Effects of sedative antidepressants on prefrontal cortex activity during verbal fluency task in healthy subjects: a near-infrared spectroscopy study

Rationale

Japanese researchers have recently conducted studies using near-infrared spectroscopy (NIRS) to help diagnose psychiatric disorders based on changes in brain activity. However, the influence of psychotropic drugs on NIRS measurements has not been clarified.

Objective

To assess the effects of sedative antidepressants on prefrontal cortex activity in healthy subjects using NIRS in a double-blinded, placebo-controlled, crossover trial.

Methods

Nineteen healthy males received nocturnal doses of mirtazapine 15 mg, trazodone 25 mg, or placebo for eight consecutive days in rotation, with a washout period of more than 1 week between each rotation. Subjects performed a verbal fluency task during NIRS on a total of seven occasions during the study period: more than a week prior to receiving the first dose of the first medication; and on days 2 and 9 of each rotation. The number of words correctly generated during the task (behavioral performance) was also recorded. Stanford Sleepiness Scale (SSS) scores were determined each day.

Results

Mirtazapine 15 mg significantly increased oxyhemoglobin (oxy-Hb) concentration change in NIRS on day 9, compared to trazodone 25 mg and placebo. Mirtazapine 15 mg significantly increased SSS on day 2, compared to the other conditions. No significant differences in behavioral performance were observed.

Conclusions

Administration of mirtazapine for eight consecutive days affected oxy-Hb changes on NIRS. This result indicates that researchers should consider how certain types of antidepressant could influence brain function when the brain activity of patients with psychiatric disorders is assessed.     

Comprehensive tumor profiling identifies numerous biomarkers of drug response in cancers of unknown primary site: Analysis of 1806 cases

Background

Cancer of unknown primary (CUP) accounts for approximately 3% of all malignancies. Despite extensive laboratory and imaging efforts, the primary site usually cannot be unequivocally confirmed, and the treatment for the most part remains empirical. Recently, identification of common cancer pathway alterations in diverse cancer lineages has offered an opportunity to provide targeted therapies for patients with CUP, irrespective of the primary site.

Patients and Methods

1806 cancers of unknown primary were identified among more than 63,000 cases profiled at Caris Life Sciences. Multiplatform profiling of the tumor samples included immunohistochemistry, gene sequencing and in situ hybridization methods in an effort to identify changes in biomarkers that are predictive of drug responses.

Results

Biomarkers associated with a potential drug benefit were identified in 96% of cases. Biomarkers identified included those associated with potential benefit in nearly all classes of approved cancer drugs (cytotoxic, hormonal, targeted biological drugs). Additionally, biomarkers associated with a potential lack of benefit were identified in numerous cases, which could further refine the management of patients with CUP.

Conclusion

Comprehensive biomarker profiling of CUP may provide additional choices in treatment of patients with these difficult to treat malignancies.     

Simvastatin and amlodipine induced thrombocytopenia in the same patient: double trouble and a literature review

What is known and objective: Drug‐induced thrombocytopenia (DITP) may be a fatal adverse reaction to many drugs. It is often misdiagnosed as primary immune thrombocytopenia (ITP), and thus diagnosis can be delayed and patients can be treated inappropriately. Amlodipine a calcium‐channel blocker, and simvastatin, a statin, have very rarely been implicated in DITP. We report on an investigation of the causal relationship of amlodipine and simvastatin with thrombocytopenia occurring in the same patient, and review the literature. Case summary: We present the case of a 78‐year‐old female hypertensive diabetic patient with three successive DITPs. The first attack of acute severe thrombocytopenia occurred after a 2‐week course of amlodipine, and was initially misdiagnosed as ITP. Her platelet count normalized after the amlodipine was discontinued. The second attack followed her restarting simvastatin 3 weeks later. She had stopped it 2 months earlier having previously taken it for over 5 years. Again, she recovered once the simvastatin was discontinued. The third DITP attack occurred when she accidently took a single dose of amlodipine 9 months later. What is new and conclusion: We provide clear evidence of a causal association of amlodipine with thrombocytopenia, and probable evidence of a causal association of simvastatin with thrombocytopenia. This is the first reported case of DITPs occurring with two of the most widely prescribed drugs in the same patient. Many hypertensive patients need to take multiple drugs in order to achieve their treatment goals and this increases their risk of drug‐induced adverse reactions and makes identification of the causal drug (or drugs) extremely difficult.     

The Additive Diagnostic Role of Coronary Flow Reserve in Noninvasive Evaluation of Coronary Stenosis on Left Descending Artery Previously Detected by Multislice Computed Tomography

Purpose: Multislice computed coronary angiography (MSCT) provides valuable morphological information about coronary artery disease, but precise quantification of coronary stenosis remains difficult. Transthoracic color Doppler echocardiography (TDE) gives a new insight into the functional significance of coronary luminal narrowing. We have tried to assess the additive value of coronary flow reserve (CFR) determined by TDE over MSCT in prediction of a significant stenosis on the left anterior descending artery (LAD) using the invasive coronary angiography (ICA) as a reference method. Methods: This prospective study included 63 patients in stable cardiac status with previously detected atherosclerotic lesions on LAD by MSCT. CFR assessment by TDE with adenosine infusion was obtained to all patients (feasibility was 96.92%). CFR was determined as ratio between the peak diastolic flow velocity during adenosine infusion and at basal condition, a cutoff value indicating significant stenosis was <2. ICA was preformed to all patients 24–48 hours after CFR. Results: MSCT had sensitivity of 86.36%, specificity 53.66%, positive predictive value 50.00%, negative predictive value 88.00%, and diagnostic accuracy of 65.07% in detection of significant LAD stenosis. CFR had sensitivity 81.81%, specificity 97.06%, positive predictive value 94.74%, negative predictive value 89.19%, and diagnostic accuracy of 91.07%. When the results of both methods were agreed diagnostic accuracy was improved to 92.72%. Conclusion: Additional assessment of CFR by TDE increase diagnostic accuracy of MSCT angiography in detection of significant coronary artery lesions.     

Acute application of antioxidants protects against hyperoxia‐induced reduction of plasma nitrite concentration

We investigated the effects of acute intake of antioxidants on hyperoxia‐induced oxidative stress, reduction of plasma nitrite and change in arterial stiffness. Twelve healthy males randomly consumed either placebo or an oral antioxidant cocktail (vitamin C, 1000 mg; vitamin E, 600 IU; alpha‐lipoic acid, 600 mg). Every therapy was consumed once, a week apart, in a cross‐over design, 30 min before the experiment. The volunteers breathed 100% normobaric oxygen between 30th and 60th min of 1‐h study protocol. Plasma levels of nitrite, lipid peroxides (LOOH) and vitamin C, arterial stiffness (indicated by augmentation index, AIx) and arterial oxygen (P_tcO₂) pressure were measured before and after hyperoxia. Exposure to oxygen caused a similar increase of P_tcO₂ in both placebo and antioxidants groups, confirming comparable exposure to hyperoxia (438 ± 100 versus 455 ± 83 mm Hg). Vitamin C was increased in the antioxidants group confirming successful application of antioxidants (69 ± 14 versus 57 ± 15 μm ). Hyperoxia resulted in increased AIx and LOOH and decreased nitrite in placebo (?32 ± 11 versus ?47 ± 13%, 72 ± 7 versus 62 ± 6 μm H₂O₂ and 758 ± 184 versus 920 ± 191 nm , respectively), but not in the antioxidants group (?42 ± 13 versus ?50 ± 13%, 64 ± 9 versus 61 ± 8 μm H₂O₂ and 847 ± 156 versus 936 ± 201 nm , respectively). The acute intake of selected antioxidants was effective in preserving bioavailabity of ˙NO and vascular function, against hyperoxia‐induced oxidative stress.