolipram significantly less (P<0.05), inhibition of total cAMP PDE activity in monocytes from asthmatics (n=4) than from healthy individuals (n=5). cAMP PDE activity was inhibited with equal potency by theophylline in monocytes from healthy and asthmatic subjects [10].
• In contrast to their effects vs. allergic airway smooth muscle contraction, both milrinone and siguazodan potently relaxed leukotriene C4 (LTC4)-induced contraction in isolated trachea from non-sensitized animals [11].

Associations of SkF94836 with other chemical compounds

• In contrast, siguazodan was 15 times less potent that rolipram in guinea-pig airways suggesting a greater role for the type IV PDE [12].
• 3. In platelet-rich plasma (PRP), siguazodan inhibited U46619-induced aggregation more potently than that induced by ADP and collagen [13].
• The effects of the isoform-selective inhibitors, 8-methoxymethyl-IBMX (PDE 1 inhibitor), siguazodan (PDE3 inhibitor), rolipram (PDE4 inhibitor), denbufylline (PDE4 inhibitor), Org 30029 (mixed PDE3 and 4 inhibitor) and zaprinast (PDE5 inhibitor), were studied [14].
• However, the limited inhibitory effects of the PDE3 inhibitor, siguazodan, suggest that zardaverine is acting primarily via PDE4 inhibition [15].

Gene context of SkF94836

• Treatment of the PRP with aspirin had no effect on the potency of siguazodan [13].
• Despite a significant increase in the biochemical activity of PDE3 in monocytes from asthmatic subjects, the PDE3 inhibitor siguazodan, failed to significantly reduce TNF alpha release from human monocytes [10].

Analytical, diagnostic and therapeutic context of SkF94836

• 8. The duration of action of SK&F 94836 was sustained following both i.v. and oral administration [1].

References