One of the critical mechanisms by which alcohol heightens aggression involves forebrain serotonin (5-HT) systems, possibly via actions on 5-HT1A receptors. The present experiments tested the hypothesis that activating 5-HT1A receptors by selective agonists will block the aggression-heightening effects of ethanol. Initially, the selective antagonist WAY 100635 was used to assess whether or not the changes in aggressive behavior after treatment with 8-OH-DPAT and flesinoxan result from action at the 5-HT1A receptors. Resident male CFW mice engaged in aggressive behavior (i.e. attack bites, sideways threats, tail rattle) during 5-min confrontations with a group-housed intruder male. Quantitative analysis of the behavioral repertoire revealed systematic reductions in all salient elements of aggressive behavior after treatment with 8-OH-DPAT (0.1-0.3 mg/kg, i.p.) or flesinoxan (0.1-1.0 mg/kg, i.p.). The 5-HT1A agonists also reduced motor activities such as walking, rearing and grooming, although to a lesser degree. Pretreatment with the antagonist WAY 100635 (0.1 mg/kg, i.p.) shifted the agonist dose-effect curves for behavioral effects to the right. In a further experiment, oral ethanol (1.0 g/kg, p.o.) increased the frequency of attacks in excess of 2 SD from their mean vehicle level of attacks in 19 out of 76 resident mice. Low doses of 8-OH-DPAT (0.03-0.3 mg/kg) and flesinoxan (0.1, 0.3, 0.6 mg/kg), given before the ethanol treatment, attenuated the alcohol-heightened aggression in a dose-dependent fashion. By contrast, these low 5-HT1A agonist doses affected motor activity in ethanol-treated resident mice to a lesser degree, suggesting behavioral specificity of these anti-aggressive effects. The current results support the hypothesized significant role of 5-HT1A receptors in the aggression-heightening effects of alcohol. If these effects are in fact due to action at somatodendritic 5-HT1A autoreceptors, then the anti-aggressive effects would be associated with decreased 5-HT neurotransmission.
Immunomodulatory drugs like thalidomide and lenalidomide are being increasingly used for the treatment of patients with multiple myeloma and myelodysplastic syndromes. In contrast to thalidomide, which undergoes nonenzymatic hydrolysis in the plasma, approximately two-thirds of lenalidomide is eliminated unchanged through the kidneys in healthy volunteers. The risk of adverse reactions is expected to be greater in lenalidomide-treated patients with impaired renal function. 1,2 We would like to alert clinicians to the possibility of lenalidomide-induced hepatotoxicity when the drug is given in the setting of mild renal impairment after observing this rare side effect in a patient with multiple myeloma.A He began treatment with thalidomide (200 mg daily) and dexamethasone for 2 cycles but subsequently developed peripheral neuropathy and fatigue. His disease remained refractory to treatments including vincristine, adriamycin, and dexamethasone (VAD); bortezomib; and autologous stem cell transplantation. He was hospitalized for hypercalcemia, which improved from 0.45 mM to 0.275 mM (1.8 mg/dL to 1.1 mg/dL) after conservative management, and renal insufficiency. The patient was started on lenalidomide 25 mg orally daily and dexamethasone 40 mg orally on days 1 to 4, with warfarin 1 mg and aspirin 325 mg as venous thromboembolism prophylaxis. He was not receiving any hepatotoxic medications. One week later, he developed significant fatigue and hyperbilirubinemia (Figure 1). Lenalidomide was considered as a potential source of the liver function test abnormalities and discontinued. Further evaluation included an abdominal sonogram that showed mild hepatomegaly (16.5 cm) and 2 incidental hemangiomas (辖 2 cm) but no bile duct dilatation or thrombi in hepatic veins. An abdominal magnetic resonance imaging (MRI) confirmed the hemangiomas but did not reveal any other specific pathology. He had complete normalization of his liver function profile 16 days following discontinuation of lenalidomide.In a review of lenalidomide toxicities by Hussein, 3 grade 2 liver enzyme elevations were described in 1 patient in a single-agent lenalidomide study. There was a similar association with fatigue, and a liver biopsy showed no specific pathology. Elevations in liver enzymes recurred after the patient was rechallenged with a lower dose.It is possible that our patient's reduced renal function played a role in the development of hepatotoxicity. The development of hepatotoxicity in this patient and its subsequent improvement coincided with the initiation and discontinuation of lenalidomide. This provides a temporal relationship and the basis for a strong association of hepatotoxicity induced by lenalidomide. As use of this drug expands, clinicians must recognize hepatotoxicity as a rare but potential complication of lenalidomide therapy. Since the drug is excreted mainly via the kidney as unchanged drug, higher caution would be warranted in patients with preexisting liver or kidney disease.
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