Biomedical subjects
Publications and source records attributed to David Griffith.
Aryl sulfonamide-based endothelin antagonists were synthesized and covalently linked to the reactive lysine of the m38C2 antibody to create a series of CovX-Bodies. These chemically programmed antibodies behaved as potent endothelin receptor antagonists in vitro and had antitumor efficacy in a prostate cancer xenograft model which, on a molar basis, far exceeded the activity of the parent small molecule.
Following the optimization of diamine-containing efflux pump inhibitors with respect to in vitro potentiation activity, in vivo stability and acute toxicity, we addressed the question of how to control the pharmacokinetic properties of the series. Upon intravenous administration in the rat, tissue levels of MC-04,124 (the lead compound) were high and prolonged compared to those in the serum. The lipophilicity and basicity of analogues of this compound were systematically varied, and effects on potency and pharmacokinetics explored. The ratio of drug levels in tissue versus serum was not significantly reduced in any of the active analogues examined.
Conformational restriction of the ornithine residue of the efflux pump inhibitor D-ornithine-D-homophenylalanine-3-aminoquinoline (MC-02,595, 2) furnished bioisosteric proline derivatives that were less toxic in vivo and as active as the lead in potentiating the activity of the fluoroquinolone levofloxacin via the inhibition of efflux pumps in Pseudomonas aeruginosa.
SAR studies in a series of related 3-(heteroarylthio)cephems determined that a relatively high chemical reactivity of the beta-lactam ring, modulated by electronic effects of substituents at C-3 and C-7, is necessary to achieve high in vitro activity against methicillin-resistant Staphylococcus aureus (MRSA). Such high reactivity results in lowered hydrolytic stability and concomitantly increases susceptibility to beta-lactam ring opening mediated by serum enzymes. Therefore, optimization of anti-MRSA activity versus stability toward serum-mediated degradation required a fine balance of substituent effects. Serum stability studies (measured as percentage of parent drug degraded after 60 min incubation) revealed up to 80-fold difference in degradation rate in a series of closely related (3-heteroarylthio)cephems. Of the compounds evaluated, RWJ-333441 (MC-04,546) possessed the best balance of serum stability (6% degradation after 60 min incubation) and in vitro activity versus MRSA (S. aureus COL MIC=1 microgram/mL). Accordingly, RWJ-333441 displayed excellent in vivo efficacy versus methicillin-susceptible Staphylococcus aureus (MSSA, ED(50)=0.39 mg/kg in mouse sepsis model with S. aureus Smith) and good pharmacokinetic properties in the rat (Cl(total)=0.39 L/h/kg).
Current guidelines advise discussion with patients before issuing a 'do not attempt resuscitation' (DNAR) order. We report five audit cycles of cardiopulmonary resuscitation (CPR) documentation after introducing a proforma, the last cycle following the latest guidelines. In first audit data were collected from 75 patient discharges. CPR decisions were documented in 27 (36%). Four subsequent point prevalence audits carried out on all inpatients following proforma introduction showed documentation improved to 102/109 (94%), 135/148 (91%), 131/140 (94%) and 102/119 (86%) in cycles two, three, four and five, respectively. The last three audits also revealed that consultants consistently made more DNAR orders than trainee doctors. However, following the introduction of the latest guidelines the proportion of patients in whom a decision was made, and the percentage of those decisions that were DNAR, fell.
We audited documentation rates and implementation of cardiopulmonary resuscitation (CPR) decisions for patients admitted under the Department of Elderly Care Medicine, Mayday University Hospital, Croydon, as new guidelines and a proforma were introduced. For the first audit, data were collected from 75 departmental discharges. Following introduction of a proforma, six point prevalence audits were performed of all elderly care inpatients. Consultant documentation improved from 27/75 (36%) to 102/109 (94%), 135/148 (91%), 133/140 (95%), 96/119 (81%), 148/157 (94%) and 167/169 (98%) in audits 2, 3, 4, 5, 6 and 7 respectively. The percentages of decisions that were Do Not Attempt Resuscitation (DNAR) were 64% 72%, 45%, 68% and 62% in audits 3 to 7 respectively. For audit 5 our guidelines required discussion with patient before making a DNAR order, whereas the guidelines applicable for the other audits did not stipulate discussion. The fall in documentation rates and proportion of CPR decisions that were DNAR in audit 5 were statistically significant. There was no significant difference in age, diagnosis, cognitive function or disability between patients in those audits (3-7) when these parameters were recorded. Introducing a proforma significantly improved CPR decision documentation. Obligatory discussion with a patient before issuing a DNAR order was associated with a fall in documentation of decisions.