Clinical Trial Simulation to Inform Phase 2: Comparison of Concentrated vs. Distributed First-in-Patient Study Designs in Psoriasis.

Clinical trial simulation (CTS) and model-based meta-analysis (MBMA) can increase our understanding of small, first-in-patient (FIP) trial design performance to inform Phase 2 decision making. In this work, we compared dose-ranging designs vs. designs testing only placebo and the maximum dose for early decision making in psoriasis. Based on MBMA of monoclonal antibodies in the psoriasis space, a threshold of greater than a 50 percentage point improvement over placebo effect at the highest feasible drug dose was required for the advancement in psoriasis. Studies testing only placebo and the maximum dose made the correct advancement decision marginally more often than dose-ranging designs in the majority of the cases. However, dose-ranging studies in FIP trials offer important design advantages in the form of dose-response (D-R) information to inform Phase 2 dose selection. CTS can increase the efficiency and quality of drug development decision making by studying the limitations and benefits of study designs prospectively.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e58; doi:10.1038/psp.2013.32; published online 24 July 2013.

Modeling biofilm antimicrobial resistance.

A computer model capable of integrating mechanisms of biofilm resistance to disinfection by antimicrobial agents was developed. Resistance mechanisms considered included retarded penetration due to a stoichiometric reaction between the antimicrobial agent and biomass, incomplete penetration due to a catalytic reaction between the antimicrobial agent and the biomass, and the existence of a fraction of the cells in a resistant phenotypic state. Mathematical models of these processes were derived and solved in the computer simulation package MATLAB. Four sets of fitted experimental data on the disinfection of Pseudomonas aeruginosa biofilms were fit to each of the three models. No one model fit all of the data sets adequately. Killing of a 2-day old biofilm by tobramycin was best described by the physiological limitation model. Killing by hypochlorite was best described by the stoichiometric transport model. Killing by hydrogen peroxide was best simulated by the catalytic transport model. These results suggest that multiple mechanisms of biofilm reduced susceptibility are manifested even in biofilms of the same species and that the particular resistance mechanism depends on the biofilm age, antimicrobial agent, and biofilm thickness. The models presented in this article may be useful for diagnosing mechanisms of biofilm resistance from experimental data.

An improved method for bonding heparin to intravascular cannulae.

The patency of chronically implanted intravascular cannulae is usually limited by thrombus formation at the cannula tip. In the present experiments, methods of improving the antithrombotic properties of the cannulae have been examined using a number of different heparin-bonding treatments. These treatments were evaluated by determining cannula patency in the thoracic aorta of a chronically cannulated rat preparation. Cannulae treated with a heparin-bonding procedure remained patent longer than untreated cannulae. Cannulae treated with tridodecylmethylammonium chloride-heparin-glutaraldehyde remained patent longest (mean patency, 13.3 days compared with 4.0 days in rats with untreated cannulae). This technique provides a simple and effective method of improving the antithrombotic properties of intravascular cannulae by bonding heparin to the lumenal and extralumenal surfaces.

Synthesis and biological activity of some cardiotonic compounds related to digitoxigenin.

3 beta-Amino compounds with 17 beta-(3-furyl) and (4-pyridazinyl) ring systems were prepared from digitoxigenin 1b and found to have similar cardiotonic properties to the analogous 3 beta-hydroxy compounds when tested in the isolated guinea-pig atrial preparation. Derivatives with 3 alpha-acetoxy functions were found to have higher than expected activities. Particularly potent was the pyridazine N1-oxide 19. All isocardenolides and the unsaturated anhydride 18 were devoid of activity.

Synthesis and biological activity of some 3-amino compounds related to digoxigenin.

3 alpha-Amino 1a and 3 beta-amino 1b analogues of digoxigenin 14 and their 12 beta-acetate derivatives 2a and 2b were prepared and tested for inotropic activity in the isolated guinea-pig atrial preparation. The 3 alpha-amino compounds were inactive whereas the 3 beta-amino compounds showed comparable activity to their 3 beta-hydroxy counterparts. The replacement of the 17 beta-butenolide ring by other ring systems was investigated. Compounds with a 3'-furyl ring, 9b and 16 were found to possess appreciable activity. A compound with a 4'-pyridazinyl ring 13b exhibited weak activity, whereas the isomeric butenolide compound 11b proved inactive. N-monomethylation of the amine 2b reduced activity and N-dimethylation abolished activity. Acetylation of the 12 beta-hydroxyl function gave less active compounds.

A new series of steroidal antidysrhythmic agents.

With the aim of finding an antidysrhythmic agent suitable for intravenous or oral administration we have examined a range of steroids carrying basic substituents. The primary screen involved control of cardiac dysrhythmias induced by intravenous infusion of aconitine into pentobarbitone-anaesthetised artificially-respired rats. The best activity was found among a series of 11 alpha-alkylamino steroids and structure-activity studies included modification of the alkylamino group and variation of substituents in ring A and at the 17-position. Good oral and intravenous activity was found among 17 beta-methoxycarbonyl-5 alpha-androstanes and methyl 2 beta-ethoxy-3 alpha-hydroxy-11 alpha-(3-methylbutylamino)-5 alpha-androstane-17 beta-carboxylate hydrochloride (CCI 22277) was selected for more detailed pharmacological study.

Anaesthetic, cardiovascular and respiratory effects of a new steroidal agent CT 1341: a comparison with other intravenous anaesthetic drugs in the unrestrained cat.

1. The anaesthetic, cardiovascular, respiratory and adverse effects produced by the intravenous injection of CT 1341, thiopentone, methohexitone, pentobarbitone, propanidid and ketamine have been compared in unrestrained cats prepared with chronically implanted venous and arterial cannulae. Aortic blood pressure and heart rates were monitored before, during and after loss of consciousness.2. CT 1341 produced rapid induction of anaesthesia followed by moderately rapid recovery, was active over a wide range of doses and caused minimal respiratory depression and few adverse effects. It caused an initial short-lasting tachycardia and fall in aortic blood pressure succeeded by a secondary depressor response.3. The safety margin was narrower with the barbiturate drugs than with CT 1341, and large doses induced apnoea and respiratory depression. Small doses of methohexitone elicited excitatory effects and large doses caused severe respiratory and circulatory depression, and recovery from anaesthesia was protracted.4. Propanidid induced short-lasting light anaesthesia. The safety margin was narrowest with this drug and induction was associated with adverse circulatory, respiratory and other effects.5. Ketamine was active over a wide range of doses but exhibited qualitatively different properties from the other anaesthetics. Induction was slower after small doses and these produced circulatory stimulation, catatonia and bizarre behavioural effects. Large doses caused respiratory and circulatory depression and recovery was protracted.6. It is concluded that CT 1341 has a wider therapeutic latitude, produces less respiratory depression and has other advantages over the currently used intravenous anaesthetics.

Enhancement by potent diuretics of renal tubular necrosis induced by cephaloridine.

1. Administration of frusemide or ethacrynic acid to cephaloridine-treated mice increased both the incidence and extent of proximal renal tubular necrosis compared with that obtained in cephaloridine-treated control mice.2. Administration of frusemide to cephaloridine-treated rats produced significant changes in urine output, electrolyte excretion and proteinuria, and plasma urea nitrogen and creatinine values were significantly increased compared with controls or rats that received frusemide or cephaloridine alone.3. Histological examination of the kidneys showed a higher incidence and greater extent of tubular necrosis in rats that received both frusemide and cephaloridine.4. It is suggested that this adverse drug interaction may have contributed to the deterioration in renal function observed in some patients treated with diuretics and cephaloridine concurrently.