Br. J. lin. Pharma. (1977), 4, 513-517 CRDOVSCULR FFCTS OF W OTROPC GT, U.K. 14275, PTTS WTH CORORY HRT DSS 1. HUTTO, W.S. HLLS, C.. LGH, J.M. COLY & T.D.V. LWR University of Glasgow Department of Medial Cardiology, The Royal nfirmary, Glasgow G4 OSF The hronotropi and inotropi properties of U.K. 14275, a phosphodiesterase inhibitor were assessed in patients with ronary heart disease. 2 Left ventriular funtion was assessed in eight patients with aute myoardial infartion using the non-invasive measurement of systoli time intervals. 3 Twelve patients with angina petoris were studied during diagnosti ronary arteriography. Left ventriular funtion was assessed using a high fidelity atheter tipped transduer in the left ventrile. 4 n both groups of patients U.K. 14275 infused intravenously in doses of 32, 64, 128 and 256 tg kg-' bodyweight min-' enhaned the ntratile state of the left ventrile without altering the heart rate. ntrodution The introdution of ronary are units has redued the mortality from dysrhythmias mpliating reent myoardial infartion but no impat has, as yet, been made on the mortality assoiated with left heart failure, hypotension and the redued ardia output state sometimes referred to as 'pump failure'. Sympathomimeti amines have been used in the management of suh ases and also to provide inotropi support following ardia surgery. oradrenaline stimulates both a and, adrenergi reeptors resulting in inreased ardia ntration and intense peripheral vasonstrition with subsequent elevation of the arterial blood pressure but with inreased myoardial oxygen nsumption. soprenaline is a potent P-adrenoeptor stimulant and inreases heart rate in addition to its inotropi ation. The exessive tahyardia and the propensity to ventriular dysrhythmia produed by isoprenaline has stimulated researh into pharmalogial mpounds whih an exert inotropi effets but have no hronotropi ation. Dobutamine has been shown both in man (Jewitt, Mithell, Birkhead & Dollery, 1974) and in the experimental animal (Vatner, MRithie & Braunwald, 1974) and (Willerson, Hutton, Watson, Platt & Templeton, 1976) to have suh properties but, in patients after open heart surgery, it has been shown to have hronotropi properties similar to isoprenaline (Kersting, Follath, Moulds, Muklow, MCloy, Shearer & Dollery, 1976). 1-Butyl-3 (1-(6,7-dimethoxyquinazolin-4-yl) piperidin-4-yl ure (U.K. 14275, Pfizer Laboratories, Figure 1) is a new pharmalogial mpound whih inhibits yli MP phosphodiesterase thus inreasing ellular 3,5 yli MP whih should enhane the ntratile state of the myoardium. Follath, Kersting, Lewis, Walden, Woolhouse & Dollery (1976) have shown in human volunteers that the intravenous infusion of U.K. 14275 resulted in an inrease in myoardial ntratility without signifiant alteration in heart rate or blood pressure. The objet of the present study was to assess the ardiovasular effets of U.K. 14275 in patients with ronary heart disease undergoing ronary angiography and in patients with reent myoardial infartion. Methods Twelve male patients with ronary heart disease undergoing ronary angiography were studied at the time of ardia atheterization. The patients were all in sinus rhythm and /B-adrenoeptor bloking agents had been disntinued 48 h prior to the investigation. ight patients with aute myoardial infartion being treated in an intensive ronary are unit who were nsidered to have linial evidene of left ventriular dysfuntion as evidened by tahyardia, additional heart sounds and lung base repitations, were also studied by non-invasive tehniques-the systoli time intervals. The nature of the study was arefully explained to eah patient and their nsent was obtained. pproval for the study had also been obtained from the hospital ethial mmittee.
514 1. HUTTO, W.S. HLLS, C.. LGH, J.M. COLY & T.D.V. LWR CH3 CH 3-3 H C CH2CH2CH2 CH3 1 Figure 1 The struture of U.K. 14275, 1 -butyl-3-1 - (6,7-dimethoxyquinazoline-4-y) piperidin-4-yl urea. Haemodynami study high fidelity left ventriular (LV) pressure was obtained using a Millar transduer tipped atheter (PC-35). The atheter has a flat frequeny response from -25 khz. The LV pressure wave form was rerded on an f.m. instrumentation tape rerder and subsequently analysed on a PDP-8 mputer. The mputer digitized 8 s of rerded signal at a rate of 25 samples/send. The rate of rise of pressure dp/dt was then alulated between suessive samples from end diastole to peak systole and dp/dt (max) and dp/dt over simultaneously developed pressure (P) was then determined for eah beat analysed. The results presented are the mean values of all beats within an 8 s sample. Heart rate was obtained from a ntinuous rerding of the eletroardiogram, systemi blood pressure was measured from the Miller atheter and ardia output was determined using a dye-dilution tehnique (Waters nstrumentations DCR 71). ll ardia outputs were done in dupliate and the mean of the results was taken. on-invasive study The systoli time intervals total eletromehanial systole (QS2), left ventriular ejetion time (LVT), pre-ejetion period (PP) and ratio of PP/LVT were measured from simultaneous high speed rerdings of the eletroardiogram, phonoardiograms and arotid pulse wave traing (Weissler, Harris & Shoenfield, 1968). ah interval was measured to the nearest 5 ms mean values of six ardia yles being obtained. Blood pressure was measured by sphygmomanometer. The left ventriular filling pressure was measured by means of a flowguided ballon atheter plaed in the pulmonary artery (Swan, Ganz, Forrester, Marus, Diamond & Chonetti, 197). Heart rate was again measured from a ntinuous rerding of the eletroardiogram. xperimental protol n the haemodynami study after baseline measurements U.K. 14275 was infused intravenously at doses of 64, 128 and 256 1tg kg-' bodyweight min-'. The drug was dissolved in dextrose and infused over a 5-8 min period using a alibrated infusion pump (Sage nstruments). The dosage inrements used in the patients with myoardial infartion were 16, 32, 64 and 128 tg kg-1 bodyweight min-', eah infusion level being given for 5 minutes. Results Haemoaynami study Detailed results are noted in Table 1. dp/dt (max) inreased by 27% at the highest rate of infusion from 1518±65 to 1936+97 mmhg/s (P <.2) dp/dt/p inreased from 73.3 + 3. to 82.2 + s-' (P <.2). Left ventriular end diastoli pressure (LVDP) did not hange 1 + 2 and 8 +±1 mmhg. Heart rate was not signifiantly altered at any of the infusion rates 76+ 2 to 77+ 2 beats/min at 256 gg kg-' bodyweight min-'. There was no signifiant hange in the systemi blood pressure. Systoli blood pressure was 132 + 9 at the start of the infusion and 129±8 mmhg at the end. Diastoli blood pressure 79 + 8 and 8 + 6 mmhg and the mean blood pressure was 97 + 8 and 96 ± 8 mmhg. Cardia output inreased from 5.9 +.14 1/min to 6.3+.131/min (P<.1), at the 256j±gkg-' bodyweight mm-' infusion. There was an inrease in stroke volume from 78 + 18 to 85 + 17 ml (P<.1). Myoardial infartion group The detailed results are found in Table 2. The pre-ejetion period (PP) signifiantly shortened at the highest rate of infusion 128 ±g kg-' bodyweight min-' from 112+6 to 91+8ms (P <.5) representing a 2% inrease in left ventriular ntratility. Similarly the ratio PP/LVT shortened from.46+.5 to.34+.2 (P <.5). Heart rate was unhanged 76 7 and 74 +5 beats/min. LVDP was unaltered 12±2 and 1+3 mmhg. There was again no hange in the systemi blood pressure, systoli blood pressure was 128 ± 8 mmhg at the start of the infusion and 126±9 mmhg at the end, diastoli blood pressure was 8+7 and 78 ± 6 mmhg mean blood pressure was 94+6 and 95± 7 mmhg. The inrease in dp/dt showed a linear relationship to the log of plasma nentration of U.K. 14275 (Figure 2). Plasma drug nentrations were determined by extration from plasma ethyl aetate, the extrat then being hromatographed by thin layer hromatography (t.l..) and the quantity of the drug measured by diret absorption densitometry on the t.l.. plate (Department of Drug Metabolism, Pfizer Limited, Sandwih). There was a dose related derease
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516. HUTTO, W.S. HLLS, C.. LGH, J.M. COLY & T.D.V. LWR 4 r 4r n._.5_ -) O OX U - ) 31-2F 11- '.. Q.) CL ) O 3 F 2p- 1k f OX 2 5 1 Plasma nentration (pg ml-') Figure 2 The relationship between the perentage hange in left ventriular dp/dt and log of plasma nentration of U.K. 14275. o ativity is evident with plasma levels less than 2 9g ml-'. 16 32 64 128 nfusion rate (pg kg-'min-') Figure 3 The relationship between the perentage hange in the duration of the pre-ejetion period with inreasing infusion rates of U.K. 14275. Mean ±s.e. mean for eah level shown. in the PP with infusion rates of 16, 32, 64 and 128 tg kg-' bodyweight min-' (Figure 3). Side effets There was a modest degree of venous irritation in two of the twenty patients to whom U.K. 14275 was infused intravenously. o adverse biohemial effets were found, nor was evidene of hepati or renal damage obtained. Disussion The data obtained from this study would suggest that U.K. 14275 has a signifiant inotropi ation on patients with ronary heart disease with little or no effet on heart rate. The invasive measurements of dp/dt (max) and dp/dt/p have been shown to be aeptable indies of myoardial ntratility, to be relatively insensitive to hanges in pre-load or afterload and to be partiularly appliable in the interpretation of diretional haemodynami hanges produed by a drug or other intervention (Furnival, Linden & Snow, 197); (Mason, Braunwald, vell, Sonnenblik & Ross, 1971) and (Vatner, Higgins, Patrik, Franklin & Braunwald, 1971). n this study the heart rate was unaltered, left ventriular end diastoli pressure was unhanged as was systemi blood pressure, and thus the highly signifiant inreases in dp/dt (max) and dp/dt/p indiated that U.K. 14275 has a positive inotropi ation. This was further nfirmed by the signifiant inreases in ardia output and stroke volume. lthough U.K. 14275 appears to exert a positive inotropi ation in patients with angina petoris its linial appliation might be more relevant to an aute situation suh as reent myoardial infartion. t seemed appropriate to evaluate the drug in this linial ntext. The assessment of left ventriular funtion in these ill patients was arried out by measurement of systoli time intervals using a noninvasive tehnique. n the absene of hanges in preload and afterload the duration of pre-ejetion period is determined by the rate of rise of left ventriular pressure (dp/dt) (Talley, Meyer & May, 1971). The ratio of PP/LVT rrelates losely with the ejetion frations measured by ventriulography (Garrard, Weissler & Dodge, 197). n the present study there was signifiant shortening of the PP and a derease in PP/LVT indiating enhaned ntratility. gain this was assoiated with no hange in heart rate nor in preload and afterload. Thus U.K. 14275 exerts a positive inotropi effet in the patients with reent myoardial infartion. These hanges in myoardial ntratility in both groups of patients were dose-related and were maximum at the highest infusion rate. These results are similar to those found experimentally in the anaesthetized dog where ardia output and L.V. dp/dt inreased progressively with
CRDOVSCULR FFCTS OF U.K. 14275 517 the dose administered (Follath et al., 1976). The only differene was the transient effet of the drug in both groups of patients in ntrast to the persistene of the inotropi ation for some 3 min found in the experimental study. Pharmalogial agents whih have an inotropi but not a hronotropi effet might be useful in the management of the low output state mpliating reent myoardial infartion or ardia surgery. Dobutamine, reported to have a powerful inotropi ation in patients undergoing diagnosti ardia atheterization but with little inrease in heart rate (Jewitt et al., 1974) was found to have no advantage over isoprenaline in the post-operative ardia surgial patient (Kersting et al., 1976). Cardiogeni shok mpliating pump failure is now the prinipal ause of death in patients being treated in the ronary are unit and one of the major areas of ardiovasular researh is direted towards protetion of the ishaemi myoardium and limitation of the ultimate areas of myoardial nerosis. xperimentally fators whih augment myoardial oxygen nsumption have been shown to extend the area of ishaemi injury and of ultimate nerosis. These fators inlude isoprenaline, ouabain and tahyardia (Maroko, Kjekshus, Sobel, Watanase, vell, Ross & Braunwald, 1971) and (Redwood, Smith & pstein, 1972). Dobutamine has been shown in both the anaesthetized and nsious dog, with myoardial ishaemia, to inrease myoardial ntratility as muh if not more than myoardial blood flow and if heart rate were to inrease in addition, then the extent of myoardial damage would be greater (Willerson et al., 1976). Thus, despite the lak of effet on heart rate, U.K. 14275 should be used with aution in patients with aute myoardial infartion unless there is evidene of left ventriular dysfuntion. The main potential use for this new inotropi agent would appear to be in the management of patients with established ronary heart disease, who have ventriular dysfuntion and hroni ardia failure. Supplies of the drug were obtained from Pfizer Researh Laboratories, Sandwih, Kent. Referenes FOLLTH, R., KRSTG, F., LWS, G.R.J., WLD, R.J., WOOLHOUS, M.M. & DOLLRY, C.T. (1976). Cardiovasular effets of a new inotropi drug in dog and normal man. Clin. Pharma. Ther., 2, 24-3. FURVL, C.M., LD, R.J. & SOW, H.M. (197). notropi hanges in the left ventrile: The effet of hanges in heart rate, aorti pressure and end diastoli pressure. J. Physiol., 211, 359-387. GRRRD, C.L. Jr., WSSLR,.M. & DODG, H.T. (196). The relationship of alterations in systoli time intervals to ejetion fration in patients with ardia disease. Cirulation, 42, 455-462. JWTT, D., MTCHLL,., BRKHD, J. & DOLLRY, C.T. (1974). Clinial ardiovasular pharmalogy of dobutamine. Lanet, ii, 363-367. KRSTG, F., FOLLTH, R., MOULDS, R., MUCKLOW, J., MCLOY, R., SHRR, J. & DOLLRY, C.T. (1976). mparison of ardiovasular effets of dobutamine and isoprenaline after open heart surgery. Br. Heart J., 38, 622-627. MROKO, P.R., KJKSHUS, J.K., SOBL, B.., WTB, T., COVLL, J.W., ROSS, J. Jr. & BRUWLD,. (1971). Fators influening infart size following experimental ronary artewy olusion. Cirulation, 43, 67-82. MSO, D.T., BRUWLD,., COVLL, J.W., SOBLCK,.H. & ROSS, J. Jr. (1971). ssessment of ardia ntratility. The relation between the rate of pressure rise and ventriular pressure during isovolumi systole. Cirulation, 44, 47-58. RDWOOD, D.R., SMTH,.R. & PST, S.. (1972). ronary artery olusion in the nsious dog. ffets of alteration in heart rate and arterial pressure on the degree of myoardial ishaemia. Cirulation, 46, 323-332. TLLY, R.C., MYR, J.F. & MY, J.C. (1971). valuation of the pre-ejetion period as an estimate of myoardial ntratility in dogs. m. J. Cardiol., 27, 384-39. SW, H.J.C., GZ, W., FORRSTR, J., MRCUS, H., DMOD, G. & CHOTT, D. (197). Catheterization of the heart in man with use of a flow-direted balloon-tipped atheter. ew ngl. J. Med., 283, 447-451. VTR, S.F., HGGS, C.B., PTRCK, T., FRKL, F. & BRUWLD,. (1971). ffets of ardia depression and of anaesthesia on the myoardial ation of a ardia glyside. J. lin. nvest., S, 2585-2595. VTR, S.F., MRTCH, R.J. & BRUWLD,. (1974). ffets of dobutamine on left ventriular performane. ronary dynamis and distribution of ardia output in nsious dogs. J. lin. nvest., 53, 1265-1273. WSSLR,.M., HRRS, W.S. & SCHOFLD, C.D. (1968). Systoli time intervals in heart failure in man. Cirulation, 37, 149-159. WLLRSO, J.T., HUTTO,., WTSO, J.T., PLTT, M.R. & TMPLTO, G.H. (1976). nfluene of dobutamine on regional myoardial blood flow and ventriular performane during aute and hroni myoardial ishaemia in dogs. Cirulation, 33, 828-833. (Reeived ovember 3, 1976) 34