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Click here to view the Original article by Rannikko et al. [ABSTRACT FROM AUTHOR]

The previously described anti-endotoxin effect of colistin has not been investigated in humans yet. We performed a randomized, double-blind, placebo-controlled crossover trial to determine the degree of colistin-driven modulation of inflammatory response in blood of lipopolysaccharide (LPS)-challenged healthy volunteers in a human endotoxemia model. After a single intravenous dose of 2.5 million IU colistin methanesulfonate, interleukin (IL)-6, IL-8, tumor necrosis factor alpha (TNF-α), and IL-1β concentrations as well as other biomarkers of inflammation such as C-reactive protein, differential leukocyte counts, and body temperature were measured up to 24 h postdose. Colistin significantly decreased the inflammatory cytokine response to LPS in blood of healthy volunteers. This effect was most evident for IL-6, IL-8, and TNF-α. This study is the first to confirm the anti-endotoxin effect of colistin in humans in vivo. Further studies might increase our knowledge on the interaction between colistin and the effectors of the immune system. [ABSTRACT FROM AUTHOR]

ABCB1 and ABCG2 work together at the blood-brain barrier (BBB) to limit brain distribution of dual ABCB1/ABCG2 substrates. In this pilot study we used positron emission tomography (PET) to assess brain distribution of two model ABCB1/ABCG2 substrates ([11C]elacridar and [11C]tariquidar) in healthy subjects without (c.421CC) or with (c.421CA) the ABCG2 single-nucleotide polymorphism (SNP) c.421C>A. Subjects underwent PET scans under conditions when ABCB1 and ABCG2 were functional and during ABCB1 inhibition with high-dose tariquidar. In contrast to the ABCB1-selective substrate ( R)-[11C]verapamil, [11C]elacridar and [11C]tariquidar showed only moderate increases in brain distribution during ABCB1 inhibition. This provides evidence for a functional interplay between ABCB1 and ABCG2 at the human BBB and suggests that both ABCB1 and ABCG2 need to be inhibited to achieve substantial increases in brain distribution of dual ABCB1/ABCG2 substrates. During ABCB1 inhibition c.421CA subjects had significantly higher increases in [11C]tariquidar brain distribution than c.421CC subjects, pointing to impaired cerebral ABCG2 function. [ABSTRACT FROM AUTHOR]

Previous results in volunteers have indicated the effective dose in 99% of subjects (ED99 ) of local anaesthetic volume to be 0.10 ml.mm(-2) of cross-sectional nerve area for sciatic nerve blockade. The objective of this prospective, randomised, double-blind study was to investigate the ED99 of local anaesthetic for ultrasound-guided sciatic nerve blockade in patients undergoing foot surgery, according to Dixon's up-and-down method and probit analysis. A starting volume of 0.20 ml local anaesthetic per mm(2) cross-sectional nerve area was used. If surgical anaesthesia was judged to be adequate, the volume of local anaesthetic for the next case was reduced by 0.02 ml.mm(-2), until the first block failed. Thereafter, the volume of local anaesthetic was increased by 0.02 ml.mm(-2). The ED99 volume of local anaesthetic for ultrasound-guided sciatic nerve blockade was calculated to be 0.15 ml.mm(-2) cross-sectional nerve area, which is higher than the previously evaluated ED99 volume in volunteers. [ABSTRACT FROM AUTHOR]

Previous results in volunteers have indicated the effective dose in 99% of subjects ( ED99) of local anaesthetic volume to be 0.10 ml.mm−2 of cross-sectional nerve area for sciatic nerve blockade. The objective of this prospective, randomised, double-blind study was to investigate the ED99 of local anaesthetic for ultrasound-guided sciatic nerve blockade in patients undergoing foot surgery, according to Dixon's up-and-down method and probit analysis. A starting volume of 0.20 ml local anaesthetic per mm2 cross-sectional nerve area was used. If surgical anaesthesia was judged to be adequate, the volume of local anaesthetic for the next case was reduced by 0.02 ml.mm−2, until the first block failed. Thereafter, the volume of local anaesthetic was increased by 0.02 ml.mm−2. The ED99 volume of local anaesthetic for ultrasound-guided sciatic nerve blockade was calculated to be 0.15 ml.mm−2 cross-sectional nerve area, which is higher than the previously evaluated ED99 volume in volunteers. [ABSTRACT FROM AUTHOR]

Drug disposition is highly regulated by membrane transporters. Some transporter-mediated drug-drug interactions (DDIs) may not manifest themselves in changes in systemic exposure but rather in changes in tissue exposure of drugs. To better assess the impact of transporter-mediated DDIs in tissues, positron emission tomography (PET)-a noninvasive imaging method-plays an increasingly important role. In this article, we provide examples of how PET can be used to assess transporter-mediated DDIs in different organs. [ABSTRACT FROM AUTHOR]

Using positron emission tomography (PET) imaging we assessed, in vivo, the interaction between a microdose of (R)-[11C]verapamil (a P-glycoprotein (Pgp) substrate) and escalating doses of the Pgp inhibitor tariquidar (3, 4, 6, and 8 mg/kg) at the blood-brain barrier (BBB) in healthy human subjects. We compared the dose-response relationship of tariquidar in humans with data obtained in rats using a similar methodology. Tariquidar was equipotent in humans and rats in its effect of increasing (R)-[11C]verapamil brain uptake (expressed as whole-brain volume of distribution (VT)), with very similar half-maximum-effect concentrations. Both in humans and in rats, brain VT approached plateau levels at plasma tariquidar concentrations >1,000 ng/ml. However, Pgp inhibition in humans led to only a 2.7-fold increase in brain VT relative to baseline scans (before administration of tariquidar) as compared with 11.0-fold in rats. The results of this translational study add to the accumulating evidence that there are marked species-dependent differences in Pgp expression and functionality at the BBB. [ABSTRACT FROM AUTHOR]

Purpose Although topical drug delivery is the most widely used ocular drug administration route, the in-vivo pharmacokinetic profile of topically applied drugs is only inadequately described. This is mainly caused by the fact that in the eye the assessment of in-vivo pharmacokinetics is difficult and technically demanding. Here, we propose a new technique for the in-vivo assessment of pharmacokinetic parameters of topically applied drugs using in-vivo microdialysis in a rabbit model. Methods 8 Female New Zealand White rabbits were included in the experiments. A linear microdialysis probe (30 kDa molecular weight cut off [MWCO]) was implanted in the anterior chamber, a concentric probe (20 kDa MWCO) in the posterior segment of the same eye. After a run-in period to obtain stabile conditions, a single drop of ciprofloxacin eye drops was administered on the cornea. Microdialysis samples were collected every 30 min for 6 h. Probes were analyzed using HPCL. Results In the anterior chamber, the maximum total drug concentration was reached after 116 ± 36 minutes (Tmax) and amounted to 0.373 ± 0.281 μg/ml (Cmax). AUC (0-n) for ciprofloxacin in the anterior chamber was 78.8 ± 47 μg min/ml. In the vitreous, drug concentration was considerably lower. A Cmax of 0.02 ± 0.03 μg/ml was reached after 106 ± 60 min. AUC (0-n) for ciprofloxacin in the vitreous was 0.286 ± 370 μg min/ml. Conclusions Here, we present in-vivo microdialysis as a new method for the in-vivo assessment of pharmacokinetic profiles. Maximum drug concentration in the anterior chamber was reached approximately 2 hours after single drug administration. Although the drug concentration in the vitreous was considerably lower, time course of drug concentration was comparable. In summary, our data show that microdialysis is an excellent method to assess in-vivo pharmacokinetics with a high temporal resolution. [ABSTRACT FROM AUTHOR]

Previous results in volunteers have indicated the effective dose in 99% of subjects ( ED99) of local anaesthetic volume to be 0.10 ml.mm−2 of cross-sectional nerve area for sciatic nerve blockade. The objective of this prospective, randomised, double-blind study was to investigate the ED99 of local anaesthetic for ultrasound-guided sciatic nerve blockade in patients undergoing foot surgery, according to Dixon's up-and-down method and probit analysis. A starting volume of 0.20 ml local anaesthetic per mm2 cross-sectional nerve area was used. If surgical anaesthesia was judged to be adequate, the volume of local anaesthetic for the next case was reduced by 0.02 ml.mm−2, until the first block failed. Thereafter, the volume of local anaesthetic was increased by 0.02 ml.mm−2. The ED99 volume of local anaesthetic for ultrasound-guided sciatic nerve blockade was calculated to be 0.15 ml.mm−2 cross-sectional nerve area, which is higher than the previously evaluated ED99 volume in volunteers. [ABSTRACT FROM AUTHOR]

Aims: Clomipramine (CLOMI) has shown effectiveness in treating premature ejaculation but is linked to erectile dysfunction and reduced libido. Yohimbine (YOH), by contrast, is effective in treating erectile dysfunction and may improve libido. Combining CLOMI and YOH could potentially leverage the benefits of both drugs. This study aimed to investigate the interactions between these drugs and to evaluate their safety profile., Methods: A prospective, open-labelled, single-centre, pharmacokinetic (PK) drug-drug interaction study was performed in 15 healthy male subjects. Single-dose and steady-state PK were investigated using noncompartmental analysis after mono- and combination therapy of the 2 orally applied drugs. Plasma sampling was performed at baseline, 0.5 (YOH), 1, 1.5 (YOH), 2, 3, 4, 5, 6, 8, 12 and 24 h (CLOMI). Differences in the area under the curve after multiple dosing (MD) were determined using an equivalence boundary of 80-125%., Results: The geometric mean ratio of the area under the curve up to 12 h for MD CLOMI (combination vs. monotherapy) was 112% (90% confidence interval: 104-120%), whereas for MD YOH this ratio was 137% (90% confidence interval: 112-168%). The study drugs were safe and well tolerated as mono- and combination therapy, with no major adverse events reported., Conclusion: A PK assessment of clomipramine and yohimbine indicated a clinically significant drug-drug interaction for MD YOH in combination with CLOMI. This might be explained by competitive, CLOMI-related inhibition of YOH metabolism, probably mediated by cytochrome P450 2D6. However, according to European Medicines Agency guidelines, the effect can be classified as interaction absent (<1,25 fold) or minor (>1.25-<2-fold). Given the complimentary mechanisms of action and the favourable safety profiles, the findings pave the way for future efficacy studies., (© 2024 British Pharmacological Society.)

The effects of the human endotoxin challenge on tissue pharmacokinetics are unknown. In the present study, we aimed to assess the effect of the endotoxin challenge on interstitial fluid pharmacokinetics of tedizolid in healthy volunteers using intramuscular microdialysis. Eight healthy male subjects were treated with 200 mg of tedizolid phosphate for 6 days. On Day 6, an intravenous bolus of lipopolysaccharide (LPS) (2 ng/kg body weight) was administered. LPS infusion did not affect plasma pharmacokinetics of tedizolid. In contrast, following LPS infusion, median muscle tissue fAUC (0.83 [0.75-1.15] vs. 1.14 [1.11-1.43] mg × h/L, P = .0078) and muscle tissue fC max (0.15 [0.14-0.19] vs. 0.19 [0.18-0.24] mg/L, P = .0078) were significantly increased by 38% and 24%, respectively. The human endotoxin challenge was associated with increased tissue concentrations of tedizolid, without affecting its plasma concentration-time profile. The human endotoxin challenge combined with microdialysis may be used to investigate the influence of systemic inflammation on tissue pharmacokinetics., (© 2022 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Aims: Doxycycline (DFD-09) oral capsules 40 mg are approved for the treatment of inflammatory lesions of rosacea. Unlike the food-induced lowering of doxycycline's peak plasma concentration (C max ), 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 (d-ISF) and plasma of healthy volunteers were assessed in parallel groups under fed (n = 6) and fasting (n = 6) conditions during a 14-day once-daily treatment course with doxycycline oral capsules 40 mg (DFD-09). Sampling of d-ISF and plasma was performed on days 1, 10 (fasting group d-ISF only) and 14., Results: Twelve subjects were randomized, and 11 analysed. No causally drug-related adverse events occurred. Dermal doxycycline exposures (C max 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 between-group 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., (© 2018 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Aims: The efflux transporter P-glycoprotein (ABCB1) acts at the blood-brain barrier (BBB) to restrict the distribution of many different drugs from blood to the brain. Previous data suggest an age-associated decrease in the expression and function of ABCB1 at the BBB. In the present study, we investigated the influence of age on the magnitude of an ABCB1-mediated drug-drug interaction (DDI) at the BBB., Methods: We performed positron emission tomography scans using the model ABCB1 substrate (R)-[ 11 C]verapamil in five young [26 ± 1 years, (mean ± standard deviation)] and five elderly (68 ± 6 years) healthy male volunteers before and after intravenous administration of a low dose of the ABCB1 inhibitor tariquidar (3 mg kg -1 )., Results: In baseline scans, the total distribution volume (V T ) of (R)-[ 11 C]verapamil in whole-brain grey matter was not significantly different between the elderly (V T  = 0.78 ± 0.15) and young (V T  = 0.79 ± 0.10) group. After partial (incomplete) ABCB1 inhibition, V T values were significantly higher (P = 0.040) in the elderly (V T  = 1.08 ± 0.15) than in the young (V T  = 0.80 ± 0.18) group. The percentage increase in (R)-[ 11 C]verapamil V T following partial ABCB1 inhibition was significantly greater (P = 0.032) in elderly (+40 ± 17%) than in young (+2 ± 17%) volunteers. Tariquidar plasma concentrations were not significantly different between the young (786 ± 178 nmol l -1 ) and elderly (1116 ± 347 nmol l -1 ) group., Conclusions: Our results provide the first direct evidence of an increased risk for ABCB1-mediated DDIs at the BBB in elderly persons, which may have important consequences for pharmacotherapy of the elderly., (© 2017 The British Pharmacological Society.)

Aim: Muscle injuries and extensive exercise are associated with cyclo-oxygenase dependent formation of inflammatory prostaglandins. Since the effect of topical administration of non-steroidal anti-inflammatory drugs (NSAIDs) on local cyclo-oxygenase is unknown, the present exploratory, open label, non-randomized study set out to measure exercise induced release of prostaglandins before and after epicutaneous administration of diclofenac., Methods: Microdialysis was used to determine the local interstitial concentration of PGE2 and 8-iso-PGF2α as well as diclofenac concentrations in the vastus lateralis under rest, dynamic exercise and during recovery in 12 healthy subjects at baseline and after a treatment phase applying a total of seven plasters medicated with 180 mg of diclofenac epolamine over 4 days., Results: At baseline PGE2 concentrations were 1169 ± 780 pg ml(-1) at rest and 1287 ± 459 pg ml(-1) during dynamic exercise and increased to 2005 ± 1126 pg ml(-1) during recovery. After treatment average PGE2 concentrations were 997 ± 588 pg ml(-1) at rest and 1339 ± 892 pg ml(-1) during exercise. In contrast with the baseline phase no increase in PGE2 concentrations was recorded during the recovery period after treatment (PGE2 1134 ± 874 pg ml(-1)). 8-iso-PGF2α was neither affected by exercise nor by treatment with diclofenac. Local and systemic concentrations of diclofenac were highly variable but comparable with previous clinical pharmacokinetic studies., Conclusions: We can hypothesize an effect of topical diclofenac epolamine plaster on limiting the increase of local concentrations of the pro-inflammatory prostaglandin PGE2 induced in the muscle of healthy human subjects following standardized physical exercise. No effect of diclofenac treatment on 8-iso-PGF2α concentrations was observed, mainly since isoprostane is produced by a free radical-catalyzed lipid peroxidation mechanism independent of cyclo-oxygenases., (© 2013 The Authors. British Journal of Clinical Pharmacology © 2013 The British Pharmacological Society.)

Aims: The present study addressed the ability of levofloxacin to penetrate into subcutaneous adipose tissues in patients with soft tissue infection., Methods: Tissue concentrations of levofloxacin in inflamed and healthy subcutaneous adipose tissue were measured in six patients by microdialysis after administration of a single intravenous dose of 500 mg. Levofloxacin was assayed by high-performance liquid chromatography., Results: The mean concentration vs time profile of free levofloxacin in plasma was identical to that in inflamed and healthy tissues. The ratios of the mean area under the free levofloxacin concentration vs time curve from 0 to 10 h (AUC(0,10 h)) in tissue to that in plasma were 1.2 +/- 1.0 for inflamed and 1.1 +/- 0.6 for healthy subcutaneous adipose tissue (mean +/- SD). The mean difference in the ratio of the AUC(tissue) : AUC(plasma) for inflamed and healthy tissue was 0.09 (95% confidence interval -0.58, 0.759, P > 0.05). Interindividual variability in tissue penetration was high, as indicated by a coefficient of variation of approximately 82% for AUC(tissue) : AUC(plasma) ratios., Conclusions: The penetration of levofloxacin into tissue appears to be unaffected by local inflammation. Our plasma and tissue data suggest that an intravenous dose of 500 mg levofloxacin provides effective antibacterial concentrations at the target site. However, in treatment resistant patients, tissue concentrations may be sub-therapeutic.