Effect of Dexketoprofen on the Disposition Kinetics of Moxifloxacin in Plasma and Lung in Male and Female Rats.

BACKGROUND: The simultaneous use of NSAIDs and antibiotics is recommended for bacterial diseases in human and veterinary medicine. Moxifloxacin (MFX) and dexketoprofen (DEX) can be used simultaneously in bacterial infections. However, there are no studies on how the simultaneous use of DEX affects the pharmacokinetics of MFX in rats. OBJECTIVES: The aim of this study was to determine the effect of DEX on plasma and lung pharmacokinetics of MFX in male and female rats. METHODS: A total of 132 rats were randomly divided into 2 groups: MFX (n=66, 33 males/33 females) and MFX+DEX (n=66, 33 females/33 males). MFX at a dose of 20 mg/kg and DEX at a dose of 25 mg/kg were administered intraperitoneally. Plasma and lung concentrations of MFX were determined using the highperformance liquid chromatography-UV and pharmacokinetic parameters were evaluated by noncompartmental analysis. RESULTS: Simultaneous administration of DEX increased the plasma and lung area under the curve from 0 to 8 h (AUC0-8) and peak concentration (Cmax) of MFX in rats, while it significantly decreased the total body clearance (CL/F). When female and male rats were compared, significant differences were detected in AUC0-8, Cmax, CL/F and volume of distribution. The AUC0-8lung/AUC0-8plasma ratios of MFX were calculated as 1.68 and 1.65 in female rats and 5.15 and 4.90 in male rats after single and combined use, respectively. CONCLUSION: MFX was highly transferred to the lung tissue and this passage was remarkably higher in male rats. However, DEX administration increased the plasma concentration of MFX in both male and female rats but did not change its passage to the lung. However, there is a need for a more detailed investigation of the difference in the pharmacokinetics of MFX in male and female rats.

Pharmacokinetics, Safety, and Tolerability of Intravenous Felbinac Trometamol in Healthy Chinese Volunteers: A First-in-Human Single- and Multiple-Dose Escalation Phase I Study with a Randomized, Double-Blind, Placebo-Controlled Design.

BACKGROUND: Felbinac trometamol, an anti-inflammatory and analgesic drug, has been used to treat immediate postoperative pain. OBJECTIVE: The aim of this study was to evaluate the safety, tolerability, and pharmacokinetics of single or multiple intravenous infusions of felbinac trometamol in healthy Chinese volunteers. METHODS: A total of 56 healthy subjects were enrolled in a single-ascending dose study (11.78-377.00 mg), meanwhile 36 subjects were enrolled in a multiple-ascending dose study (47.13-188.50 mg). Safety endpoints included treatment-emergent adverse events, vital signs, electrocardiograms, and laboratory parameters. Pharmacokinetic endpoints included exposure of subjects to felblinac and metabolites of the drug in plasma, urine, and feces. RESULTS: Felblinac time to maximum plasma concentration was obtained at 0.5 h, corresponding to the end of the infusion. Maximum plasma concentration and area under the curve increased in a dose-dependent manner for felblinac and its metabolite, showing linear pharmacokinetic characteristics at single and multiple doses. After intravenous infusions of multiple doses three times (30 min each time) per day, the accumulation ratio of felblinac and its metabolite based on the area under the curve had a range of 1.34-1.45 and 1.60-1.87, respectively, across cohorts. After administration of the fourth dose, the plasma concentration of both felblinac and its metabolites was maintained at a steady state. Felbinac trometamol was well tolerated. Neither treatment-emergent adverse event frequency nor severity increased with increasing felbinac trometamol dose. CONCLUSIONS: Felbinac trometamol was well tolerated in our study. Based on the dose range in this study, 94.25 mg is the recommended target dose for a phase II study. CLINICAL TRIAL REGISTRATION: CTR20170496 and CTR20180896. The dates of registration are 2017-06-19 and 2018-07-02 ( https://www.chinadrugtrials.org.cn/ ).

Combined site-specific release retardant mini-matrix tablets (C-SSRRMT) for extended oral delivery of dexketoprofen trometamol: in vitro evaluation and single versus multiple doses pharmacokinetic study in human volunteers.

Development of extended release oral formulations of dexketoprofen trometamol (DT), a rapidly eliminated drug with high solubility, poses a great challenge especially when a portion of the dose is to be absorbed from the colon. In this study, site-specific release-retardant mini-matrix tablets (SSRRMTs) were developed and functionally coated with pH-responsive materials to achieve a site-specific delivery of DT at the duodenojejunal (DSRRMT) and ileocecal (ISRRMT) regions. Stomach-specific coated mini-tablets (SSCMTs) were manufactured for immediate release of about 16% of the daily dose of DT in the stomach. The SSCMT, DSRRMT, and ISRRMT were combined into a solid dosage form (C-SSRRMT tablets or capsules) to achieve the required linear release profile for once daily administration of DT. The SSRRMT and C-SSRRMT formulations were evaluated for the physical properties, in vitro-disintegration and in vitro dissolution and proved to be consistent with the pharmacopeial specifications. The in vitro release profiles of both C-SSRRMT tablets and capsules showed a constant release rate of about 6 mg/h and were similar to that of the theoretical target linear release profile. The pharmacokinetic study using human volunteers showed the bioequivalence of a single oral dose of C-SSRRMT capsules compared to three-successive oral doses of the immediate release market tablets with less ups and downs in the drug levels. The C-SSRRMT capsules formulation, may therefore, constitute an advance in the extended oral delivery of DT without the lack of efficacy and the adverse events frequently encountered in multiple daily dosing of the immediate release tablets.

Safety Assessment of Tromethamine, Aminomethyl Propanediol, and Aminoethyl Propanediol as Used in Cosmetics.

The Cosmetic Ingredient Review (CIR) Expert Panel (Panel) reviewed the safety of tromethamine, aminomethyl propanediol, and aminoethyl propanediolas used in cosmetics. All 3 ingredients are reported to function in cosmetics as pH adjusters, and tromethamine and aminomethyl propanediol are also reported to function as fragrance ingredients. The Panel reviewed relevant animal and human data related to these ingredients, along with a previous safety assessment of aminomethyl propanediol. The Panel concluded that tromethamine, aminomethyl propanediol, and aminoethyl propanediol are safe in cosmetics in the practices of use and concentration as given in this safety assessment.

Extended release of flurbiprofen from tromethamine-buffered HPMC hydrophilic matrix tablets.

The pH-dependent solubility of a drug can lead to pH-dependent drug release from hydrophilic matrix tablets. Adding buffer salts to the formulation to attempt to mitigate this can impair matrix hydration and negatively impact drug release. An evaluation of the buffering of hydrophilic matrix tablets containing a pH-dependent solubility weak acid drug (flurbiprofen), identified as possessing a deleterious effect on hydroxypropyl methylcellulose (HPMC) solubility, swelling and gelation, with respect to drug dissolution and the characteristics of the hydrophilic matrix gel layer in the presence of tromethamine as a buffer was undertaken. The inclusion of tromethamine as an alkalizing agent afforded pH-independent flurbiprofen release from matrices based on both HPMC 2910 (E series) and 2208 (K series), while concomitantly decreasing the apparent critical effect on dissolution mediated by this drug with respect to the early pseudo-gel layer formation and functionality. Drug release profiles were unaffected by matrix pH-changes resulting from loss of tromethamine over time, suggesting that HPMC inhibited precipitation of drug from supersaturated solution in the hydrated matrix. We propose that facilitation of diffusion-based release of potentially deleterious drugs in hydrophilic matrices may be achieved through judicious selection of a buffering species.

Carbon nanotube membranes to predict skin permeability of compounds.

In the present study, carbon nanotube (CNT) membranes were prepared to predict skin penetration properties of compounds. A series of penetration experiments using Franz diffusion cells were performed with 16 different membrane compositions for model chemicals. Similar experiments were also carried out with same model molecules using five different commercially available synthetic membranes and human skins for the comparison. Model chemicals were selected as diclofenac, dexketoprofen and salicylic acid. Their permeability coefficients and flux values were calculated. Correlations between permeability values of model compounds for human skins and developed model membranes were investigated. Good correlations were obtained for CNT membrane, isopropyl myristate-treated CNT membrane (IM-CNT membrane) and bovine serum albumin-cholesterol, dipalmitoyl phosphatidyl choline-treated membrane (BSA-Cholesterol-DPPC-IM-CNT membrane). An artificial neural network (ANN) model was developed using some molecular properties and penetration coefficients from pristine CNT membranes to predict skin permeability values and quite good predictions were made.

Preparation, optimization, characterization and in vivo pharmacokinetic study of asiatic acid tromethamine salt-loaded solid lipid nanoparticles.

PURPOSE: To enhance the oral bioavailability of asiatic acid tromethamine salt (AAS) by encapsulation in solid lipid nanoparticles (SLN). METHODS: The AAS-loaded SLN (AASLN) was prepared by the modified solvent injection method with glycerin monostearate (GMS) as lipid and poloxamer 188 as surfactant. A Box-Behnken design was used to optimize the formulations. Physicochemical characterization was carried out by using dynamic light scattering, scanning electron microscopy (SEM), differential scanning calorimetry (DSC) and X-ray diffraction (XRD). Stabilities at 4 °C and pH 1.2 were investigated by particle size or/and entrapment efficiency (EE%). The in vivo pharmacokinetics was evaluated by HPLC-MS/MS. RESULTS: The optimal formulation of AASLN had an average size of 237 nm with zeta potential of -35.9 mV, and EE% of 64.4%. SEM showed that the AASLN had spherical shape with smooth surface. Furthermore, DSC and X-ray analyses indicated that AAS was amorphous state and the crystal degree of GMS was significantly decreased in the formulation. AASLN showed excellent stability at 4 °C for 1 month and no coacervation at pH 1.2. The bioavailability of AAS in SLN was found to be 2.5-fold higher than that of AAS alone after a single oral administration in rats. CONCLUSIONS: This study reveals that SLN is developed as a promising oral delivery system of AAS with significantly enhanced bioavailability and good storage stability.

Comparison of the efficacy of low doses of methylprednisolone, acetaminophen, and dexketoprofen trometamol on the swelling developed after the removal of impacted third molar

BACKGROUND: The aim of the present study was to compare the efficacy of low doses of methylprednisolone, acetaminophen and dexketoprofen trometamol, which are among the drug groups used in our clinic, on postoperative swelling developing after removal of impacted third molar. MATERIAL AND METHODS: The three group of patients received either 40 mg methylprednisolone or 300 mg acetaminophen or 12.5 mg dexketoprofen trometamol one hour before the procedure, according to the patient groups. The patients in the methylprednisolone group were injected with methylprednisolone at a dose of 20 mg 24 hour after the procedure and prescribed 300 mg acetaminophen as rescue analgesic. During the postoperative period, the doses that were given before the procedure were continued 3 times a day for 2 days in the acetaminophen and dexketoprofen trometamol groups. Maximal swelling was assessed preoperatively and at the postoperative 48 hours by ultrasound images. RESULTS: Swelling was 34% lower in the methylprednisolone than in the other groups; however, no statistically significant difference was found between the groups. The acetaminophen and dexketoprofen trometamol groups exhibited clinical results close to each other. CONCLUSIONS: Combination of low doses of methylprednisolone and acetaminophen provide a safe and adequate clinical success on swelling

Effect of low-dose dexketoprofen trometamol and paracetamol on postoperative complications after impacted third molar surgery on healthy volunteers: A pilot study

OBJECTIVES: The aim of the present study was to investigate the analgesic and anti-inflammatory effects of dexketoprofen trometamol (DT) and paracetamol on deep acute somatic pain and inflammation in patients undergoing impacted third molar surgery. This study was planned to present benefits that we could obtain with low burden of drug. Study DESIGN: Effects of drugs, which were administered preemptively before the procedure, on pain, mouthopening limitation, and swelling were assessed by visual analogue scale (VAS), magnetic resonance imaging (MRI), and mouth-opening measurement. Following surgery, time intervals when the patients first need to receive the drug were measured. RESULTS: The VAS scores of the patients were lower in the side treated with DT than that in the paracetamol treated side. There was no significant difference between the groups in terms of mouth-opening limitation. MRI recordings revealed that swelling was lower in the side treated with paracetamol than DT treated side. CONCLUSIONS: Administration of the drugs before surgery contributed to the postoperative patient comfort. The analgesic activity of 12.5 mg dose of DT was similar to, even better than, the analgesic activity of 500 mg dose of paracetamol; however, DT had insufficient anti-inflammatory efficacy

Pharmacokinetics of felbinac after intravenous administration of felbinac trometamol in rats.

Felbinac trometamol (trishydroxymethylaminomethane 4-biphenylacetate) is a new water-soluble salt of felbinac currently undergoing clinical evaluation as an intravenous (i.v.) formulation for the treatment of severe post-operative pain. This article reports the pharmacokinetics of felbinac after i.v. administration of felbinac trometamol in Sprague-Dawley rats. The maximum plasma concentration (C(0)) and area under the plasma concentration-time curve (AUC) of felbinac administered at doses of 3.36, 8.40 and 21.0 mg/kg felbinac trometamol increased linearly with dose. Felbinac was highly protein bound (~95%) at plasma concentrations up to 75 µg/ml and extensively metabolized with only small amounts being excreted unchanged in urine (0.318%), feces (0.530%) and bile (0.465%). 4'-Hydroxyfelbinac was the principal metabolite in urine, feces and bile together with felbinac glucuronide, 4'-hydroxyfelbinac glucuronide and sulfate. The majority of the administered dose was excreted in urine (63.6%) mostly as 4'-hydroxyfelbinac. Total drug in urine and feces accounted for about 72% of the dose. It would appear that felbinac trometamol has the potential to replace lipid-based NSAID formulations and progress to clinical evaluation.

Fosfomicina trometamol. Dosis múltiples como pauta larga en el tratamiento de las infecciones urinarias bajas / Fosfomycin trometamol: Multiple-dose regimen for the treatment of lower urinary tract infections

Introducción. El tratamiento de las infecciones urinarias del tracto inferior no complicadas se realiza con pautas de tratamiento cortas. En otras circunstancias no está tan clara la pauta que hay que seguir. Cuando la infección urinaria del tracto inferior no se produce en una mujer joven, la recomendación terapéutica es la utilización de antibióticos durante al menos 7 días, y son las quinolonas y el cotrimoxazol los antibióticos utilizados con mayor frecuencia. Pero debido al porcentaje de resistencias de los microorganismos implicados en este tipo de infecciones, es aconsejable evaluar otras pautas de tratamiento, de forma que habría que evaluar, entre otros, el uso de antibióticos con un menor índice de resistencias como fosfomicina trometamol, en períodos de tratamiento más largos que el uso tan extendido en dosis única. Métodos. Desde los datos de eliminación urinaria de fosfomicina obtenidos en voluntarios sanos en un estudio previo, se han simulado las concentraciones de este antibiótico en orina tras la administración de 2 dosis. Se ha calculado el intervalo más idóneo para mantener concentraciones urinarias por encima del punto de corte de Escherichia coli para fosfomicina (16 mg/l), uno de los microorganismos implicados con mayor frecuencia en este tipo de infecciones. Resultados. Las concentraciones de fosfomicina en orina se mantienen por encima del punto de corte durante 161 h cuando se administran 2 dosis de 3 g de fosfomicina trometamol separadas 72 h. Éste supone un tiempo de eficacia del 96% en un período total de 7 días. Conclusión. La pauta teórica, desde el punto de vista farmacocinético, para conseguir concentraciones de fosfomicina en orina por encima del punto de corte de E. coli es la administración de 2 dosis de 3 g de fosfomicina trometamol separadas 72 h (AU)

Introduction. A short antibiotic regimen is recommended for the treatment of uncomplicated lower urinary tract infection. Nevertheless, the treatment to follow in other situations is not so clearly defined. When the person affected by lower urinary tract infection is not a young woman, it is recommended to treat at least 7 days, and quinolones or cotrimoxazole are the antibiotics most often used. However, because of the frequency of drug resistance in this type if infection, it is advisable to apply antibiotics with lower rates of resistance, such as fosfomycin trometamol, for longer treatment periods than the often-used single dose. Methods. Using the data on urinary elimination of fosfomycin after a single dose obtained in a prior study in healthy volunteers, we simulated the urinary concentrations of this antibiotic following administration of two doses. In addition, we calculated the interval of administration required to achieve urinary concentrations greater than 16 mg/L, the critical concentration of sensitivity for Escherichia coli, one of the most commonly implicated microorganisms in these infections. Results. Fosfomycin concentrations in urine persisted above the defined cut-off for 161 hours after administration of two 3-g doses of fosfomycin trometamol, 72 hours apart. This implied an efficacy time of 66% in a period of 7 days. Conclusion. From the pharmacokinetic viewpoint, the optimum dosage of fosfomycin trometamol to achieve appropriate urinary concentrations along 7 days is administration of two 3-g doses, 72 hours apart (AU)

Ionic basis of a mechanotransduction current in adult rat dorsal root ganglion neurons.

Sensory mechanical transduction - necessary for hearing, proprioception, and the senses of touch and pain - remains poorly understood. In somatosensation, even the basic properties of the mechanically sensitive excitatory ionic currents that are assumed to mediate mechanical transduction are largely undescribed. We have recorded, from the soma of rat dorsal root ganglion (DRG) neurons in vitro, whole-cell ionic currents induced by the impact of a piezo-electrically driven glass probe. This transient mechanically activated current was observed in virtually all DRG neurons tested. In ion substitution experiments the current could be carried nonselectively by most cations, including divalent and organic cations, but not by chloride or sulfate ions. In addition, the mechanically activated current carried by monovalent cations was consistently blocked by millimolar concentrations of external calcium or magnesium. Based on these results, the transient mechanical transduction current observed in somatosensory neurons in vitro is mediated by large-pore mechanically gated channels nonselective for cations but impermeable to anions.

Clinical pharmacokinetics of parenteral dexketoprofen trometamol in healthy subjects.

Dexketoprofen trometamol, a highly water-soluble salt of the active enantiomer of rac-ketoprofen, is a nonsteroidal antiinflammatory drug used for pain relief. Two studies were conducted to determine the pharmacokinetics of the drug in healthy subjects following single intravenous (i.v.) and intramuscular (i.m.) doses of dexketoprofen. In the first study, 6 male and 6 female volunteers received 50 mg dexketoprofen (74 mg dexketoprofen trometamol) by i.v. bolus. In the second one, another 6 male and 6 female subjects received 25 mg and 50 mg of dexketoprofen by the i.m. route. Dexketoprofen plasma concentrations were determined by reverse-phase high-performance liquid chromatography (HPLC). No serious adverse events were observed and all volunteers completed the study. The main pharmacokinetic parameters were determined by a noncompartmental approach. Following the i.v. bolus, mean (+/- SEM) area under the curve AUC0-x and clearance (CL) were 9005 +/- 422 ng.h/ml and 0.089 +/- 0.004 l/h/kg. Volumes of distribution Vi and Vss averaged 0.060 +/- 0.006 l/kg and 0.104 +/- 0.003 l/kg. Mean elimination half-life (t1/2e) and MRT were 1.05 +/- 0.04 h and 1.18 +/- 0.05 h. Following single i.m. 25 mg and 50 mg dexketoprofen, a rapid absorption was observed, with tmax values ranging from 0.17 h to 0.75 h. The corresponding Cmax averaged 1851 +/- 182 ng/ml and 3813 +/- 169 ng/ml, and mean AUC0-x were 3033 +/- 193 ng.h/ml and 5878 +/- 228 ng.h/ml, respectively. No significant differences by gender were obtained following both parenteral routes. A dose proportionality in Cmax and AUC0-x was observed. Dexketoprofen pharmacokinetics following i.v. and i.m. routes, together with the availability of a single 2 ml formulation, allows for a potential advantageous rapid switch to the oral formulation when clinically possible.

Single and repeated dose pharmacokinetics of dexketoprofen trometamol in young and elderly subjects.

Dexketoprofen trometamol, a high water-soluble salt of the active enantiomer of rac-ketoprofen, is a nonsteroidal antiinflammatory drug (NSAID) widely used for pain relief. This study was conducted to determine the pharmacokinetics of this analgesic agent in elderly subjects and to compare them with young volunteers following single and repeated oral doses. Twelve healthy young and 12 elderly subjects received 25 mg oral dexketo- profen (equivalent to 37 mg of its tromethamine salt) as a single dose (day 1) and 3-day repeated doses (1 dose every 8 h for a total of 10 doses). Serial concentrations of dexketoprofen were determined in plasma and urine by a reverse-phase HPLC/ultraviolet procedure over 24 h on day 1 and after the last 10th repeated t.i.d. dose. Compared to young subjects, elderly subjects showed significant increases in AUC and t1/2,z and decreases in CL/F following single and repeated doses. After single dosing, the corresponding mean +/- SD values were 5106.6 +/- 1873.0 vs. 3605.4 +/- 897.9 ng.h/ml (p = 0.015); 1.59 +/- 0.40 vs. 1.12 +/- 0.20 h (p < 0.001); and 1.11 +/- 0.29 vs. 1.63 +/- 0.36 ml/min/kg (p < 0.001). After the repeated dose, AUC, t1/2,z and CL/F averaged 5067.8 +/- 1373.4 vs. 3194.4 +/- 694.3 ng.h/ml (p < 0.001); 1.65 +/- 0.44 vs. 1.11 +/- 0.29 h (p < 0.005); and 1.12 +/- 0.23 vs. 1.87 +/- 0.42 ml/min/kg (p < 0.001). Median tmax was 0.5 h. Cumulative excretions in urine up to 24 h of unbound, conjugated and total dexketoprofen were similar among the groups. These results suggest that dexketoprofen elimination is reduced in the elderly. Although no drug accumulation in plasma was observed after single and repeated dosing, the renal function decline in elderly patients calls for a cautious dose-adjustment in this population.

Pharmacokinetics of dexketoprofen trometamol in subjects with mild and moderate chronic renal insufficiency.

The influence of mild to moderate chronic renal insufficiency on the pharmacokinetics of dexketoprofen trometamol was evaluated. Dexketoprofen was administered to volunteers with mild (n = 8) or moderate (n = 8) renal impairment and to healthy subjects (n = 8), as a single 12.5 mg oral dose (equivalent to 18.5 mg of the tromethamine salt). All subjects completed the study and no serious adverse events were recorded. Mild and moderate renal insufficiency increased Cmax by approximately 22% and 37%, respectively, as related to normal subjects (p < 0.05 for moderate renal dysfunction). No statistically significant differences between groups were obtained for tmax, AUC, CL/F, renal CL and V/F. The cumulative urinary excretion of unchanged dexketoprofen, assessed up to 24 hours postdose, was similar in all groups (median values of 7.0%, 8.1% and 9.7% of the administered dose). On the contrary, cumulative urinary excretions of conjugated dexketoprofen decreased in subjects with mild or moderate renal insufficiency when compared to healthy controls (median and 95% CI for differences: -3.3% (-14.8% to 2.6%) and -7.3% (-22.2% to -0.2%), respectively). Conservatively, a dose adjustment of dexketoprofen in patients with impaired renal function is recommended.

Single and repeated dose pharmacokinetics of dexketoprofen trometamol in patients with impaired liver function.

Dexketoprofen trometamol, a high water-soluble salt of the active enantiomer of rac-ketoprofen, is a nonsteroidal antiinflammatory drug (NSAID) used for pain relief. This study compared the pharmacokinetics of dexketoprofen in patients with impaired liver function and normal subjects following single and repeated oral dosing. Subjects with normal liver function (n = 6) and with Child-Pugh A (n = 7) or Child-Pugh B (n = 5) hepatic impairment scores completed this open-label and parallel study. They received 25 mg dexketoprofen (equivalent to 37 mg of its tromethamine salt) as a single (day 1) and a 3-day repeated dose (1 dose every 8 hours for a total of 10 doses). Dexketoprofen concentrations were determined in plasma and urine by reverse-phase high performance liquid chromatography (HPLC). Model-independent pharmacokinetic parameters were obtained. All subjects completed the study. No serious adverse events were recorded. Following the single dose, mean (+/- SEM) Cmax were 3027.7 +/- 429.3 ng/ml (healthy subjects), 2856.3 +/- 340.3 ng/ml (Child-Pugh A) and 1937.2 +/- 328.0 ng/ml (Child-Pugh B). Median tmax were 0.49 h (0.33-0.68) h, 0.50 h (0.33-0.67) h and 0.67 h (0.33-1.50) h. AUC0-x averaged 3778.0 +/- 439.0 ng.h/ml, 4890.4 +/- 539.1 ng.h/ml and 3985.0 +/- 712.0 ng.h/ml. Mean CL/F were 101.1 +/- 11.3 ml/h/kg, 73.3 +/- 9.9 ml/h/kg and 88.8 +/- 15.5 ml/h/kg and V/F averaged 0.192 +/- 0.018 l/kg, 0.162 +/- 0.006 l/kg and 0.214 +/- 0.044 l/kg. Following the repeated administration, similar results were obtained showing no drug accumulation. As related to the administered dose, median excretions of unchanged and conjugated dexketoprofen in urine were 2.1% and 67.1% in healthy subjects, 2.8% and 60.9% in Child-Pugh A subjects and 4.4% and 47.7% in Child-Pugh B volunteers. A trend towards a reduced urinary excretion of conjugated dexketoprofen in hepatic patients, more evident in the Child-Pugh B than in the Child-Pugh A groups, was observed when compared with healthy volunteers (median and 95% CI for differences: -5.4% [-19.9% to 2.0%] and -19.4% [-45.6% to 0.4%]). Conservatively, a dose adjustment of dexketoprofen trometamol in patients with impaired hepatic function is recommended.

Assessment of optical path length in tissue using neodymium and water absorptions for application to near-infrared spectroscopy.

Quantitative analysis of blood oxygen saturation using near-IR spectroscopy is made difficult by uncertainties in both the absolute value and the wavelength dependence of the optical path length. We introduce a novel means of assessing the wavelength dependence of path length, exploiting the relative intensities of several absorptions exhibited by an exogenous contrast agent (neodymium). Combined with a previously described method that exploits endogenous water absorptions, the described technique estimates the absolute path length at several wavelengths throughout the visible/near-IR range of interest. Isolated rat hearts (n = 11) are perfused separately with Krebs-Henseleit buffer (KHB) and a KHB solution to which neodymium had been added, and visible/near-IR spectra are acquired using an optical probe made up of emission and collection fibers in concentric rings of diameters 1 and 3 mm, respectively. Relative optical path lengths at 520, 580, 679, 740, 800, 870, and 975 nm are 0.41+/-0.13, 0.49+/-0.21, 0.90+/-0.09, 0.94+/-0.01, 1.00, 0.84+/-0.01, and 0.78+/-0.08, respectively. The absolute path length at 975 nm is estimated to be 3.8+/-0.6 mm, based on the intensity of the water absorptions and the known tissue water concentration. These results are strictly valid only for the experimental geometry applied here.

Tris lipidation--a novel drug delivery system that alters biodistribution.

Tris-lipidation uses Tris to produce drug-fatty acyl conjugates. Radiolabelled Tris-fatty acyl conjugates of methotrexate (MTX) were examined in biodistribution studies in BALB/c mice. Following delivery via a variety of routes, the Tris-lipidated compounds demonstrated features in common with other colloid drug delivery systems. Tissues of the reticuloendothelial system localised the drug following intravenous administration, and the compounds showed prolongation at the site of injection into muscle or fatty tissue, subcutaneously or when inhaled. These findings indicate that the Tris-lipidation platform could be classed as an alternative colloid drug delivery system.

Amphiphilic oligomers: a new kind of macromolecular carrier of antimitotic drugs.

The last three decades have seen the development of new concepts in the biomedical and medical field based on the principle of drug carrying and in vivo pharmaco-targeting using synthetic carriers such as nanoparticles, liposomes or polymers. This review deals with the synthesis and biomedical applications of a new kind of macromolecular compounds: end-capped oligomers called telomers. The telomers, derived from Tris(hydroxymethyl)aminomethane bearing either a hydro- or a fluorocarbon tail, are described. Their functionality and biocompatibility enhance their potential in the biomedical and medical fields. Such compounds exhibit no cytotoxicity and are able to cross cell membranes by endocytosis. After i.v or per os administration in the animal, they exhibit a very good bio-availability and a homogeneous distribution in all tissues without any accumulation. Their ability to carry in vivo antimitotic drugs has been shown. Moreover, the grafting of different glycoside moieties onto the hydroxyl groups of telomers allows the selective targeting of specific receptors called integrins. Finally, we have shown the potential use of telomers bearing specific peptide ligands, such as RGD sequences, in the selective carrying of antimitotic drugs to the angiogenic zone surrounding tumors.