Being directed at TLR4, these therapies may be efficacious only in bacterial Gram-negative sepsis, and their effectiveness will thus be critically dependent on the nature of the infecting organism.
Many of the targeted agents that are now being developed will probably be efficacious only in a specific subset of patients, and it is likely that neither toxicity nor significant tumour shrinkage will be suitable surrogate end points for detecting activity or selecting the appropriate dose.
Approval criteria were based on post hoc reanalysis of PROWESS by the FDA; DrotAA was efficacious only in the sickest patients with severe sepsis - those with multiorgan failure and Acute Physiologic and Chronic Health Evaluation (APACHE) score ≥25 [ 3].
The potential is therefore real that RBC transfusions are efficacious only in very specific situations in intensive care medicine, such as when pretransfusion oxygen delivery is low [ 5], or that RBC transfusions are associated with significant side effects so that the overall balance is negative.
Indeed, in patients who have disease progression (DP) after irinotecan- or oxaliplatin-based chemotherapies combined with bevacizumab, the addition of cetuximab to irinotecan (Cunningham et al, 2004), or cetuximab or panitumumab as monotherapy are efficacious only in wild-type KRAS tumours (Amado et al, 2008; Karapetis et al, 2008).
The issue was whether the supernatural grace in question is efficacious by itself, in other words, intrinsically efficacious, or whether it is efficacious only by virtue of the independent, divinely foreknown cooperation of the one who receives the grace (Vansteenberghe 1928, #2154 65).
Furthermore, many new targeted therapeutics are likely to be efficacious in only one subgroup, such as smoothened inhibitors for SHH pathway-driven MB [ 1, 2].
Golimumab, one of the newest TNF blockers, was recently shown to be efficacious in improving not only the signs and symptoms of PsA, but also in treating the structural damage caused by the disease making it a reasonable option in treating moderate to severe PsA.
If blood COHb levels indeed reflect the amount of CO delivered to peripheral tissues, it is possible that inhaled CO would only be efficacious in humans once COHb reaches 'close to toxic' levels comparable to those achieved in rodent studies (e.g. 15 30%).
This may indicate that the D-enantiomers of the ceramide analogues we have used have additional actions (either direct or indirect) on APP processing that remain to be discovered and that inhibition of GSL synthesis alone (i.e. using siRNA targeting) may only be efficacious in situations where membrane GSL levels are increased above their physiological concentrations.
In 1998 the only drugs available to treat pulmonary hypertension were calcium channel antagonists and intravenous epoprostenol, although epoprostenol was only shown to be efficacious in children with IPAH in 1999.
