Search

Competing Interests: Competing interests: None declared.

A review of the evidence behind the DigiFab® dosing calculator, which provides dosing for digoxin immune Fab in patients with confirmed digoxin poisoning or overdose.

Complications related to methamphetamine use and abuse are common presentations seen in the emergency department. Standard management focuses on addressing the central nervous system and cardiovascular effects with the use of sedation and hemodynamic support. We describe a case report of a patient with methamphetamine toxicity and subsequent severe cardiomyopathy refractory to conventional management that responded to cardiovascular support with extracorporeal membrane oxygenation therapy (ECMO). A 22-year-old female was admitted in severe cardiogenic shock following intravenous administration of methamphetamine and oral fentanyl use. Despite aggressive treatment with benzodiazepines, intravenous fluids, vasopressors, vasodilators, antibiotics and inotropes, the patient's clinical status deteriorated, and she suffered a cardiac arrest. The patient was successfully resuscitated, and following the return of spontaneous circulation, ECMO was initiated. After 82 hours the patient was successfully weaned from ECMO with the recovery of her left ventricular function and no neurologic sequelae. The patient developed leg ischemia requiring embolectomy and open repair as a complication of ECMO cannulation. In our case, ECMO was used successfully in treating severe cardiac dysfunction from acute methamphetamine-induced cardiomyopathy and was used as a bridge to recovery. The complications seen in this patient emphasize the potential risks associated with this intervention and highlight the need for careful patient selection.

Intentional insulin overdose may lead to severe and refractory hypoglycemia. Exogenous dextrose administration is the mainstay of therapy for these patients and is effective in most cases. However, in patients with a functional pancreas, exogenous dextrose administration may precipitate endogenous insulin release leading to rebound hypoglycemia. We describe a case report of a 41-year-old woman who injected 300 units of insulin aspart with suicidal intent. Her initial blood glucose was 2.3 mmol/L (41 mg/dL). Over the next 12 hours, she experienced recurrent hypoglycemic episodes despite 10% dextrose infusions and 14 ampoules of 50% dextrose. Our patient experienced complications, including peripheral edema, related to the large volumes of intravenous dextrose required to attempt to maintain euglycemia. Octreotide, a somatostatin analogue, may help prevent dextrose-induced hypoglycemia and improve the management in select insulin overdose patients; large infusion volumes resulted in significant peripheral edema. Treatment with octreotide was initiated 12.5 hours post-injection and was followed by a stabilization of blood glucose concentration in this non-diabetic patient.

The preferred conformations of the orphan G-protein coupled receptor agonists (des-bromo) neuropeptide B [1-23] and neuropeptide W [1-23], referred to as NPB and NPW, have been determined by (1)H NMR, CD, and molecular modeling. The sequences of NPB and NPW are WYKPAAGHSSYSVGRAAGLLSGL and WYKHVASPRYHTVGRAAGLLMGL, respectively. These are hypothalamic peptides that exert their biological actions on GPR7 and GPR8 receptors. Micellar solutions using the membrane mimetic, sodium dodecylsulphate-d(25) (SDS), were used to mimic a physiological environment for the peptides. The secondary structure of NPB consists of a type II beta-turn involving residues Lys(3) to Ala(6). The C-terminal region of NPB exists in a conformational equilibrium between different secondary structures, including an alpha-helix from residues Arg(15) to Ser(21), and a 3(10)-helix from residues Ser(12) to Ser(21). The N-terminus of NPW exhibits a cation-pi interaction between the Lys(3) side chain and the quadrupole moment of the Trp(1) indole group. At the C-terminus of NPW, a well-defined alpha-helical conformation exists from Arg(15) to Met(21). As NPB and NPW have 91% sequence homology from residues Val(13) to Leu(23), with only residue 21 differing between the two peptides, the similar C-terminal secondary structures of these two peptides are consistent with the sequences. This is supported by the similar CD spectra. The different secondary structures at the N-termini for NPB and NPW point to the importance of the N-terminus in receptor binding. This is consistent with the work of Fujii et al. [J. Biol. Chem. 277, 34010-34016 (2002)] who observed that iodination of the NPB Tyr(2) resulted in decreased agonistic activity at GPR7. In addition, Tanaka et al. [Proc. Natl. Acad. Sci. USA 100, 6251-6256 (2003)] showed that deletion of Trp(1) from NPB or NPW drastically decreased activity at GPR7 for NPB and GPR7 and GPR8 for NPW. Therefore, we postulate that the N-terminus is involved in membrane recognition and receptor binding.

The preferred conformation of orexin-B, an orphan G-protein coupled receptor agonist (the human sequence is RSGPPGLQGRLQRLLQASGNHAAGILTM-NH(2)) has been determined by (1)H and (13)C 2D NMR spectroscopy and molecular modeling. Orexin-B has been implicated in sleep-wakefulness and feeding regulation. The membrane mimetic, sodium dodecylsulphate-d(25) (SDS), was used to mimic a physiological environment for the peptide. The secondary structure of orexin-B in SDS consists of two helical sections; helix I spans Leu(7) to Ser(18) and helix II spans Ala(22) to Leu(26). Helices I and II are believed to be involved in membrane binding, as is supported by the results of the spin label studies with 5-doxylstearic acid. Lee et al. (Eur. J. Biochem. 266, 831-839 (1999)) determined the [Phe(1)]-orexin-B conformation in water solution by NMR and showed that helix II extends from Ala(23) to Met(28). The C-terminal dipeptide, Thr(27)-Met(28), is unstructured is SDS, whereas in water it forms the end of helix II. The lack of apparent structure for Thr(27)-Met(28) in SDS allows the dipeptide to have conformational freedom to interact with the receptor. The conformation of orexin-B can now be used to explain the Ala substitution mutagenesis experiments and the D-amino acid substitution experiments (S. Asahi et al., Bioorg. Med. Chem. Lett. 13, 111-113, 2003). Asahi et al. have shown that Ala substitution from Gly(24) to Met(28) or D-amino acid substitution from Ala(23) to Met(28) causes a significant reduction in the potency of orexin-B for both OX(1)R and OX(2)R receptors. We postulate that helix II is involved in membrane recognition, and its binding to the membrane is essential for Thr(27)-Met(28) to adopt the correct receptor-binding conformation.