A hot flash on tamoxifen metabolism.
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Antidepressive Agents, Second-Generation↗
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CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment.
BACKGROUND: The efficacy of tamoxifen therapy for the treatment of breast cancer varies widely among individuals. Plasma concentrations of the active tamoxifen metabolite endoxifen are associated with the cytochrome P450 (CYP) 2D6 genotype. We examined the effects of concomitant use of selective serotonin reuptake inhibitor antidepressants, which are CYP2D6 enzyme inhibitors commonly prescribed to treat hot flashes in women who take tamoxifen, and genotypes for genes that encode tamoxifen-metabolizing enzymes on plasma concentrations of tamoxifen and its metabolites. METHODS: Eighty patients with newly diagnosed with breast cancer who were beginning tamoxifen therapy (20 mg/day orally), 24 of whom were taking CYP2D6 inhibitors, were genotyped for common alleles of the CYP2D6, CYP2C9, CYP3A5, and sulfotransferase (SULT) 1A1 genes. Plasma concentrations of tamoxifen and its metabolites were measured after 1 and 4 months of tamoxifen therapy. Differences in plasma concentrations of tamoxifen and its metabolites between genotype groups were analyzed by the Wilcoxon rank sum test. All statistical tests were two-sided. RESULTS: Among all women, plasma endoxifen concentrations after 4 months of tamoxifen therapy were statistically significantly lower in subjects with a CYP2D6 homozygous variant genotype (20.0 nM, 95% confidence interval [CI] = 11.1 to 28.9 nM) or a heterozygous genotype (43.1 nM, 95% CI = 33.3 to 52.9 nM) than in those with a homozygous wild-type genotype (78.0 nM, 95%CI = 65.9 to 90.1 nM) (both P = .003). Among subjects who carried a homozygous wild-type genotype, the mean plasma endoxifen concentration for those who were using CYP2D6 inhibitors was 58% lower than that for those who were not (38.6 nM versus 91.4 nM, difference = -52.8 nM, 95% CI = -86.1 to -19.5 nM, P = .0025). The plasma endoxifen concentration was slightly reduced in women taking venlafaxine, a weak inhibitor of CYP2D6, whereas the plasma endoxifen concentration was reduced substantially in subjects who took paroxetine (a potent inhibitor of CYP2D6). Genetic variations of CYP2C9, CYP3A5, or SULT1A1 had no statistically significant associations with plasma concentrations of tamoxifen or its metabolites. CONCLUSION: Interactions between CYP2D6 polymorphisms and coadministered antidepressants and other drugs that are CYP2D6 inhibitors may be associated with altered tamoxifen activity.
Adult↗
Effects of components of Artemisia annua on coccidia infections in chickens.
Four experiments were run to test the anticoccidial activity of dried Artemisia annua leaves and several of their chemical constituents for possible use as prophylactic feed additives. When fed over a period of 3 wk at a level of 5%, a dried leaf supplement of A. annua provided significant protection against lesions due to Eimeria tenella but not Eimeria acervulina or Eimeria maxima. When fed over a period of 5 wk at a level of 1% to chicks undergoing immunization with a live vaccine, it provided significant protection in partially immunized chicks against E. acervulina and E. tenella lesions from a dual species challenge infection. It also afforded lower mean lesion scores in challenged chicks immunized over a period of 5 wk. Artemisinin, an antimalarial component of A. annua, was present at a level of 0.034% in the dried leaf preparation. A 5% supplement thus afforded about 17 ppm artemisin. When the pure compound was fed at that level for a period of 3 wk, it protected weight gains and significantly reduced lesion scores attributable to E. tenella but not E. acervulina. Other components of A. annua, camphor and 1,8-cineole, at 119 ppm also protected weight gains, and reduced E. tenella lesion scores. Camphor reduced E. acervulina lesions. Artemisinin fed for 4 wk at levels of 2, 8.5, and 17 ppm significantly reduced oocyst output from separate E. acervulina and E. tenella infections and a dual species infection. Pure artemisinin thus appears to be effective against at least two coccidia species when used as a feed additive, and its activity may depend, in part, on the length of time it is administered before a challenge infection.
Analysis of Variance↗
Relative toxicity of venlafaxine and selective serotonin reuptake inhibitors in overdose compared to tricyclic antidepressants.
BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) and venlafaxine have been regarded as less toxic in overdose than tricyclic antidepressants (TCAs). Within the TCAs, dothiepin has greater toxicity. Venlafaxine may be more toxic than SSRIs. AIM: To assess the toxicity in overdose of venlafaxine and SSRIs compared to TCAs, and of dothiepin compared to other TCAs. DESIGN: Cohort study of prospectively collected data from the Hunter area, NSW, Australia. METHODS: First admissions with antidepressant deliberate self-poisoning (DSP) (November 1994 to April 2000) were identified; the presence of seizures, life-threatening arrhythmias, coma, serotonin toxicity or ICU admission, and QRS duration were noted. RESULTS: There were 538 admissions, with no deaths. The odds ratio (OR) for seizures with dothiepin vs. other TCAs was 3.4 (95%CI 1.2-9.9). Seizures occurred in 7/51 (14%) venlafaxine overdoses; all patients with seizures consumed > or =900 mg. The OR for seizures vs. TCAs was 4.4 (95%CI 1.4-13.8). Coma was less likely with venlafaxine and SSRIs. SSRIs, but not venlafaxine, were less likely to prolong the QRS to > or =100 ms. ICU admission was less likely for SSRIs. Serotonin toxicity was much more common with venlafaxine and SSRIs. DISCUSSION: Venlafaxine and dothiepin are pro-convulsant in overdose. Venlafaxine is more likely to cause serotonin toxicity, but less likely to cause coma than TCAs. SSRIs are less likely to cause coma, require ICU admission, or prolong the QRS, but are more likely to cause serotonin toxicity. Antidepressants other than TCAs or venlafaxine should be considered in patients at risk of seizure or suicide.
Adolescent↗
Reversible focal myositis in a patient taking venlafaxine.
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Adult↗
Validation of a Dutch translation of the fibromyalgia impact questionnaire.
OBJECTIVES: To validate a Dutch translation of the fibromyalgia impact questionnaire (FIQ). MATERIALS AND METHODS: Data were taken from two randomized clinical trials on Spa treatment and venlafaxine in fibromyalgia (FM). Participants completed the Dutch FIQ and a set of validated questionnaires for general health (RAND-36), depression (Beck depression inventory, BDI), pain (McGill pain questionnaire, MPQ) and fatigue (checklist individual strength, CIS). Internal consistency within the FIQ item 'physical functioning' was studied using Cronbach's alpha. Test-retest reliability was studied with intra-class-correlation (ICC) in a subsample of 76 control subjects over a 3 month period without specific intervention. Construct validity was evaluated by correlating the FIQ to other questionnaires. Sensitivity to change was studied using standardized response means (SRM). RESULTS: The study sample consisted of 213 women and 11 men (mean age 47 yrs, mean disease duration 11 yrs). Cronbach's alpha for the item 'physical functioning' was 0.91, indicating high internal consistency. Test-retest reliability was acceptable, with ICC ranging from 0.45 for 'morning tiredness' to 0.71 for 'physical function'. FIQ correlated significantly with the RAND-36, with Spearman's rho ranging from -0.60 to -0.70 for items measuring the same concept. Similar patterns of correlation were seen with MPQ, BDI and CIS. Sensitivity to change was sufficient, with SRM after Spa treatment ranging from 0.3 for 'work days missed' to 0.9 for 'days felt good'. Similar SRM were found in the venlafaxine trial for patients reporting general improvement. CONCLUSION: The Dutch FIQ is a valid instrument for measuring health status in FM, showing sufficient reliability, construct validity and responsiveness.
Activities of Daily Living↗
Report of a case of immunosuppression with prednisone in an 8-year-old boy with an acute onset of hypocretin-deficiency narcolepsy.
OBJECTIVE: To explore whether acute destruction of hypocretin cells in a patient with narcolepsy could be detected and if the course of the disease could be reversed or altered by the use of prednisone for immunosuppression. DESIGN: Case report. SETTING: A sleep-clinic population in a tertiary-care hospital. PATIENT: An 8-year-old boy with a very acute recent (< 2 month) onset of sleepiness. METHODS: Sleep studies; fluid-attenuated inversion recovery and gadolinium magnetic resonance imaging studies with a focus on the hypothalamus; examinations of cerebrospinal fluid for cytology, protein, and hypocretin-1 levels; and HLA typing were performed. INTERVENTION: A 3-week regimen of 1 mg x kg(-1) x day(-1) of prednisone was administered in an attempt to modify the course of the disease. RESULTS AND CONCLUSION: Sleep evaluations were consistent with a diagnosis of narcolepsy. Hypocretin-1 was absent in the cerebrospinal fluid, and HLA-DQB1*0602 was present. All other results were within normal limits, and prednisone did not have any noticeable effects. Clinical manifestation of narcolepsy might occur when the hypocretin cell damage is too advanced to be reversible.
Acute Disease↗
Activation of brain-type cannabinoid receptors interferes with preimplantation mouse embryo development.
The recent identification and cloning of guanine nucleotide regulatory protein-coupled brain-type and spleen-type cannabinoid receptors (CB1-R and CB2-R, respectively) provide evidence that many of the effects of cannabinoids are mediated via these receptors. Our recent observation of expression of both CB1-R and CB2-R genes in the preimplantation mouse embryo suggests that it could also be a target for cannabinoids. Indeed, cannabinoid agonists interfered with preimplantation embryo development in vitro. To examine whether cannabinoid effects on preimplantation embryos are mediated via CB1-R, we developed rabbit antipeptide antibodies against the N-terminal region of CB1-R and examined the receptor protein in the blastocyst by Western blotting and its spatiotemporal distribution in preimplantation mouse embryos by immunohistochemistry. Cannabinoid binding sites in the blastocyst were examined by Scatchard analysis, while the reversibility of cannabinoid-induced embryonic arrest in vitro was monitored using a specific antagonist to CB1-R, SR141716A. Western blot analysis detected a major band of approximately 59 kDa and a minor band of approximately 54 kDa in the blastocyst. Immunocytochemistry detected this receptor protein from the 2-cell through the blastocyst stages. Scatchard analysis using 3H-anandamide (an endogenous ligand) showed a single class of binding sites in Day 4 blastocysts with an apparent Kd of 1.0 nM and Bmax of 0.09 fmol/blastocyst. Considering the total number of cells (approximately 50) and total protein content (approximately 20 ng) of a blastocyst, it is apparent that the mouse blastocyst has many more high-affinity receptors than those in the mouse brain (Kd: 1.8 nM and Bmax: 18.8 pmol/mg membrane protein). Cannabinoid agonists and the CB1-R antagonist SR141716A effectively competed for anandamide binding in the blastocyst. To determine whether cannabinoid inhibition of embryonic development could be reversed by SR141716A, 2-cell embryos were cultured in the presence of cannabinoid agonists with or without SR141716A for 72 h. Most of the 2-cell embryos cultured in the absence of the agonists developed into blastocysts (approximately 90%). In contrast, the addition of cannabinoid agonists anandamide, Win 55212-2, or CP 55,940 in the culture medium severely compromised embryonic development: more than 60% of the 2-cell embryos failed to develop to blastocysts. A reduction in trophectoderm cell numbers was noted in those blastocysts that escaped the developmental arrest in the presence of cannabinoid agonists. However, this reduction was corrected when embryos were cultured simultaneously with an agonist and SR141716A. Furthermore, embryonic arrest was reversed when embryos were cultured simultaneously in the presence of an agonist and SR141716A. The addition of SR141716A alone in the culture medium apparently had no effects on embryonic development: more than 90% of the embryos developed into blastocysts. The results suggest that the CB1 receptors in preimplantation mouse embryos are biologically active and cannabinoid effects on them are primarily mediated by these receptors.
Analgesics↗
Lethal combination of tramadol and multiple drugs affecting serotonin.
The death of a 36-year-old alcoholic man who died after developing seizure activity while being treated with tramadol, as well as with venlafaxine, trazodone, and quetiapine, all of which interact with the neurotransmitter serotonin, is reported. The decedent, who had a history of chronic back pain, alcoholism, depression, mild hypertensive cardiovascular disease, and gastritis, had just been discharged from the hospital after 4 days of alcohol detoxification treatment. During the admission, no withdrawal seizures were noted. The morning after discharge, a witness observed the decedent exhibiting seizure activity and then collapsing. An autopsy was performed approximately 6 hours after death, and the anatomic findings were consistent with seizure activity and collapse, which included biting injuries of the tongue and soft-tissue injuries of the face. Toxicologic analysis identified tramadol, venlafaxine, promethazine, and acetaminophen in the urine; tramadol (0.70 mg/L) and venlafaxine (0.30 mg/L) in the heart blood, and 0.10 mg of tramadol in 40 ml of submitted stomach contents. No metabolites, such as acetate, acetone, lactate, and pyruvate, were found in the specimens that would be characteristically found in a person with alcohol withdrawal syndrome. The threshold for seizures is lowered by tramadol. In addition, the risk for seizure is enhanced by the concomitant use of tramadol with selective serotonin reuptake inhibitors or neuroleptics, and its use in patients with a recognized risk for seizures, i.e., alcohol withdrawal. The cause of death in this individual was seizure activity complicating therapy for back pain, depression, and alcohol withdrawal syndrome. The data in Adverse Event Reporting System of the Food and Drug Administration from November 1, 1997 to September 8, 1999 was reviewed along with a MEDLINE search from 1966 to the present. This case appears to be the first reported death caused by seizure activity in a patient taking tramadol in combination with drugs that affect serotonin.
Adult↗
Presence of cannabinoid binding sites in the brain from early postnatal ages.
The present study demonstrates the presence of cannabinoid receptors in the brain from early postnatal ages. Specific and saturable binding was observed in the forebrain and remaining brain from early postnatal ages (2 and 5 days after birth). Female neonate forebrain exhibited a higher receptor density at 2 days after birth than males, but this trend was inverted at 5 days. From postnatal day 10, the receptors could be measured in more defined brain areas, i.e. the striatum, limbic forebrain and ventral mesencephalon. The ontogeny of the receptors in these three areas was relatively similar, exhibiting a progressive increase which maximised on days 30 or 40 and then subsequently decreased to adult values. Subtle sexual dimorphism was found in the striatum and ventral mesencephalon but not the limbic forebrain.
Aging↗
Chronic CP-55,940 alters cannabinoid receptor mRNA in the rat brain: an in situ hybridization study.
Using in situ hybridization we found that chronic treatment with CP-55,940 (0.4 mg kg-1, i.p. daily for 11 days), a synthetic cannabinoid receptor ligand, changed cannabinoid receptor mRNA levels in rat brain. CP-55,940 produced the expected tolerance: the decrease in locomotor activity (75%) caused by an acute dose was diminished to 25% after the 11 days of treatment. Thirty minutes after the last injection the animals were killed and in situ hybridization indicated that the levels of cannabinoid receptor mRNA in the caudate-putamen were reduced by 33%, with no alteration in the other brain areas. We suggest that the altered cannabinoid receptor expression is part of the adaptive changes underlying cannabinoid tolerance.
Animals↗
Induction of the Krox 24 transcription factor in striosomes by a cannabinoid agonist.
The striatum is composed of two compartments arranged as a mosaic, the striosomes (patches) and the matrix, which differ in their neurochemical and neuroanatomical properties. Along with a large number of neurotransmitter-related differences, these regions have recently been shown to differ in their immediate early gene (IEG) response to indirect dopamine agonists. Both Fos and Krox 24 can be preferentially induced in the striosomal compartment of the striatum by amphetamine. This compartmentalization of response suggests that there are functionally distinct molecular signalling pathways in striosomes and matrix. This paper examines the response of Krox 24 to i.p. administration of the cannabinoid agonist CP55,940 and demonstrates a selective induction of this protein within the striosomes 2 h after drug administration. This result suggests that cannabinoid receptors may regulate striatal gene expression.
Animals↗
Antisense oligodeoxynucleotide treatment to the brain cannabinoid receptor inhibits antinociception.
Studies using agonists from at least three major cannabinoid ligand groups suggest the mediation of several distinct effects (e.g. psychotropic, analgesia, and antiemetic) by the recently cloned CB1 cannabinoid receptor. However, other studies suggest the presence of multiple cannabinoid receptors and at least one other receptor (CB2) has been cloned. The present investigation was undertaken to determine whether one of the potential therapeutic actions of cannabinoids (i.e. antinociception) is mediated by the CB1 receptor using the antisense oligodeoxynucleotide 'knock-down' approach. Synthetic oligodeoxynucleotides complementary to the 5' end of the coding region of the mouse CB1 receptor mRNA were administered to mice by the intracerebro-ventricular (i.c.v.) route twice daily for 3 days. Mismatch oligodeoxynucleotides of similar sequence, but containing six mismatched positions out of the 18 nucleotides within the oligodeoxynucleotide were administered to other mice. Treatment with antisense oligodeoxynucleotides, but not mismatched oligodeoxynucleotides, greatly inhibited the antinociceptive response of the cannabinoid agonist CP-55,940. Untreated mice and those treated with mismatched oligodeoxynucleotides showed similar, full response antinociception after CP-55,940 administration. The data provides strong evidence that the CB1 receptor-ligand interaction is essential for the antinociceptive effect.
Analgesics↗
Cannabinoid-induced working memory impairment is reversed by a second generation cholinesterase inhibitor in rats.
Cannabinoids which impair rat working memory appear to inhibit hippocampal extracellular acetylcholine (Ach) release and reduce choline uptake through an interaction with CB1 cannabinoid receptors. Here we report that CP 55,940, a potent bicyclic synthetic cannabinoid analog, dose-dependently impaired rat performance, when given i.p. 20 min before an eight-arm radial maze test. The selective CB1 cannabinoid receptor antagonist SR 141716A, given i.p. 20 min earlier, significantly reduced the memory deficit Pretreatment with eptastigmine, a second generation cholinesterase inhibitor, given orally 100 min before the cannabinoid agonist, relieved the memory impairment without affecting CP 55,940-induced behavioural alterations such as reduced spontaneous motor activity, analgesia and hind limb splaying. These data suggest that cannabinoid-induced working memory impairment is mediated through a central cholinergic blockade.
Animals↗
Dramatic recovery of paclitaxel-disabling neurosensory toxicity following treatment with venlafaxine.
Venlafaxine is an antidepressant which acts through the inhibition of the reuptake of norepinephrine and serotonin. Venlafaxine is active against neuropathic and chronic pain. We report the case of a 69-year-old woman who presented a paclitaxel-induced neuropathy. She presented paresthesias, pin pricks in both hands with functional impairment. Venlafaxine hydrochloride was introduced at 37.5 mg twice daily. The patient noticed a dramatic recovery of her symptoms within 2 days, with both reduction of the paresthesias and functional improvement. This is the first report of efficacious use of venlafaxine for the treatment of paclitaxel cumulative neurosensory toxicity.
Adenocarcinoma↗
Protection against oxaliplatin acute neurosensory toxicity by venlafaxine.
Venlafaxine (Effexor; Wyeth Lederlé) has previously shown therapeutic effects for the management of chronic and neuropathic pains. We report here the efficacy of venlafaxine upon acute neurosensory symptoms secondary to oxaliplatin toxicity. A dose of 50 mg of venlafaxine was given orally at the beginning of the oxaliplatin infusion. Patients did not experience any or very low paresthesias, even in the cold. As the results were very dramatic and reproducible, we propose that venlafaxine may be of use in the daily management of oxaliplatin-related neurosensory toxicity.
Adult↗
Clinical activity of venlafaxine and topiramate against oxaliplatin-induced disabling permanent neuropathy.
Venlafaxine (Effexor; Wyeth Lederle), a serotoninergic-like anti-depressant, and Topiramate (Epitomax; Jansen Cilag), a new anti-epileptic drug, share some evidence of clinical activity in the treatment of neuropathic pain. Several anti-cancer agents have neurosensory toxicity as limiting toxicity of their repeated administration. One of the most recent and the most widely used is oxaliplatin. No medication is presently known to be active against oxaliplatin permanent neurosensory toxicity. We observed that venlafaxine hydrochloride or low-dose topiramate could be active against the permanent neuropathy-related symptoms of oxaliplatin. Both agents allowed pain relief and a significant autonomy improvement. These preliminary results invite us to evaluate further venlafaxine hydrochloride and topiramate for the treatment of permanent anti-cancer chemotherapy-induced neuropathies.
Aged↗
Effect of halving the dose of venlafaxine to adjust for putative pharmacokinetic and pharmacodynamic changes in an animal model of chronic hepatic encephalopathy.
Patients with chronic hepatic encephalopathy display monoaminergic perturbations together with affective symptoms. Thus, these patients belong to a group with a probability of receiving antidepressant drug treatment. The liver impairment may result in pharmacokinetic alterations of the antidepressant drug, which in turn may affect the already perturbed monoaminergic function. Venlafaxine (VEN) was administered as a single subcutaneous challenge to portacaval shunted (experimental hepatic encephalopathy model) rats (5 mg/kg) and sham-operated rats (5 and 10 mg/kg). The aims were to investigate whether a reduced dose in portacaval shunted rats resulted in higher concentrations of VEN and serotonin as compared to control rats, which had been demonstrated earlier when the rats received the same dose (10 mg/kg). A 50% reduction of the dose of VEN administered to portacaval shunted rats resulted in elevated levels of VEN in serum, brain parenchyma, and brain dialysate about 300 minutes after the injection. The VEN challenge increased the serotonin and noradrenaline concentrations in dialysate in portacaval shunted rats and both sham groups, but the three VEN groups did not differ in any major way in serotonin and noradrenaline output. Therefore, when the dose of VEN administered to experimental hepatic encephalopathy was reduced 50% as compared to control rats, mainly pharmacokinetic, and possibly also monoaminergic, alterations were observed.
Animals↗