Evidence-based paediatrics

Evidence-based medicine is practised widely in some specialties and is now part of many undergraduate and graduate medical curricula. However, the extent to which it is used in clinical paediatric practice is not known and its expansion remains a major challenge. Access to technology which facilitates literature searching, and development of journals addressing specific paediatric problems, will encourage the use of evidence-based medicine by the busy paediatrician. Informed practice of evidence-based medicine will ensure that clinical expertise is complemented by a thorough search, evaluation and judicious application of relevant information from the medical literature.     

Dominant role for osmolality in the efficacy of glucose and glycine-containing oral rehydration solutions: studies in a rat model of secretory diarrhoea

The effect of osmolality on the efficacy of oral rehydration solutions (ORS) and the contribution of the amino acid glycine to water absorption from ORS have been studied in an animal model of secretory diarrhoea. After exposure to pure cholera toxin, rat small intestine (excluding the duodenum) was perfused in situ with seven different ORS. All ORS were derived from a "basic" solution containing Na 50, K 25, Cl 75 and glucose 50 mmol/l to which 25 or 50 mmol/l of glycine, glucose, or mannitol was added. All ORS reversed water secretion to absorption, but maximum water absorption was obtained with the "basic" solution with an osmolality of 200 mOsm/kg. When the osmolality of the "basic" solution was raised to 225 and 250 mOsm/kg by adding mannitol, water absorption decreased. At each of these osmolalities, substitution of mannitol by glycine or glucose resulted in similar increases in water absorption, but all modifications compared unfavourably with the "basic" solution. Net sodium secretion occurred with all ORS tested, despite net water absorption. These findings in a perfusion model of rat small intestine suggest that osmolality is a key factor influencing the efficacy of ORS and that addition of a second substrate, such as glycine, has no beneficial effects. Our results suggest that there is a maximal rate for water absorption from the small intestine which is inversely related to the osmolality of the perfusate.     

Anti-inhibitor Coagulant Complex (Autoplex) for treatment of factor VIII inhibitors in hemophilia

Fourteen individuals with severe hemophilia complicated by factor VIII inhibitors (1 to 132 Bethesda Units) were treated for 33 bleeding episodes with a new activated prothrombin complex concentrate, Anti- Inhibitor Coagulant Complex (Autoplex, Hyland, Glendale, Calif.). Excellent or good results were observed in 21 of 25 minor bleeding episodes treated, which included joint, soft tissue, and mucous membrane hemorrhages. Eight major bleeding problems (an epidural bleed, a puncture wound, 2 serious soft tissue hemorrhages, 2 lacerations, and 2 major surgical procedures) were treated with excellent (6) or good (2) results. No serious complications were encountered, but two children developed transient hypofibrinogenemia following Autoplex infusion. Although some shortening of the prothrombin time and activated partial thromboplastin time was noted after infusion of Autoplex, there is no useful laboratory test for monitoring therapy. Despite the unknown mechanism of action for bypassing factor VIII, Autoplex appears to be a useful and needed interim product and is safe and effective. In view of the possible potentiation of thrombosis concurrent use of fibrinolytic inhibitors should be avoided.     

LASSBio-881: an N-acylhydrazone transient receptor potential vanilloid subfamily type 1 antagonist orally effective against the hypernociception induced by capsaicin or partial sciatic ligation

Background and purpose:

Compound LASSBio-881 is an orally effective antinociceptive that binds to cannabinoid receptors and is active mainly on the neurogenic component of pain models. We investigated whether transient receptor potential vanilloid subfamily type 1 (TRPV1) channels are involved in the effects of LASSBio-881.

Experimental approach:

Modulation of capsaicin (CAP)- and low pH-induced currents was evaluated in TRPV1-expressing Xenopus oocytes. In vivo effects were evaluated in CAP-induced acute and inflammatory changes in nociception, as well as in partial sciatic ligation-induced thermal hypernociception.

Key results:

LASSBio-881 inhibited TRPV1 currents elicited by CAP with an IC₅₀ of 14 µM, and inhibited proton-gated currents by 70% at 20 µM. Functional interaction with CAP was surmountable. Locally applied LASSBio-881 decreased time spent in CAP-elicited nocifensive behaviour by 30%, and given orally it reduced measures of CAP- or carrageenan-evoked thermal hypernociception by 60 and 40% respectively. In addition, LASSBio-881 decreased the paw withdrawal responses to thermal stimuli of animals with sciatic neuropathy 7–11 days after nerve ligation, at a dose of 300 µmol·kg⁻¹·day⁻¹ p.o. At this dose, hyperthermia was not observed within 4 h following oral administration.

Conclusions and implications:

LASSBio-881 is a TRPV1 antagonist that apparently competes with CAP. Accordingly, LASSBio-881 inhibited nociception in models of acute, inflammatory and neuropathic pain presumed to involve TRPV1 signalling. These in vivo actions were not hindered by hyperthermia, a common side effect of other TRPV1 antagonists. We propose that the antinociceptive properties of LASSBio-881 are due to TRPV1 antagonism, although other molecular interactions may contribute to the effects of this multi-target drug candidate.