Direct Current Auditory Evoked Potentials During Wakefulness, Anesthesia, and Emergence from Anesthesia

Direct current auditory evoked potentials (DC-AEPs) are a sensitive indicator of depth of anesthesia in ani-mals. However, they have never been investigated in humans. To assess the potential usefulness of DC-AEPs as an indicator of anesthesia in humans, we performed an explorative study in which DC-AEPs were recorded during propofol and methohexital anesthesia in hu-mans. DC-AEPs were recorded via 22 scalp electrodes in 19 volunteers randomly assigned to receive either propofol or methohexital. DC-AEPs were evoked by binaurally presented 2-s, 60-dB, 800-Hz tones; meas-urements were taken during awake baseline, anesthesia, and emergence. Statistical analysis included analy-sis of variance and discriminant analysis of data acquired during these three conditions. About 500 ms after stimulus presentation, DC-AEPs could be ob-served. These potentials were present only during base-line and emergence—not during anesthesia. Statistically significant differences were found between baseline and anesthesia and between anesthesia and emergence. In conclusion, similar effects, as reported in animal studies of anesthetics on the DC-AEPs, could be observed in anesthetized humans. These results dem-onstrate that DC-AEPs are potentially useful in the assessment of cortical function during anesthesia and might qualify the method for monitoring anesthesia in humans

On the relationship of first-episode psychosis to the amphetamine-sensitized state: a dopamine D2/3 receptor agonist radioligand study.

Schizophrenia is characterized by increased behavioral and neurochemical responses to dopamine-releasing drugs. This prompted the hypothesis of psychosis as a state of "endogenous" sensitization of the dopamine system although the exact basis of dopaminergic disturbances and the possible role of prefrontal cortical regulation have remained uncertain. To show that patients with first-episode psychosis release more dopamine upon amphetamine-stimulation than healthy volunteers, and to reveal for the first time that prospective sensitization induced by repeated amphetamine exposure increases dopamine-release in stimulant-naïve healthy volunteers to levels observed in patients, we collected data on amphetamine-induced dopamine release using the dopamine D2/3 receptor agonist radioligand [11C]-(+)-PHNO and positron emission tomography. Healthy volunteers (n = 28, 14 female) underwent a baseline and then a post-amphetamine scan before and after a mildly sensitizing regimen of repeated oral amphetamine. Unmedicated patients with first-episode psychosis (n = 21; 6 female) underwent a single pair of baseline and then post-amphetamine scans. Furthermore, T1 weighted magnetic resonance imaging of the prefrontal cortex was performed. Patients with first-episode psychosis showed larger release of dopamine compared to healthy volunteers. After sensitization of healthy volunteers their dopamine release was significantly amplified and no longer different from that seen in patients. Healthy volunteers showed a negative correlation between prefrontal cortical volume and dopamine release. There was no such relationship after sensitization or in patients. Our data in patients with untreated first-episode psychosis confirm the "endogenous sensitization" hypothesis and support the notion of impaired prefrontal control of the dopamine system in schizophrenia

Low pH reduces the activity of ceftolozane/tazobactam in human urine, but confirms current breakpoints for urinary tract infections

BACKGROUND: Acidic pH has been shown to impact the antibiotic activity of non-β-lactams in urine. OBJECTIVES: To investigate the in vitro activity of ceftolozane/tazobactam compared with meropenem at different pH settings in urine. METHODS: We determined the MICs for 30 clinical isolates of Escherichia coli, 25 clinical isolates of Klebsiella pneumoniae and 24 clinical isolates of Proteus mirabilis in pooled human urine and standard growth medium at pH 5 and 7. Time-kill curves were produced for one representative clinical isolate of tested bacterial strains in urine at pH 5, 6 and 7 for both antibiotics at concentrations above and below the MIC. HPLC analysis of the stability of ceftolozane/tazobactam and meropenem was performed at different pH values. RESULTS: The median MICs of both antibiotics were up to 8-fold higher at pH 5 than at pH 7. Bacterial growth of E. coli was not impacted by pH, while for K. pneumoniae and P. mirabilis low pH slightly reduced growth. Compared with pH 7, pH 5 resulted in a significant decrease in antibiotic activity with a delta of up to 3 log10 bacterial counts after 24 h. Impact of acidic pH was lowest for P. mirabilis; however, this strain metabolically increased the pH during experiments. Stability was not impacted by low pH. CONCLUSIONS: Acidic pH had a significant negative impact on the activity of ceftolozane/tazobactam and meropenem in urine. Considering concentrations achieved in urine, our results confirm existing breakpoints and do not advocate increasing ceftolozane/tazobactam breakpoints for urinary tract infections

British Journal of Clinical Pharmacology / Target site pharmacokinetics of doxycycline for rosacea in healthy volunteers is independent of food-effect

Aims Doxycycline (DFD09) oral capsules 40 mg are approved for the treatment of inflammatory lesions of rosacea. Unlike the foodinduced lowering of doxycycline's peak plasma concentration (Cmax), its exposure under fed conditions in the skin, the drug's target site for rosacea, is unknown. The present study explored the effect of food on the dermal pharmacokinetics of doxycycline. Methods The pharmacokinetics of doxycycline in the dermal interstitial fluid (dISF) and plasma of healthy volunteers were assessed in parallel groups under fed (n = 6) and fasting (n = 6) conditions during a 14day oncedaily treatment course with doxycycline oral capsules 40 mg (DFD09). Sampling of dISF and plasma was performed on days 1, 10 (fasting group dISF only) and 14. Results Twelve subjects were randomized, and 11 analysed. No causally drugrelated adverse events occurred. Dermal doxycycline exposures (Cmax and area under the curve) under the fed state were about 30% lower than under the fasting state at day 1 but were similar at steady state. In analogy to skin, plasma exposure showed no betweengroup difference at steady state. Accumulation ratios were higher in the skin than in plasma. Correcting for plasma protein binding (90%), dermal doxycycline exposure was approximately threefold higher than unbound plasma exposure. Conclusions At steady state, doxycycline concentrations in the skin of fed and fasting healthy volunteers were comparable. Doxycycline's efficacy in rosacea is possibly due to considerable dermal accumulation of unbound doxycycline and is independent of the effect of food.(VLID)340588