Clozapine-N-oxide (CNO) has long been the ligand of choice for selectively activating Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). However, recent studies have challenged the ...long-held assertion that CNO is otherwise pharmacologically inert. The present study aimed to 1) determine whether CNO is reverse-metabolized to its parent compound clozapine in mice (as has recently been reported in rats), and 2) determine whether CNO exerts clozapine-like interoceptive stimulus effects in rats and/or mice. Following administration of 10.0 mg/kg CNO, pharmacokinetic analyses replicated recent reports of back-conversion to clozapine in rats and revealed that this phenomenon also occurs in mice. In rats and mice trained to discriminate 1.25 mg/kg clozapine from vehicle, CNO (1.0-20.0 mg/kg) produced partial substitution for the clozapine stimulus on average, with full substitution being detected in some individual animals of both species at doses frequently used to activate DREADDs. The present demonstration that CNO is converted to clozapine and exerts clozapine-like behavioral effects in both mice and rats further emphasizes the need for appropriate control groups in studies employing DREADDs, and highlights the utility of the drug discrimination procedure as a tool with which to screen the off-target effects of novel DREADD agonists.
The Predictors of Remission in Depression to Individual and Combined Treatments PReDICT study aimed to identify clinical and biological factors predictive of treatment outcomes in major depressive ...disorder among treatment-naive adults. The authors evaluated the efficacy of cognitive-behavioral therapy (CBT) and two antidepressant medications (escitalopram and duloxetine) in patients with major depression and examined the moderating effect of patients' treatment preferences on outcomes.
Adults aged 18-65 with treatment-naive major depression were randomly assigned with equal likelihood to 12 weeks of treatment with escitalopram (10-20 mg/day), duloxetine (30-60 mg/day), or CBT (16 50-minute sessions). Prior to randomization, patients indicated whether they preferred medication or CBT or had no preference. The primary outcome was change in the 17-item Hamilton Depression Rating Scale (HAM-D), administered by raters blinded to treatment.
A total of 344 patients were randomly assigned, with a mean baseline HAM-D score of 19.8 (SD=3.8). The mean estimated overall decreases in HAM-D score did not significantly differ between treatments (CBT: 10.2, escitalopram: 11.1, duloxetine: 11.2). Last observation carried forward remission rates did not significantly differ between treatments (CBT: 41.9%, escitalopram: 46.7%, duloxetine: 54.7%). Patients matched to their preferred treatment were more likely to complete the trial but not more likely to achieve remission.
Treatment guidelines that recommend either an evidence-based psychotherapy or antidepressant medication for nonpsychotic major depression can be extended to treatment-naive patients. Treatment preferences among patients without prior treatment exposure do not significantly moderate symptomatic outcomes.
Abstract
Background
Venlafaxine is a dual serotonin (5-HT) and norepinephrine reuptake inhibitor. The specific dose at which it begins to efficiently engage the norepinephrine transporter (NET) ...remained to be determined. Paroxetine is generally considered as a selective 5-HT reuptake inhibitor but exhibits some affinity for NET. Atomoxetine is a NET inhibitor but also has some affinity for the 5-HT reuptake transporter (SERT).
Methods
This study examined the effects of forced titration of venlafaxine from 75 to 300 mg/d, paroxetine from 20 to 50 mg/d, or atomoxetine from 25 to 80 mg/d in 32 patients with major depressive disorder. Inhibition of SERT was estimated using the depletion of whole-blood 5-HT. Inhibition of NET was assessed using the attenuation of the systolic blood pressure produced by i.v. injections of tyramine.
Results
All 3 medications significantly reduced 5-HT levels at the initiating regimens: venlafaxine and paroxetine by approximately 60% and atomoxetine by 16%. The 3 subsequent regimens of venlafaxine and paroxetine reduced 5-HT levels by over 90%, but the highest dose of atomoxetine only reached a 40% inhibition. Atomoxetine dose dependently inhibited the tyramine pressor response from the lowest dose, venlafaxine from 225 mg/d, and paroxetine left it unaltered throughout.
Conclusion
These results confirm that venlafaxine and paroxetine are potent SERT inhibitors over their usual therapeutic range but that venlafaxine starts inhibiting NET only at 225 mg/d, whereas paroxetine remains selective for SERT up to 50 mg/d. Atomoxetine dose dependently inhibits NET from a low dose but does not inhibit SERT to a clinically relevant degree.
To characterize the magnitude and time course of pregnancy-related clearance changes for different antiepileptic drugs (AEDs): levetiracetam, oxcarbazepine, topiramate, phenytoin, and valproate. A ...secondary aim was to determine if a decreased AED serum concentration was associated with increased seizure frequency.
Women with epilepsy were enrolled preconception or early in pregnancy and prospectively followed throughout pregnancy and the first postpartum year with daily diaries of AED doses, adherence, and seizures. Study visits with AED concentration measurements occurred every 1-3 months. AED clearances in each trimester were compared to nonpregnant baseline using a mixed linear regression model, with adjustments for age, race, and hours postdose. In women on monotherapy, 2-sample
test was used to compare the ratio to target concentrations (RTC) between women with seizure worsening each trimester and those without.
AED clearances were calculated for levetiracetam (n = 18 pregnancies), oxcarbazepine (n = 4), topiramate (n = 10), valproate (n = 5), and phenytoin (n = 7). Mean maximal clearances were reached for (1) levetiracetam in first trimester (1.71-fold baseline clearance) (
= 0.0001), (2) oxcarbazepine in second trimester (1.63-fold) (
= 0.0001), and (3) topiramate in second trimester (1.39-fold) (
= 0.025). In 15 women on AED monotherapy, increased seizure frequency in the first, second, and all trimesters was associated with a lower RTC (
< 0.05).
AED clearance significantly changes by the first trimester for levetiracetam and by the second trimester for oxcarbazepine and topiramate. Lower RTC was associated with seizure worsening. Early therapeutic drug monitoring and dose adjustment may be helpful to avoid increased seizure frequency.
Using high-frequency blood sampling, we demonstrate glucocorticoid fast feedback (FF) mediated by endogenous cortisol in 6 normal humans.
We stimulated adrenocorticotropic hormone (ACTH) secretion by ...ovine corticotropin-releasing hormone (oCRH) with the experimental paradigm in which a high-frequency blood sampling was designed for plasma ACTH and cortisol determinations.
We saw previously unrecognized variability in the timing of key events such as onsets of ACTH and cortisol secretion, onset and offset of FF, and in FF duration. This variability mandated analyses referenced to case-wise event times rather than referenced simply to time since oCRH administration. The mean time of FF onset was 4.0 min (range 0-9; median 3) after cortisol secretion began, and the mean FF duration was 7.5 min (range 3-18; median 6.0). The FF effect was rate-sensitive and does not reflect level-sensitive cortisol feedback. In agreement with previous estimates using hydrocortisone infusions, the rate of rise of cortisol that triggered FF was approximately 44 nmol/L/min or 1.6 µg/dL/min. FF onset followed the trigger cortisol slope with an average lag of 1 min (range 0-3; median 0). Unexpectedly, this trigger cortisol slope quickly declined within the FF period.
This experimental design may enable new physiological studies of human FF that is mediated by endogenous cortisol, including mechanisms, reproducibility, and generalizability to other activating stimuli.
Abstract
Background
Plasma bedaquiline clearance is reportedly more rapid with African ancestry. Our objective was to determine whether genetic polymorphisms explained between-individual variability ...in plasma clearance of bedaquiline, its M2 metabolite, and clofazimine in a cohort of patients treated for drug-resistant tuberculosis in South Africa.
Methods
Plasma clearance was estimated with nonlinear mixed-effects modeling. Associations between pharmacogenetic polymorphisms, genome-wide polymorphisms, and variability in clearance were examined using linear regression models.
Results
Of 195 cohort participants, 140 were evaluable for genetic associations. Among 21 polymorphisms selected based on prior genome-wide significant associations with any drug, rs776746 (CYP3A5∗3) was associated with slower clearance of bedaquiline (P = .0017) but not M2 (P = .25). CYP3A5∗3 heterozygosity and homozygosity were associated with 15% and 30% slower bedaquiline clearance, respectively. The lowest P value for clofazimine clearance was with VKORC1 rs9923231 (P = .13). In genome-wide analyses, the lowest P values for clearance of bedaquiline and clofazimine were with RFX4 rs76345012 (P = 6.4 × 10−7) and CNTN5 rs75285763 (P = 2.9 × 10−8), respectively.
Conclusions
Among South Africans treated for drug-resistant tuberculosis, CYP3A5∗3 was associated with slower bedaquiline clearance. Different CYP3A5∗3 frequencies among populations may help explain the more rapid bedaquiline clearance reported in Africans. Associations with RFX4 and CNTN5 are likely by chance alone.
In a cohort of patients treated for drug-resistant tuberculosis in South Africa, CYP3A5∗3was associated with slower plasma bedaquiline clearance. Different CYP3A5∗3minor allele frequencies among populations may help explain the more rapid bedaquiline clearance previously reported with African ancestry.
ObjectivesThis study examined patterns of sexual violence against adults and children in Kenya during the COVID-19 pandemic to inform sexual violence prevention, protection, and response ...efforts.DesignA prospective cross-sectional research design was used with data collected from March to August 2020.SettingKenya.Participants317 adults, 224 children.Main measuresPerpetrator and survivor demographic data, characteristics of the assault.ResultsBivariate analyses found that children were more likely than adults to be attacked during daytime (59% vs 44%, p<0.001) by a single perpetrator rather than multiple perpetrators (31% vs 13%, p<0.001) in a private as opposed to a public location (66% vs 45%, p<0.001) and by someone known to the child (76% vs 58%, p<0.001). Children were violated most often by neighbours (29%) and family members (20%), whereas adults were equally likely to be attacked by strangers (41%) and persons known to them (59%). These variables were entered as predictors into a logistic regression model that significantly predicted the age group of the survivor, χ2(5, n=541)=53.3, p<0.001.ConclusionsPatterns of sexual violence against adult and child survivors during the COVID-19 pandemic are different, suggesting age-related measures are needed in national emergency plans to adequately address sexual violence during the pandemic and for future humanitarian crises.
Proteomics: a new diagnostic frontier Hortin, Glen L; Jortani, Saeed A; Ritchie, Jr, James C ...
Clinical chemistry (Baltimore, Md.),
07/2006, Letnik:
52, Številka:
7
Journal Article
Recenzirano
Odprti dostop
Analysis of proteins has been an integral part of the field of clinical chemistry for decades. Recent advances in technology and complete identification of the human genome sequence have opened up ...new opportunities for analysis of proteins for clinical diagnostic purposes.
Content of a recent conference of proteomics is summarized.
New analytical methods allow the simultaneous analysis of a large number of proteins in biological fluids such as serum and plasma, offering partial views of the complete set of proteins or proteome. Plasma presents many analytical challenges, such as the complexity of components, predominance of a few major components, and the large concentration range of components, but the number of proteins that can be detected in plasma has expanded dramatically from hundreds to thousands. At the same time, there is increased capability to detect structural variations of proteins. Recent studies also identified the presence of complex sets of small protein fragments in plasma. This set of protein fragments, the fragmentome or peptidome, is potentially a rich source of information about physiologic and disease processes.
Advances in proteomics offer great promise for the discovery of markers that might serve as the basis for new clinical laboratory tests. There are many challenges, however, in the translation of newly discovered markers into clinical laboratory tests.
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