A case-controlled comparison of postoperative analgesic dosing between girls with Rett syndrome and girls with and without developmental disability undergoing spinal fusion surgery.

BACKGROUND: Rett syndrome is associated with severe motor and communicative impairment making optimal postoperative pain management a challenge. There are case reports documenting reduced postoperative analgesic requirement in Rett syndrome. AIM: The goal of this preliminary investigation was to compare postoperative analgesic management among a sample of girls with Rett syndrome compared to girls with and without developmental disability undergoing spinal fusion surgery. METHOD: The medical records of eight girls with Rett syndrome (mean age = 13.2 years, sd = 1.9), eight girls with developmental disability (cerebral palsy; mean age = 13.1 years, sd = 2.0), and eight girls without developmental disability (adolescent idiopathic scoliosis; mean age = 13.4, sd = 1.8) were reviewed. Data related to demographics, medications, and route of drug administration were recorded. RESULTS: Girls with Rett syndrome received significantly fewer morphine equivalent opioids postoperatively (M = 0.26 mg·kg-1 ·day-1 , sd = 0.10) compared to girls with adolescent idiopathic scoliosis (M = 0.47mg·kg-1 ·day-1 , sd = 0.13; 95% CI -0.34 to -0.08; P = 0.001) and girls with CP (M = 0.40 mg·kg-1 per day, sd = 0.14; 95% CI -0.27 to -0.02; P = 0.01). Girls with Rett syndrome received significantly fewer opioid patient-controlled analgesic (PCA) bolus doses (given by proxy; M = 42.63, sd = 17.84) compared to girls with adolescent idiopathic scoliosis (M = 98.25, sd = 52.77; 95% CI -96.42 to -14.83; P = 0.01). There was also some evidence indicating girls with Rett syndrome received fewer bolus doses compared to girls with CP (M = 80.88, sd = 38.93; 95% CI -79.05 to 2.55; P = 0.06). On average, girls with Rett syndrome also received smaller total doses of acetaminophen, diazepam, and hydroxyzine. CONCLUSION: This study highlights possible discrepancies in postoperative pain management specific to girls with Rett syndrome and suggests further investigation is warranted to determine best practice for postoperative analgesic management for this vulnerable patient population.

Brain extracellular γ-hydroxybutyrate concentrations are decreased by L-lactate in rats: role in the treatment of overdoses.

PURPOSE: L-lactate represents a potential treatment for GHB overdose by inhibiting GHB renal reabsorption mediated by monocarboxylate transporters. Our objective was to assess the dose-dependence of L-lactate treatment, with and without D-mannitol, on GHB toxicokinetics/toxicodynamics (TK/TD). METHODS: Rats were administered GHB 600 mg/kg i.v. with L-lactate (low and high doses), D-mannitol, or L-lactate (low dose) with D-mannitol. GHB-induced sleep time and GHB plasma, urine and brain extracellular fluid (ECF) concentrations (by LC/MS/MS) were determined. The effect of L-lactate and D-mannitol on the uptake and efflux of GHB was assessed in rat brain endothelial RBE4 cells. RESULTS: L-lactate treatment increased GHB renal clearance from 1.4 ± 0.1 ml/min/kg (control) to 2.4 ± 0.2 and 4.7 ± 0.5 ml/min/kg after low and high doses, respectively, and reduced brain ECF AUC values to 65 and 25% of control. Sleep time was decreased from 137 ± 12 min (control) to 91 ± 16 and 55 ± 5 min (low and high L-lactate, respectively). D-mannitol did not alter GHB TK/TD and did not alter L-lactate's effects on GHB TK/TD. L-lactate, but not D-mannitol, inhibited GHB uptake, and increased GHB efflux from RBE4 cells. CONCLUSIONS: L-lactate decreases plasma and brain ECF concentrations of GHB, decreasing sedative/hypnotic effects.

Brain uptake of the drug of abuse γ-hydroxybutyric acid in rats.

γ-Hydroxybutyric acid (GHB) is an endogenous compound and a substrate for the ubiquitous monocarboxylate transporter (MCT) family. GHB is also a drug of abuse due to its sedative/hypnotic and euphoric effects, with overdoses resulting in toxicity and death. The goal of this study was to characterize the distribution of GHB into the brain using in vivo microdialysis and in vitro uptake studies and to determine concentration-effect relationships for GHB in a rat animal model. GHB was administered to rats (400, 600, and 800 mg/kg i.v.), and blood, dialysate, and urine were collected for 6 h post-GHB administration. The GHB plasma and extracellular fluid (ECF) concentration-time profiles revealed that GHB concentrations in ECF closely followed plasma GHB concentrations. Sleep time increased in a dose-dependent manner (91 ± 18, 134 ± 11, and 168 ± 13 min, for GHB 400, 600, and 800 mg/kg, respectively). GHB partitioning into brain ECF was not significantly different at 400, 600, and 800 mg/kg. GHB uptake in rat and human brain endothelial cells exhibited concentration dependence. The concentration-dependent uptake of GHB at pH 7.4 was best-fit to a single-transporter model [K(m) = 18.1 mM (human), 23.3 mM (rat), V(max) = 248 and 258 pmol · mg(-1) · min(-1) for human and rat, respectively]. These findings indicate that although GHB distribution into the brain is mediated via MCT transporters, it is not capacity-limited over the range of doses studied in this investigation.

Sertraline dosing trends in children and adolescents stratified by CYP2C19 genotype.

Aim: Sertraline is a CYP2C19 substrate commonly prescribed to children with anxiety. Materials & methods: This medical record review examined dosing trends and treatment discontinuation in children prescribed sertraline with documented CYP2C19 genotypes. Variables collected included age, weight, diagnosis, concomitant medications, initial sertraline dose, dose changes and CYP2C19 genotypes. Results: A total of 90 individuals (average age: 10.5 years; 40% female) were included. Nearly 80% were prescribed sertraline for anxiety. Initial weight-adjusted doses were similar, but mean weight-adjusted doses of sertraline were 65% higher in increased metabolizers (1.5 mg/kg/day) compared with normal metabolizers (0.91 mg/kg/day; p = 0.067) at the second dose change. Conclusion: While all children started at a similar sertraline dose, different trends in prescribed doses were observed across CYP2C19 genotypes at subsequent dose changes.

Proteomic analysis uncovers novel actions of the neurosecretory protein VGF in nociceptive processing.

Peripheral tissue injury is associated with changes in protein expression in sensory neurons that may contribute to abnormal nociceptive processing. We used cultured dorsal root ganglion (DRG) neurons as a model of axotomized neurons to investigate early changes in protein expression after nerve injury. Comparing protein levels immediately after DRG dissociation and 24 h later by proteomic differential expression analysis, we found a substantial increase in the levels of the neurotrophin-inducible protein VGF (nonacronymic), a putative neuropeptide precursor. In a rodent model of nerve injury, VGF levels were increased within 24 h in both injured and uninjured DRG neurons, and the increase persisted for at least 7 d. VGF was also upregulated 24 h after hindpaw inflammation. To determine whether peptides derived from proteolytic processing of VGF participate in nociceptive signaling, we examined the spinal effects of AQEE-30 and LQEQ-19, potential proteolytic products shown previously to be bioactive. Each peptide evoked dose-dependent thermal hyperalgesia that required activation of the mitogen-activated protein kinase p38. In addition, LQEQ-19 induced p38 phosphorylation in spinal microglia when injected intrathecally and in the BV-2 microglial cell line when applied in vitro. In summary, our results demonstrate rapid upregulation of VGF in sensory neurons after nerve injury and inflammation and activation of microglial p38 by VGF peptides. Therefore, VGF peptides released from sensory neurons may participate in activation of spinal microglia after peripheral tissue injury.

Concentration-effect relationships for the drug of abuse gamma-hydroxybutyric acid.

gamma-Hydroxybutyric acid (GHB) is an endogenous neurotransmitter that is abused because of its sedative/hypnotic and euphoric effects. The objectives of this study were to evaluate the concentration-effect relationships of GHB in plasma, cerebrospinal fluid (CSF), brain (whole and discrete brain regions), and brain frontal cortex extracellular fluid. This information is crucial for future studies to evaluate effects of therapeutic interventions on the toxicodynamics of GHB. GHB (200-1000 mg/kg) was administered intravenously to rats, and plasma and frontal cortex microdialysate samples were collected for up to 6 h after the dose, or plasma, CSF, and brain (whole, frontal cortex, striatum, and hippocampus) concentrations were determined at the offset of its sedative/hypnotic effect [return to righting reflex (RRR)]. GHB-induced changes in the brain neurotransmitters gamma-aminobutyric acid (GABA) and glutamate were also determined. GHB, GABA, and glutamate concentrations were measured by liquid chromatography/tandem mass spectrometry. GHB-induced sleep time significantly increased in a dose-dependent manner (20-fold increase from 200 to 1000 mg/kg). GHB concentrations in plasma (300-400 microg/ml), whole brain (70 microg/g), discrete brain regions (80-100 microg/g), and brain microdialysate (29-39 microg/ml) correlated with RRR. In contrast, CSF GHB and GABA and glutamate concentrations in discrete brain regions exhibited no relationship with RRR. Our results suggest that GHB-induced sedative/hypnotic effects are mediated directly by GHB and that at high GHB doses, GABA formation from GHB may not contribute to the observed sedative/hypnotic effect. These results support the use of a clinical GHB detoxification strategy aimed at decreasing plasma and brain GHB concentrations after GHB overdoses.

Combined active and passive immunization enhances the efficacy of immunotherapy against nicotine in rats.

Vaccination against nicotine reduces the behavioral effects of nicotine in rats, and it is under clinical evaluation as a treatment for tobacco addiction. Efficacy is limited by the need for high serum nicotine-specific antibody (NicAb) levels, and currently available nicotine vaccines do not uniformly generate the required NicAb levels. Passive immunization with a nicotine-specific monoclonal antibody (Nic311) has also shown efficacy in rats. The principal aim of this study was to determine whether the combined use of vaccination and passive immunization would produce greater effects than vaccination alone on nicotine pharmacokinetics and locomotor sensitization (LMS) to nicotine. Rats were treated with vaccination alone, Nic311 alone, both, or neither, and then they were administered 10 daily injections of 0.3 mg/kg nicotine s.c. Treatment with Nic311 or vaccination alone increased the binding of nicotine in serum, reduced the unbound serum nicotine concentration and nicotine distribution to brain, and attenuated the development of LMS. Combined use of vaccination and passive immunization produced higher total serum NicAb levels, greater changes in nicotine pharmacokinetics, and a greater attenuation of LMS than either treatment alone. The total serum NicAb concentration was significantly correlated with brain nicotine levels and locomotor activity. These data indicate that providing higher serum NicAb concentrations improves the efficacy of immunotherapy against nicotine and that supplementing vaccination with passive immunization is a potential strategy to accomplish this.

Predictors of the nicotine reinforcement threshold, compensation, and elasticity of demand in a rodent model of nicotine reduction policy.

BACKGROUND: The FDA is considering reducing the nicotine content in tobacco products as a population-based strategy to reduce tobacco addiction. Research is needed to determine the threshold level of nicotine needed to maintain smoking and the extent of compensatory smoking that could occur during nicotine reduction. Sources of variability in these measures across sub-populations also need to be identified so that policies can take into account the risks and benefits of nicotine reduction in vulnerable populations. METHODS: The present study examined these issues in a rodent nicotine self-administration model of nicotine reduction policy to characterize individual differences in nicotine reinforcement thresholds, degree of compensation, and elasticity of demand during progressive reduction of the unit nicotine dose. The ability of individual differences in baseline nicotine intake and nicotine pharmacokinetics to predict responses to dose reduction was also examined. RESULTS: Considerable variability in the reinforcement threshold, compensation, and elasticity of demand was evident. High baseline nicotine intake was not correlated with the reinforcement threshold, but predicted less compensation and less elastic demand. Higher nicotine clearance predicted low reinforcement thresholds, greater compensation, and less elastic demand. Less elastic demand also predicted lower reinforcement thresholds. CONCLUSIONS: These findings suggest that baseline nicotine intake, nicotine clearance, and the essential value of nicotine (i.e. elasticity of demand) moderate the effects of progressive nicotine reduction in rats and warrant further study in humans. They also suggest that smokers with fast nicotine metabolism may be more vulnerable to the risks of nicotine reduction.

Mechanistic toxicokinetic model for gamma-hydroxybutyric acid: inhibition of active renal reabsorption as a potential therapeutic strategy.

gamma-Hydroxybutyric acid (GHB), a drug of abuse, exhibits saturable renal clearance and capacity-limited metabolism. The objectives of this study were to construct a mechanistic toxicokinetic (TK) model describing saturable renal reabsorption and capacity-limited metabolism of GHB and to predict the effects of inhibition of renal reabsorption on GHB TK in the plasma and urine. GHB was administered by iv bolus (200-1,000 mg/kg) to male Sprague-Dawley rats and plasma and urine samples were collected for up to 6 h post-dose. GHB concentrations were determined by LC/MS/MS. GHB plasma concentration and urinary excretion were well-described by a TK model incorporating plasma and kidney compartments, along with two tissue and two ultrafiltrate compartments. The estimate of the Michaelis-Menten constant for renal reabsorption (K (m,R)) was 0.46 mg/ml which is consistent with in vitro estimates of monocarboxylate transporter (MCT)-mediated uptake of GHB (0.48 mg/ml). Simulation studies assessing inhibition of renal reabsorption of GHB demonstrated increased time-averaged renal clearance and GHB plasma AUC, independent of the inhibition mechanism assessed. Co-administration of GHB (600 mg/kg iv) and L: -lactate (330 mg/kg iv bolus plus 121 mg/kg/h iv infusion), a known inhibitor of MCTs, resulted in a significant decrease in GHB plasma AUC and an increase in time-averaged renal clearance, consistent with the model simulations. These results suggest that inhibition of renal reabsorption of GHB is a viable therapeutic strategy for the treatment of GHB overdoses. Furthermore, the mechanistic TK model provides a useful in silico tool for the evaluation of potential therapeutic strategies.

Passive immunization with a nicotine-specific monoclonal antibody decreases brain nicotine levels but does not precipitate withdrawal in nicotine-dependent rats.

Vaccination against nicotine is under investigation as a treatment for tobacco dependence. Passive immunization with nicotine-specific antibodies represents a complementary strategy to vaccination. A potential adverse effect of passive immunization in nicotine-dependent individuals is that it may lead to a rapid reduction in brain nicotine levels and trigger withdrawal. The goal of this study was to determine if passive immunization with the nicotine-specific monoclonal antibody Nic311 precipitated withdrawal in nicotine-dependent rats as measured by increases in brain reward thresholds and somatic signs. Another cohort of rats was used to measure brain nicotine levels after Nic311 administration. Nic311 30, 80 or 240 mg/kg reduced brain nicotine concentrations by 45, 83 or 92% compared to controls. None of these Nic311 doses precipitated withdrawal measured at intervals up to 72 h following antibody administration. Administration of the nicotinic antagonist mecamylamine precipitated a robust nicotine withdrawal syndrome. Therefore, a substantial, but not complete, acute reduction in brain nicotine levels following passive immunization was not sufficient to precipitate nicotine withdrawal in nicotine-dependent rats. The Nic311 doses used have been shown to attenuate the behavioral effects of nicotine, suggesting that the use of passive immunization to treat nicotine addiction is not likely to precipitate withdrawal.