A Rare Case of Cannabinoid Hyperemesis Syndrome Secondary to Cannabidiol for Refractory Epilepsy.

Cannabinoid hyperemesis syndrome (CHS) is associated with tetrahydrocannabinol, and rarely has been reported with cannabidiol. Cannabidiol is used in treatment-refractory epilepsy. This is a case of a pediatric patient with Lennox-Gastaut syndrome on cannabidiol, who was started on the ketogenic diet with significant seizure reduction. However, within 6 months he developed monthly bouts of severe emesis unresponsive to conventional anti-emetic therapy. Based on the stereotypical nature of his vomiting episodes, CHS was suspected. Cannabidiol was discontinued and within 2 months his emesis resolved. He has had no increase in seizure frequency or hospitalizations for emesis since cannabidiol was discontinued nearly 1 year ago. This is the first case of CHS secondary to cannabidiol for refractory epilepsy reported in the literature. We review the mechanism by which cannabidiol is believed to reduce seizures and be both anti- and pro-emetic, mainly through interactions with cannabinoid receptors and transient receptor channels.

The pharmacokinetics of methamphetamine self-administration in male and female rats.

BACKGROUND: Because methamphetamine (METH) pharmacokinetics after single iv doses show significant differences between male and female rats, we hypothesized that pharmacokinetic differences in METH disposition could be a contributing factor to the patterns of METH self-administration behaviors in rats. METHODS: For the studies, we used a passive (non-contingent) METH dosing schedule consisting of 27 METH iv bolus injections (0.048mg/kg) over 2h derived from a previous active (contingent) METH self-administration behavioral study in male rats. After METH dosing of male and female Sprague-Dawley rats (n=5/group), METH and amphetamine serum concentrations were determined by LC-MS/MS. Pharmacokinetic analysis, including predictive mathematical simulations of the data, was then conducted. RESULTS: Male and female rats achieved relatively stable METH serum concentrations within 20min, which remained constant from 20 to 120min. While not statistically different, METH clearance and volume of distribution values for females were 25% and 33% lower (respectively) than males. Linear regression analysis of predicted METH concentrations from pharmacokinetic simulations versus observed concentrations showed a substantially better correlation with male data than female data (r(2)=0.71 vs. 0.56; slope=0.95 vs. 0.45, respectively). At 120min, the time of predicted peak METH serum concentrations, female values were 42% higher than expected, while male values were within 3%. CONCLUSIONS: Unlike METH male pharmacokinetic data, the female data was less predictable during multiple METH administrations and produced overall higher than expected METH concentrations. These findings demonstrate that METH pharmacokinetics could contribute to differences in METH self-administration behaviors in rats.

Variable manifestations of familial hemiplegic migraine associated with reversible cerebral edema in children.

Three children with familial hemiplegic migraine presented with right-sided weakness, speech difficulty, altered mental status, and gait abnormalities. These persistent aura signs were accompanied by left-sided slowing and cerebral dysfunction, documented by electroencephalograms. Cranial magnetic resonance imaging revealed cortical edema restricted to the left cerebral hemisphere. Follow-up electroencephalogram and imaging studies produced normal results 1-4 months afterward. However, cognitive changes persisted. Genetic testing demonstrated variable results: one child manifested a CACNA1A mutation compatible with familial hemiplegic migraine type 1, whereas another demonstrated an ATP1A2 sequence alteration. No known mutations were evident in the third child, with minor head trauma thought to precipitate the familial hemiplegic migraine. These findings demonstrate the variable clinical and genetic heterogeneity of childhood familial hemiplegic migraine.

Echinomycin decreases induction of vascular endothelial growth factor and hepatocyte regeneration in acetaminophen toxicity in mice.

Up-regulation of vascular endothelial growth factor (VEGF) is important to hepatocyte regeneration in the late stages of acetaminophen (APAP) toxicity in the mouse. This study was conducted to examine the relationship of hypoxia-inducible factor 1α (HIF-1α) to VEGF and hepatocyte regeneration in APAP toxicity using an inhibitor of HIF-1α DNA-binding activity, echinomycin (EC). B6C3F1 male mice were treated with APAP (200 mg/kg IP), followed by EC (0.15 mg IP) and killed at 4 hr. Serum alanine aminotransferase (ALT), necrosis, hepatic glutathione (GSH) and APAP protein adducts were comparable in the APAP/EC and the APAP/veh mice at 4 hr. Additional studies showed that high dose EC (0.3 mg) reduced hepatic VEGF but also lowered hepatic GSH. Subsequent studies were performed using the 0.15-mg dose of EC. Although EC 0.15 mg had no effect on hepatic VEGF levels at 8 hr, by 24 hr VEGF levels were decreased by 40%. Toxicity (ALT and histopathology) was comparable in the APAP and APAP/EC groups at 24 and 48 hr. Proliferating cell nuclear antigen expression was reduced by both Western blot analysis and immunohistochemical staining in the APAP/EC mice at 48 hr. The data support the hypothesis that induction of HIF-1α, its binding to DNA and subsequent expression of VEGF are important factors in hepatocyte regeneration in APAP toxicity in the mouse.

Indocyanine green clearance varies as a function of N-acetylcysteine treatment in a murine model of acetaminophen toxicity.

Standard assays to assess acetaminophen (APAP) toxicity in animal models include determination of ALT (alanine aminotransferase) levels and examination of histopathology of liver sections. However, these assays do not reflect the functional capacity of the injured liver. To examine a functional marker of liver injury, the pharmacokinetics of indocyanine green (ICG) were examined in mice treated with APAP, saline, or APAP followed by N-acetylcysteine (NAC) treatment.Male B6C3F1 mice were administered APAP (200 mg/kg IP) or saline. Two additional groups of mice received APAP followed by NAC at 1 or 4 h after APAP. At 24 h, mice were injected with ICG (10 mg/kg IV) and serial blood samples (0, 2, 10, 30, 50 and 75 min) were obtained for determination of serum ICG concentrations and ALT. Mouse livers were removed for measurement of APAP protein adducts and examination of histopathology. Toxicity (ALT values and histology) was significantly increased above saline treated mice in the APAP and APAP/NAC 4 h mice. Mice treated with APAP/NAC 1 h had complete protection from toxicity. APAP protein adducts were increased in all APAP treated groups and were highest in the APAP/NAC 1 h group. Pharmacokinetic analysis of ICG demonstrated that the total body clearance (Cl(T)) of ICG was significantly decreased and the mean residence time (MRT) was significantly increased in the APAP mice compared to the saline mice. Mice treated with NAC at 1 h had Cl(T) and MRT values similar to those of saline treated mice. Conversely, mice that received NAC at 4 h had a similar ICG pharmacokinetic profile to that of the APAP only mice. Prompt treatment with NAC prevented loss of functional activity while late treatment with NAC offered no improvement in ICG clearance at 24 h. ICG clearance in mice with APAP toxicity can be utilized in future studies testing the effects of novel treatments for APAP toxicity.

Sex differences in (+)-amphetamine- and (+)-methamphetamine-induced behavioral response in male and female Sprague-Dawley rats.

(+)-Methamphetamine (METH) and (+)-amphetamine (AMP) are structurally similar drugs that are reported to induce similar pharmacological effects in rats of the same sex. Because pharmacokinetic data suggest female rats should be more affected than males, the current studies sought to test the hypothesis that the behavioral and temporal actions of METH and AMP should be greater in female Sprague-Dawley rats than in males. Using a dosing regimen designed to reduce the possibility of tolerance and sensitization, rats were administered 1.0 and 3.0 mg/kg intravenous drug doses. Distance traveled, rearing events and focal stereotypies (e.g., head weaving, sniffing) were measured. Female rats traveled significantly greater distances and displayed a greater number of rearing events than males after both doses. Analysis of stereotypy ratings after 3.0 mg/kg revealed that focal stereotypies were more pronounced and lasted longer in females. The second study compared the potencies of METH and AMP in inducing locomotor activity and focal stereotypies in each sex. No differences in potency were found when METH and AMP effects were compared within males or females. In summary, these studies showed female rats displayed greater and longer-lasting locomotor activity and more stereotypic behaviors, supporting earlier evidence of significant sexual dimorphism in pharmacokinetics.

Sex- and dose-dependency in the pharmacokinetics and pharmacodynamics of (+)-methamphetamine and its metabolite (+)-amphetamine in rats.

These studies investigated how (+)-methamphetamine (METH) dose and rat sex affect the pharmacological response to METH in Sprague-Dawley rats. The first set of experiments determined the pharmacokinetics of METH and its pharmacologically active metabolite (+)-amphetamine (AMP) in male and female Sprague-Dawley rats after 1.0 and 3.0 mg/kg METH doses. The results showed significant sex-dependent changes in METH pharmacokinetics, and females formed significantly lower amounts of AMP. While the area under the serum concentration-time curve in males increased proportionately with the METH dose, the females showed a disproportional increase. The sex differences in systemic clearance, renal clearance, volume of distribution, and percentage of unchanged METH eliminated in the urine suggested dose-dependent pharmacokinetics in female rats. The second set of studies sought to determine the behavioral implications of these pharmacokinetic differences by quantifying locomotor activity in male and female rats after saline, 1.0, and 3.0 mg/kg METH. The results showed sex- and dose-dependent differences in METH-induced locomotion, including profound differences in the temporal profile of effects at higher dose. These findings show that the pharmacokinetic and metabolic profile of METH (slower METH clearance and lower AMP metabolite formation) plays a significant role in the differential pharmacological response to METH in male and female rats.

Use of anti-(+)-methamphetamine monoclonal antibody to significantly alter (+)-methamphetamine and (+)-amphetamine disposition in rats.

These studies examined the effects of a high-affinity anti-(+)-methamphetamine monoclonal antibody (mAb; KD = 11 nM) on (+)-methamphetamine [(+)-METH] and (+)-amphetamine [(+)-AMP] serum and tissue disposition and serum protein binding following i.v. (+)-METH administration. Male Sprague-Dawley rats were pretreated with a buffer solution (control rats) or with anti-(+)-METH mAb [equimolar in binding sites to the (+)-METH dose]. The next day, both groups received a 1 mg/kg i.v. (+)-METH dose. At various time points after (+)-METH administration, rats were sacrificed (n = 3 per time point), and serum and tissues were collected. (+)-METH serum protein binding was increased from approximately 5% in controls to approximately 88 to 99% in the mAb-treated rats. The (+)-METH area under the concentration versus time curves from 0 to 4.5 h (AUC0-4.5 h) in mAb-treated rats showed an increase of >6600% for serum and a decrease of >60% for brain, compared with buffer-treated controls. Differential effects of anti-METH mAb on (+)-METH concentrations were observed in other tissues. For example, in the liver, anti-(+)-METH mAb caused significant increases in (+)-METH concentrations. The AUC0-4.5 h for (+)-AMP, a pharmacologically active metabolite, was decreased by approximately 50% in all tissues examined. These data show that pretreatment with an anti-(+)-METH mAb can significantly alter the disposition of (+)-METH and (+)-AMP in rats. Since the mAb has no significant cross-reactivity with (+)-AMP, the data suggest that the mAb reduced (+)-METH metabolic clearance through high-affinity binding to (+)-METH. Finally, rapidly equilibrating tissues, like the brain, appear to be preferentially protected by the mAb.