Severe toxicity following synthetic cannabinoid ingestion.

OBJECTIVE: To report a case of seizures and supraventricular tachycardia (SVT) following confirmed synthetic cannabinoid ingestion. BACKGROUND: Despite widespread use of legal synthetic cannabinoids, reports of serious toxicity following confirmed use of synthetic cannabinoids are rare. We report severe toxicity including seizures following intentional ingestion of the synthetic cannabinoid JWH-018 and detail confirmation by laboratory analysis. CASE REPORT: A healthy 48 year old man had a generalized seizure within thirty minutes of ingesting an ethanol mixture containing a white powder he purchased from the Internet in an attempt to get high. Seizures recurred and abated with lorazepam. Initial vital signs were: pulse, 106/min; BP, 140/88 mmHg; respirations, 22/min; temperature, 37.7 °C. A noncontrast computed tomography of the brain and EEG were negative, and serum chemistry values were normal. The blood ethanol concentration was 3.8 mg/dL and the CPK 2,649 U/L. Urine drug screening by EMIT was negative for common drugs of abuse, including tetrahydrocannabinol. On hospital day 1, he developed medically refractory SVT. The patient had no further complications and was discharged in his normal state of health 10 days after admission. The original powder was confirmed by gas chromatography mass spectrometry to be JWH-018, and a primary JWH-018 metabolite was detected in the patient's urine (200 nM) using liquid chromatography tandem mass spectrometry. DISCUSSION: Synthetic cannabinoids are legal in many parts of the world and easily obtained over the Internet. Data on human toxicity are limited and real-time confirmatory testing is unavailable to clinicians. The potential for toxicity exists for users mistakenly associating the dose and side effect profiles of synthetic cannabinoids to those of marijuana. CONCLUSION: Ingestion of JWH-018 can produce seizures and tachyarrhythmias. Clinicians, lawmakers, and the general public need to be aware of the potential for toxicity associated with synthetic cannabinoid use.

AP-1 activation and altered AP-1 composition in association with increased phosphorylation and expression of specific Jun and Fos family proteins induced by vinblastine in KB-3 cells.

Vinblastine and other microtubule inhibitors are important antitumor agents that cause mitotic arrest, and induce apoptosis through poorly understood mechanisms, in a wide variety of cell lines. The activating protein 1 (AP-1) transcription factor is a major target of the c-Jun NH2-terminal kinase (JNK) signaling pathway, which is activated by microtubule inhibitors. Therefore, we examined the effect of vinblastine on AP-1 composition and activity in human KB-3 carcinoma cells. Vinblastine caused highly selective effects on AP-1 proteins in a concentration- and time-dependent manner. Specifically, c-Jun, expressed at a low level in control cells, was greatly increased and phosphorylated, Jun D was phosphorylated, Jun B underwent phosphorylation and subsequently became undetectable, and Fra 1 expression was also greatly increased. In contrast. Fra 2, c-Fos, and Fos B were relatively unchanged by vinblastine. Changes in AP-1 preceded caspase 3 activation and, therefore, occurred prior to the commitment phase of apoptosis. With the exception of c-Jun, which was not affected by paclitaxel, the same alterations in AP-1 proteins occurred after exposure to vincristine, paclitaxel, and colchicine, demonstrating that these are general responses to microtubule inhibition. Supershift assays demonstrated that in control cells, AP-1 binding activity was mediated by Jun D/Fra 2 heterodimers, whereas after vinblastine treatment, AP-1 complexes also containing c-Jun and Fra 1 were present, suggesting that induction of these latter proteins by vinblastine is functionally significant. Consistent with these observations, vinblastine stimulated AP-1-dependent luciferase reporter gene transcription. These findings suggest that alterations in AP-1 composition and activity may be key events in the early response of KB-3 cells to microtubule inhibitors.