Pharmacokinetics of colistin methanesulfonate (CMS) in healthy Chinese subjects after single and multiple intravenous doses

The high prevalence of extensively drug-resistant Gram-negative pathogens has forced clinicians to use colistin as a last-line therapy. Knowledge on the pharmacokinetics of colistin methanesulfonate (CMS), an inactive prodrug, and colistin has increased substantially; however, the pharmacokinetics in the Chinese population is still unknown due to lack of a CMS product in China. This study aimed to evaluate the pharmacokinetics of a new CMS product developed in China in order to optimise dosing regimens. A total of 24 healthy subjects (12 female, 12 male) were enrolled in single- and multiple-dose pharmacokinetic (PK) studies. Concentrations of CMS and formed colistin in plasma and urine were measured, and PK analysis was conducted using a non-compartmental approach. Following a single CMS dose [2.36?mg colistin base activity (CBA) per kg, 1?h infusion], peak concentrations (C_max) of CMS and formed colistin were 18.0?mg/L and 0.661?mg/L, respectively. The estimated half-life (t_1/2) of CMS and colistin were 1.38?h and 4.49?h, respectively. Approximately 62.5% of the CMS dose was excreted via urine within 24?h after dosing, whilst only 1.28% was present in the form of colistin. Following multiple CMS doses, colistin reached steady-state within 24?h; there was no accumulation of CMS, but colistin accumulated slightly (R_AUC?=?1.33). This study provides the first PK data in the Chinese population and is essential for designing CMS dosing regimens for use in Chinese hospitals. The urinary PK data strongly support the use of intravenous CMS for serious urinary tract infections.     

Quantitative determination of colistin A/B and colistin methanesulfonate in biological samples using hydrophilic interaction chromatography tandem mass spectrometry

Colistin (polymyxin E) is a polycation antibiotic which is increasingly used (administered as colistin methanesulfonate, CMS) as a salvage therapy in critically ill patients with multidrug resistant Gram‐negative infections. Even though colistin has been used for more than 50 years, its metabolic fate is poorly understood. One of the current challenges for studying the pharmacokinetics (PK) is the precise and accurate determination of colistin in in vitro and in vivo studies. In the present study, we developed and validated a series of sensitive and robust liquid chromatography tandem mass spectrometry (LC–MS/MS) methods for analysing biological samples obtained from in vitro and in vivo disposition assays. After a zinc acetate‐mediated precipitation, hydrophilic–lipophilic‐balanced solid phase extraction (HLB‐SPE) was used for the extraction of colistin. The compounds were retained on a hydrophilic interaction liquid chromatography (HILIC) column and were detected by MS/MS. CMS was quantified by determining the produced amount of colistin during acidic hydrolysis. The developed methods are sensitive with lower limits of quantification varying between 0.009 μg/mL and 0.071 μg/mL for colistin A, and 0.002 μg/mL to 0.013 μg/mL for colistin B. The intra‐ and inter‐day precision and accuracy were within ±15%. Calibration curves of colistin were linear (0.063 μg/mL to 8.00 μg/mL) within clinically relevant concentration ranges. Zinc acetate‐mediated precipitation and the use of a HILIC column were found to be essential. The developed methods are sensitive, accurate, precise, highly efficient and allow monitoring colistin and CMS in biological samples without the need for an internal standard.     

Gender effect on the pharmacokinetics of thymoquinone: Preclinical investigation and in silico modeling in male and female rats

Thymoquinone is the most biologically active constituent of Nigella sativa (black seed). A monoterpene compound chemically known as 2-methyl-5-isopropyl-1, 4-quinone. In this study, the gender-dependent pharmacokinetic behavior of thymoquinone in rats was investigated. Thymoquinone was administered orally (20 mg/kg) and intravenously (5 mg/kg) to male and female rats and blood samples were collected at specific time points. Plasma concentration-time curves were plotted and pharmacokinetic parameters were determined using the non-compartmental analysis. In addition, simulations of steady state concentrations of thymoquinone in male and female rats were performed using GastroPlus PK software. After oral administration, the maximum plasma concentration (C_max) of thymoquinone was 4.52 ± 0.092 μg/ml in male rats and 5.22 ± 0.154 μg/ml in female rats (p = 0.002). Similarly, after intravenous administration, the C_max was 8.36 ± 0.132 μg/ml in males and 9.51 ± 0.158 μg/ml in females (p = 0.550). The area under the plasma concentration-time curve (AUC)_0-∞ following oral dosing was 47.38 ± 0.821 μg/ml·h in females and 43.63 ± 0.953 μg/ml·h in males (p = 0.014). Pharmacokinetics and plasma concentration vs. time profiles for multiple oral doses of thymoquinone in rats were predicted using a simulation model to compare the simulation results with the experimental plasma pharmacokinetic data. The differences observed in thymoquinone pharmacokinetics between male and female rats after a single dose were not evident for the simulated steady-state parameters. The findings suggest that the gender difference does not seem to play a significant role in thymoquinone disposition at steady state.     

The plasma and cerebrospinal fluid pharmacokinetics of sorafenib after intravenous administration in non-human primates

Purpose Sorafenib is a small molecule inhibitor of multiple signaling kinases thought to contribute to the pathogenesis of many tumors including brain tumors. Clinical trials with sorafenib in primary and metastatic brain tumors are ongoing. We evaluated the plasma and cerebrospinal fluid (CSF) pharmacokinetics (PK) of sorafenib after an intravenous (IV) dose in a non-human primate (NHP) model. Methods 7.3 mg/kg of sorafenib free base equivalent solubilized in 20% cyclodextrin was administered IV over 1 h to three adult rhesus monkeys. Serial paired plasma and CSF samples were collected over 24 h. Sorafenib was quantified with a validated HPLC/tandem mass spectrometry assay. PK parameters were estimated using non-compartmental methods. CSF penetration was calculated from the AUC_CSF : AUC_plasma. Results Peak plasma concentrations after IV dosing ranged from 3.4 to 7.6 μg/mL. The mean ± standard deviation (SD) area under the plasma concentration from 0 to 24 h was 28 ± 4.3 μg•h/mL, which is comparable to the exposure observed in humans at recommended doses. The mean ± SD clearance was 1.7 ± 0.5 mL/min/kg. The peak CSF concentrations ranged from 0.00045 to 0.00058 μg/mL. The mean ± SD area under the CSF concentration from 0 to 24h was 0.0048 ± 0.0016 μg•h/mL. The mean CSF penetration of sorafenib was 0.02% and 3.4% after correcting for plasma protein binding. Conclusion Sorafenib is well tolerated in NHP and measurable in CSF after an IV dose. The CSF penetration of sorafenib is limited relative to total and free drug exposure in plasma.     

Greater optimisation of pharmacokinetic/pharmacodynamic parameters through a loading dose of intravenous colistin in paediatric patients

Use of colistin in children is rising in line with the increase of multidrug-resistant Gram-negative bacteria (MDR-GNB). In adults, a colistin loading dose is recommended to achieve therapeutic concentrations within 12–24 h. Here we aimed to describe the pharmacokinetic (PK) parameters of a loading dose versus a recommended initial dose of intravenous colistimethate sodium (CMS) in paediatric patients. A prospective, open-label, PK study was conducted in paediatric patients (age 2–18 years) with normal renal function. Patients (n = 20) were randomly assigned to receive either a CMS loading dose (LD group) of 4 mg of colistin base activity (CBA)/kg/dose or a standard initial dose (NLD group) of 2.5 mg (12-h interval) or 1.7 mg (8-h interval) of CBA/kg/dose. Serial blood samples were collected. Plasma concentrations of formed colistin were measured by LC-MS/MS. PK parameters were reported. Acute kidney injury (AKI) was monitored by serum creatinine and urine NGAL. The median (interquartile range) age and body weight were 8.5 (3.5–11.3) years and 21.5 (13.5–20.0) kg. The mean (standard deviation) of first-dose PK parameters of the LD group versus the NLD group were: C_max, 6.1 (2.4) vs. 4.1 (1.3) mg/L; AUC_0–t, 26.5 (12.5) vs. 13.5 (3.6) mg/L·h; V_d, 0.7 (0.4) vs. 0.6 (0.3) L/kg; and t_1/2, 2.9 (0.6) vs. 2.6 (0.4) h. No patient developed AKI by serum creatinine criteria. A CMS loading dose is beneficial for improvement of colistin exposure without increased AKI. A higher daily dose of CMS should be considered, especially for MDR-GNB treatment.     

Arsthinol nanosuspensions: pharmacokinetics and anti‐leukaemic activity on NB4 promyelocytic leukaemia cells

Objectives The organoarsenical arsthinol was used in the 1950s in the treatment of amoebiasis and yaws and was considered as ‘highly tolerated’. The aim of this work was to study its anti‐leukaemic activity and to develop nanosuspensions of the drug, thereby limiting brain concentrations and the risk of encephalopathy. Methods Arsthinol nanosuspensions were produced by high‐pressure homogenization. The anti‐leukaemic activity was assessed on NB4 acute promyelocytic leukaemia cells (vs solutions of arsthinol, As₂O₃ and melarsoprol). In addition, a pharmacokinetics study was performed to compare the nanosuspensions and the solution of arsthinol. Key findings Arsthinol induced growth inhibition of NB4 cells at lower concentration (IC50 (concentration inhibiting growth by 50%) = 0.78 ± 0.08 μmol/l after 24 h) than As₂O₃ (IC50 = 1.60 ± 0.23 μmol/l after 24 h) or melarsoprol (IC50 = 1.44 ± 0.08 μmol/l after 24 h). When formulated as nanosuspension, arsthinol remained cytotoxic (IC50 = 1.33 ± 0.30 μmol/l after 24 h). This formulation also reduced the drug's access to the brain (C_max = 0.03 μmol/g) whereas bone marrow concentrations remained very high (C_max = 2 μmol/g). Conclusions Nanosuspensions of arsthinol could be proposed for further studies in the treatment of acute promyelocytic leukaemia.     

The pharmacokinetics of erythropoietin in the cerebrospinal fluid after intravenous administration of recombinant human erythropoietin

Objectives Erythropoietin (EPO) was originally described as a regulator of erythropoiesis. Recently, synthesis of EPO and expression of the EPO receptor (EPO-R) have been reported for the central nervous system (CNS). The potential use of EPO to prevent or reduce CNS injury and the paucity of information regarding its entry into the human CNS led us to examine the pharmacokinetics (PK) of recombinant human EPO (r-HuEPO) in the serum and cerebrospinal fluid (CSF).Methods Four patients with Ommaya reservoirs were enrolled to facilitate serial CSF sampling. R-HuEPO was given intravenously (IV) in single doses of 40,000 IU or 1,500 IU/kg and in multiple doses of 40,000 IU daily for 3 days.Results The EPO concentrations in the CSF increased after a period of slow equilibration. Linear first-order distribution kinetics were observed for serum and CSF. The concentration of EPO in the CSF was proportional to the serum concentration of EPO and the permeability of the blood-brain barrier (BBB), as determined by the albumin quotient (Q_A=[albumin] CSF/[albumin] serum). A rise in the CSF concentration was seen as early as 3 h after IV administration. Peak levels (C_max) were reached between 9 h and 24 h. After a single dose of 1,500 IU/kg, the C_max in the CSF ranged from 11 mIU/ml to 40 mIU/ml, and the ratios of CSF/serum C_max ranged from 3.6×10^–4 to 10.2×10^–4. The terminal half-life (t_1/2) values of EPO in serum and CSF were similar. The t_1/2 of r-HuEPO in the CSF ranged from 25.6 h to 35.5 h after a single dose of 1,500 IU/l. Using these parameters a PK model was generated that predicts the concentration-time profile of EPO in the CSF.Conclusions We report that r-HuEPO can cross the human BBB and describe for the first time the PK of EPO in the CSF after IV administration. Our data suggest that the concentration-time profile of EPO in the CSF can be predicted for individual patients if the serum concentration of EPO and the Q_A are known. This information may be useful in the design of clinical trials to explore the potential therapeutic effects of EPO during CNS injury.     

Safety,Tolerability, Pharmacokinetics and Pharmacodynamics of Recombinant Human Parathyroid Hormone after Single‐ and Multiple‐Dose Subcutaneous Administration in Healthy Chinese Volunteers

Abstract: Recombinant human parathyroid hormone [rhPTH(1–84)] represents a new class of anabolic agents for the treatment of osteoporosis. The present study was designed to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of rhPTH(1–84) after single‐ and multiple‐dose subcutaneous administration in healthy Chinese volunteers. Six cohorts of 32 volunteers received a single dose of rhPTH(1–84) at 0.5–5.0 μg/kg, and two cohorts of 12 volunteers received 2.0 and 3.0 μg/kg of rhPTH(1–84) once daily for 7 consecutive days to assess its safety and tolerability. The results indicated that rhPTH(1–84) appeared to be safe and well tolerated. Additionally, pharmacokinetics of rhPTH(1–84) and its active N‐terminal fragment rhPTH(1–34) were investigated after administration of single 1.0, 2.0 and 4.0 μg/kg doses of rhPTH(1–84) in 30 other volunteers and after multiple doses of 2.0 μg/kg once daily for 7 consecutive days. The pharmacokinetic parameters for rhPTH(1–84) and rhPTH(1–34) after subcutaneous administration of a single dose of 1.0, 2.0 and 4.0 μg/kg were as follows: C_max = (110.54 ± 59.18), (149.70 ± 50.61) and (372.52 ± 94.96) pg/mL; (53.93 ± 6.27), (61.12 ± 11.28) and (89.04 ± 7.08) pg/mL, respectively. AUC_0–10 = (268.87 ± 47.72), (538.93 ± 146.89) and (1364.11 ± 176.82) pg hr/mL; (197.20 ± 50.78), (207.15 ± 72.08) and (344.05 ± 77.06) pg hr/mL, respectively. t_1/2 = (2.34 ± 1.93), (2.58 ± 1.18) and (2.74 ± 1.31) hr; (3.37 ± 1.82), (4.39 ± 3.79), and (3.99 ± 1.85) hr, respectively. Plasma C_max and AUC values of rhPTH(1–84) and rhPTH(1–34) were found to be dose proportional. The pharmacokinetic parameters for rhPTH(1–84) and rhPTH(1–34) after administration of multiple doses of 2.0 μg/kg were as follows: C_{ss_max} = (164.96 ± 52.61) and (75.05 ± 7.31) pg/mL; C_{ss_min} = (6.99 ± 7.73) and (2.05 ± 2.82) pg/mL; AUC_ss = (567.26 ± 118.41) and (306.02 ± 77.55) pg hr/mL; t_1/2 = (1.81 ± 0.89) and (2.27 ± 1.11) hr; DF = (6.93 ± 2.64) and (6.00 ± 1.37), respectively. After multiple doses, the pharmacokinetic parameters for rhPTH(1–84) were consistent with those after single dose. However, the mean C_max and AUC_0–10 of rhPTH(1–34) after multiple dosing were significantly higher than the corresponding values obtained after single‐dose administration. Serum total calcium and phosphate concentrations increased and decreased significantly at 4 hr post‐dosing, respectively.     

Pharmacokinetics and bioavailability of the new drug protecor upon peroral administration in rabbits and beagle dogs

A new high-performance liquid chromatographic method with ultraviolet detection has been used to determine the levels of the new cardiotropic drug protecor in the blood of animals (chincilla rabbits, 2.2 ± 0.2 kg; and beagle dogs, 10 ± 0.5 kg). The parameters of protecor pharmacokinetics and bioavailability upon peroral administration of protecor tablets have been determined. Rabbits showed effective absorption of the drug uupon peroral administration in a single dose (100 mg/kg) with a peak concentration in the plasma (C _max= 41 μg/mL) reached within T _max= 3 h followed by rapid removal of the drug from the organism with a half-elimination time T _/12β=1.71 h. Peroral administration of protecor in a single dose (50 mg/kg) in beagle dogs was characterized by C _max= 34.6 μg/mL, T _max = 3 h, and T _/12β=0.75 h. The bioavailability of protecor upon peroral administration was estimated at 90% (rabbits) and 80.7% (beagle dogs). __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 41, No. 12, pp. 3–6, December, 2007.     

Evaluation of super-boosted lopinavir/ritonavir in combination with rifampicin in HIV-1-infected patients with tuberculosis

Rifampicin induces the metabolism of many drugs. To overcome the reduction in serum concentrations of lopinavir/ritonavir (LPV/r) when used in combination with rifampicin, 800/200 mg or 400/400 mg doses are used. This study evaluated super-boosted LPV/r (400/400 mg) in HIV/TB co-infected patients for adequate concentrations as well as short-term safety, tolerability and clinical response to therapy. This was an open-label, non-randomised pharmacokinetic (PK) study in HIV/TB patients. The primary objective was to determine the PK profile of super-boosted LPV/r when given with a rifampicin-based TB regimen. Secondary objectives were short-term safety, tolerability and clinical response. Primary endpoints were a lopinavir trough concentration (C_min) >1.0 µg/mL and a rifampicin maximum concentration (C_max) of 8–24 µg/mL. Secondary PK endpoints were a rifampicin area under the concentration–time curve from 0–24 h (AUC_0–24) of 44–70 µg·h/mL, a lopinavir C_max of 6–14 µg/mL and a lopinavir AUC_0–12 of 56–130 µg·h/mL. Eleven patients (10 male, age 25–43 years) were enrolled. Two patients were discontinued due to non-compliance. A lopinavir C_min of >1.0 µg/mL was achieved in a least one of the PK samplings in all nine subjects who completed treatment. All patients met lopinavir C_max and AUC_0–12 targets. Five patients achieved the primary endpoint of rifampicin C_max (≥8 µg/mL) in at least one of the PK samplings, and five achieved the minimum rifampicin AUC_0–24 (≥44 µg·h/mL). One grade 3 adverse event was reported. Super-boosted LPV/r was safe and effective in HIV/TB patients. [ClinicalTrials.gov ID NCT01700790.]     

The association between trough blood concentration and systemic exposure of tacrolimus: Comparison between once-daily (Advagraf®) and twice-daily (Prograf®) formulation in de novo kidney transplant recipients

Available data of early conversion from twice-daily tacrolimus (TAC-BID) to once-daily tacrolimus (TAC-OD) in de novo kidney transplant (KT) recipients are limited. We conducted a prospective study of early conversion to TAC-OD in de novo KT recipients. Eligible patients were enrolled to receive TAC-BID (Prograf®) and then converted to TAC-OD (Advagraf®) by 1:1 ratio, approximately 14 days after KT (range 9–22). Blood samples were investigated for pharmacokinetic parameters before and 7–14 days after the conversion. Fifteen patients were included and provided AUC_0-24 of 202.9 ± 44.4 ng h/mL for TAC-BID (pre-conversion) and 193.0 ± 63.4 ng h/mL for TAC-OD (post-conversion) (p = 0.41). Mean trough blood concentration (C_min) of TAC-BID and TAC-OD was 6.4 ± 1.4 ng/mL and 4.9 ± 1.6 ng/mL (p = 0.01). Correlation coefficient (r) between C_min and AUC_0-24 of TAC-BID and TAC-OD were 0.620 and 0.875. Additional analysis found that patients with a drop of C_min > 30% had a significant lower AUC_0-24 after conversion. Renal function remains stable. We conclude that early conversion to TAC-OD is safe and well tolerated with an indifferent systemic exposure. However, patients with a drop of C_min > 30% after conversion to TAC-OD will require additional dose adjustment.     

Delivery and Biodistribution of Traceable Polymeric Micellar Diclofenac in the Rat

The nonsteroidal anti-inflammatory drugs elevate cardiovascular risk, perhaps, due to their accumulation in the heart and kidneys. We designed nanodelivery systems for cardiotoxic diclofenac to reduce its presence in these organs. Diclofenac ethyl ester (DFEE) was encapsulated in traceable micelles based on poly(ethylene oxide)-b-poly(ε-caprolactone) (DFEE-PCL-TM) or poly(ethylene oxide)-b-poly(α-benzyl carboxylate-ε-caprolactone) (DFEE-PBCL-TM). Diclofenac pharmacokinetics and tissue distribution were studied after intravenous (iv) and intraperitoneal administration of the nanoformulations and compared with those after iv doses of free diclofenac (n = 3-6/group). The average diameters for DFEE-PBCL-TM and DFEE-PCL-TM were 37.2 ± 0.06 and 45.1 ± 0.06 nm, respectively. Drug concentration dropped below the assay sensitivity after free drug administration in 6 h, but persisted for 24 h following DFEE-PBCL-TM (2.3 ± 1.4 μg/mL) and DFEE-PCL-TM (1.9 ± 0.6 μg/mL) iv administration. The diclofenac heart:blood and kidney:blood ratios were 5- to 12-fold lower with the nanoformulations than with free diclofenac. Near-infrared fluorescence measurements in tissues suggested exposure patterns to nanocarriers parallel with those achieved for delivered diclofenac by nanoformulations. Administration of DFEE-PCL-TM by iv or intraperitoneal injection, resulted in comparable pharmacokinetics and 6 h postdose near-infrared fluorescence in the heart, kidneys, liver, and spleen. When compared to each other, DFEE-PBCL-TM showed significantly lower diclofenac levels in the heart compared to DFEE-PCL-TM (0.3 ± 0.03 vs. 0.5 ± 0.1 μg/g). Developed nanoformulations of diclofenac prolonged diclofenac circulation and reduced its presence in the heart and kidneys, strongly suggesting cardiac-safe delivery vehicles for diclofenac.     

Pharmacokinetics and Pharmacodynamics of Escalating Doses of SHetA2 After Vaginal Administration to Mice

SHetA2 is a novel compound with strong potential to treat cervical dysplasia, but its low aqueous solubility limits its oral bioavailability. A vaginal suppository achieved SHetA2 cervix concentrations that were severalfold above the predicted therapeutic levels. Thus, we aimed at determining the minimum dose that would achieve SHetA2 therapeutic levels while reducing cyclin D1 levels, the pharmacodynamic end point. The disposition of SHetA2 after vaginal administration of escalating SHetA2 doses and the corresponding reduction in cyclin D1 levels was compared to that after the conventional oral treatment. Vaginal administration of a 15-mg/kg dose achieved an area under the cervix concentration versus time curve (AUC_cervix) that was ～120 times larger than that after a 60 mg/kg administered orally. AUC_cervix and C_max-cervix did not increase proportionally with respect to the dose, with the 30-mg/kg dose resulting in higher AUC_cervix and C_max-cervix (1368.53 μg.mL/h and 155.38 μg/g, respectively) compared to the 15 mg/kg (334.98 μg.mL/h and 121.78 μg/g, respectively) or 60 mg/kg (1178.55 μg.mL/h and 410.38 μg/g, respectively). Likewise, the 30-mg/kg dose caused a larger reduction in cyclin D1 levels than the other doses. Thus, the 30-mg/kg dose was selected for future efficacy studies in a mouse model of cervical neoplasia.     

Pharmacokinetics and penetration of moxifloxacin into infected diabetic foot tissue in a large diabetic patient cohort

Objectives

Physiological changes occurring in patients with diabetes may affect the pharmacokinetics and penetration of antimicrobial agents into peripheral tissue. We examined the pharmacokinetics and the penetration of moxifloxacin into perinecrotic tissue of diabetic foot lesions in patients with diabetic foot infections (DFI).

Patients and methods

Adult patients suffering from type 2 diabetes mellitus and hospitalized for DFI (Texas classification of at least B2) were treated with 400?mg moxifloxacin intravenously (IV) or orally (PO) once daily. The pharmacokinetics of moxifloxacin and its concentration 3 h after administration in samples of perinecrotic tissue resected from infected diabetic foot wounds were determined at steady state (days 4?C8).

Results

A total of 53 patients with diabetes mellitus type 2 (mean age 69.4?±?10.8?years) were included in the study, of whom 28 received PO and 25 IV moxifloxacin therapy for a median of 8?days. In the PO and IV subgroups, the mean maximum observed plasma concentration (C _max) in plasma was 2.69 and 4.77?mg/l at a median of 2 [time to reach C _max (T _max) range 1.0?C8.0?h] and 1?h after administration, respectively. A mean area under the plasma concentration?Ctime curve from time 0 until the last quantifiable plasma concentration (AUC_0-24?h) of 29.36?mg h/l (PO) and 27.09?mg h/l (IV) was achieved. Mean moxifloxacin concentrations in perinecrotic tissue of infected diabetic foot wounds following PO or IV administration were 1.79?±?0.82?and 2.20?±?1.54???g/g, thus exceeding the MIC₉₀ (minimum inhibitory concentration required to inhibit growth of 90% of organisms) for Staphylococcus aureus (0.25?mg/l) by seven- and eightfold and the MIC₉₀ for Escherichia coli (0.06?mg/l) by 29-fold and 36-fold, respectively. The mean tissue-to-plasma ratios of moxifloxacin concentration 3?h after administration were 1.01?±?0.57 (PO) and 1.09?±?0.69 (IV). Significant differences between the routes of administration were observed for T _max and C _max (P?<?0.01), but not for other clinically relevant parameters (AUC_0-24; moxifloxacin DFI tissue concentration).

Conclusions

The plasma concentration?Ctime curve of moxifloxacin in diabetic patients is similar to that of healthy volunteers. We also observed a good penetration of moxifloxacin into inflamed DFI tissue which taken together with the possibility of sequential IV/PO therapy suggest that moxifloxacin 400?mg once daily is a therapeutic option in the treatment of DFI caused by susceptible organisms.     

Phytochemical profile,antioxidant and cytotoxic potential of Parkinsonia aculeata L. growing in Saudi Arabia

Parkinsonia aculeata L. growing in Saudi Arabia was investigated for its phytochemical profile, antioxidant, and cytotoxic properties. UPLC-ESI-MS/MS was employed as a powerful technique for the characterization of secondary metabolites from a hydroalcoholic extract, dichloromethane, and ethyl acetate fractions of P. aculeata L. aerial parts. Sixty-nine compounds (flavonoids, anthocyanins, phenolics and fatty acids) were detected and characterized; flavonoids were the abundant components in the analyzed samples. The dichloromethane fraction was rich in phenolics as vanillic acid hexoside, flavonols as 3,7-dimthylquercetin, and flavones as 3′-hydroxymelanettin. However, the ethyl acetate fraction was rich in flavonoid-C-glycosides as luteolin-8-C-β-D-glucoside (orientin) and apigenin-8-C-glucoside (vitexin), flavonoid- O, C-diglycosides such as luteolin 7-O-[6′'-dihydrogalloyl]-glucosyl-8-C-pentosyl-(1 → 2)-glucoside and 2′'-O-rhamnosyl isoorientin. These compounds were identified for the first time in dichloromethane and ethyl acetate fractions of Saudi P. aculeata L.Additionally, all the samples were assessed for antioxidant activity using DPPH radical scavenging method and for cytotoxic activity through MTT assay. Accordingly, the most active fraction was the ethyl acetate which showed the highest antioxidant activity (SC₅₀ = 57.4 ± 1.2 μg/mL) compared with the positive control, ascorbic acid (SC₅₀ = 12.4 ± 0.5 μg/mL) and moderate cytotoxicity against HepG-2 (hepatocellular carcinoma) and MCF-7 (breast carcinoma) cell lines with IC₅₀ = 56.9 ± 3.1 and 95.8 ± 3.8 μg/mL, respectively compared with cisplatin (IC₅₀ = 3.67 ± 0.22 and 5.71 ± 0.57 μg/mL, respectively for both cell lines). The antioxidant and cytotoxic activities may be attributed to the presence of high percentage of phenolic compounds and hydroxylated flavonoids detected in ethyl acetate fraction using UPLS-ESI-MS/MS.     

Pharmacokinetics and tissue disposition of danofloxacin in sheep

The plasma pharmacokinetics of danofloxacin administered at 1.25 mg kg⁻¹ body weight by the intravenous and intramuscular routes were determined in sheep. Tissue distribution was also determined following administration by the intramuscular route at 1.25 mg kg⁻¹ body weight. Danofloxacin had a large volume of distribution at steady state (V_ss) of 2.76±0.16 h (mean±S.E.M.) L kg⁻¹, an elimination half-life (t_1/2β) of 3.35±0.23 h, and a body clearance (C1) of 0.63±0.04 L kg⁻¹ h⁻¹. Following intramuscular administration it achieved a maximum concentration (C_max) of 0.32±0.02 μg mL⁻¹ at 1.23±0.34 h (t_max) and had a mean residence time (MRT) of 5.45±0.19 h. Danofloxacin had an absolute bioavailability (F) of 95.71±4.41% and a mean absorption time (MAT) of 0.81±0.20 h following intramuscular administration. Mean plasma concentrations of >0.06 μg mL⁻¹ were maintained for more than 8 h following intravenous and intramuscular administration. Following intramuscular administration highest concentrations were measured in plasma (0.43±0.04 μg mL⁻¹), lung (1.51±0.18 μg g⁻¹), and interdigital skin (0.64±0.18 μg g⁻¹) at 1 h, duodenal contents (0.81±0.40 μg mL⁻¹), lymph nodes (4.61±0.35 μg g⁻¹), and brain (0.06±0.00 μg mL⁻¹) at 2 h, jejunal (10.50±4.31 μg mL⁻¹) and ileal (5.25±1.67 μg mL⁻¹) contents at 4 h, and colonic contents (8.94±0.65 μg mL⁻¹) at 8 h. © 1998 John Wiley & Sons, Ltd.     

Plasma and tissue disposition of florfenicol in Escherichia coli lipopolysaccharide-induced endotoxaemic sheep

1.?The purpose of this study was to understand the effects of the acute inflammatory response (AIR) induced by Escherichia coli lipopolysaccharide (LPS) on florfenicol (FFC) and FFC-amine (FFC-a) plasma and tissue concentrations.

2.?Ten Suffolk Down sheep, 60.5?±?4.7?kg, were distributed into two experimental groups: group 1 (LPS) treated with three intravenous doses of 1?μg/kg bw of LPS at 24, 16, and 0.75?h (45?min) before FFC treatment; group 2 (Control) was treated with saline solution (SS) in parallel to group 1. An IM dose of 20?mg FFC/kg was administered at 0.75?h after the last injection of LPS or SS. Blood and tissue samples were taken after FFC administration.

3.?The plasma AUC_0–4?h values of FFC were higher (p?=?0.0313) in sheep treated with LPS (21.8?±?2.0?μg·min/mL) compared with the control group (12.8?±?2.3?μg·min/mL). Lipopolysaccharide injections increased FFC concentrations in kidneys, spleen, and brain. Low levels of plasma FFC-a were observed in control sheep (C_max?=?0.14?±?0.01?μg/mL) with a metabolite ratio (MR) of 4.0?±?0.87%. While in the LPS group, C_max increased slightly (0.25?±?0.01?μg/mL), and MR decreased to 2.8?±?0.17%.

4.?The changes observed in the plasma and tissue concentrations of FFC were attributed to the pathophysiological effects of LPS on renal hemodynamics that modified tissue distribution and reduced elimination of the drug.     

L-DOPA pharmacokinetics in the MPTP-lesioned macaque model of Parkinson's disease

ObjectiveThe 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned non-human primate is widely used to model Parkinson's disease (PD) and to evaluate the efficacy of new therapies. However, some doubts have been raised about the translatability of findings in the MPTP-lesioned monkey, because the doses of l-3,4-dihydroxyphenylalanine (l-DOPA) required to alleviate parkinsonism and elicit dyskinesia are high, on a mg/kg basis, when compared to clinical practice. Thus, in the MPTP-lesioned macaque, doses ranging from 20 to 40 mg/kg might be used, while in the clinic single l-DOPA administrations ranging from 100 to 200 mg are more typical. However, bioavailability of drugs varies between species and it is unknown how plasma l-DOPA levels providing therapeutic benefit in the non-human primate compare to those having similar actions in PD patients.MethodsWe administered acute challenges of l-DOPA 30 mg/kg orally to MPTP-lesioned macaques with established dyskinesia, and determined plasma, brain and cerebrospinal fluid (CSF) levels of l-DOPA using high-performance liquid chromatography–mass spectrometry/mass spectrometry.ResultsThe maximal plasma concentration of l-DOPA (C_max) was 18.2 ± 3.8 nmol/ml and was achieved 1.6 ± 0.3 h after administration (t_max). Half-life was 58.8 ± 22.7 min. l-DOPA levels in the caudate nucleus at peak behavioural effect were 3.3 ± 0.7 μg/g tissue protein while they were 1.5 ± 0.1 nmol/ml in the CSF.ConclusionsAlthough therapeutically-active doses of l-DOPA administered to the MPTP-lesioned macaque are higher on a mg/kg basis than those administered in clinical settings, they lead to l-DOPA C_max similar to those achieved with 200 mg l-DOPA in clinic. l-DOPA t_max and half-life are also similar to those reported in human.     

Bactericidal activity of daptomycin versus vancomycin in the presence of human albumin against vancomycin-susceptible but tolerant methicillin-resistant Staphylococcus aureus (MRSA) with daptomycin minimum inhibitory concentrations of 1–2 μg/mL

This study explored the influence of vancomycin tolerance and protein binding on the bactericidal activity of vancomycin versus daptomycin (protein binding 36.9% vs. 91.7%, respectively) against four vancomycin-tolerant methicillin-resistant Staphylococcus aureus (MRSA) [minimum inhibitory concentration/minimum bactericidal concentration (MIC/MBC) = 0.5/16, 1/32, 2/32 and 1/32 μg/mL for vancomycin and 1/1, 1/2, 2/2 and 2/4 μg/mL for daptomycin]. Killing curves were performed with vancomycin/daptomycin concentrations equal to serum peak concentrations (C_max) (65.70/98.60 μg/mL) and trough concentrations (C_min) (7.90/9.13 μg/mL) in the presence and absence of a physiological human albumin concentration (4 g/dL), controlled with curves with the theoretical free drug fraction of vancomycin/daptomycin C_max (41.45/8.18 μg/mL) and C_min (4.98/0.76 μg/mL). Vancomycin C_max and C_min concentrations, regardless of the media, showed a bacteriostatic profile not reaching a reduction of 99% or 99.9% of the initial inocula during the 24-h experimental time period. Daptomycin antibacterial profiles significantly differed when testing C_max and C_min. C_max was rapidly bactericidal (≤4 h) with >5 log₁₀ reduction in the initial inocula for all strains, regardless of the presence or not of albumin or the use of concentrations similar to free C_max. C_min exhibited similar final colony counts at 0 h and 24 h in curves with albumin, but with >3 log colony-forming units (CFU)/mL reduction at ≤4 h for strains with an MIC of 1 μg/mL and ca. 2 log CFU/mL reduction at ≤6 h for strains with an MIC of 2 μg/mL. This activity was significantly higher than the activity of the free C_min fraction. The results of this study reinforce the idea that pharmacodynamics using concentrations calculated using reported protein binding are unreliable. Daptomycin exhibited rapid antibacterial activity against vancomycin-tolerant MRSA isolates even against those with high daptomycin MICs in the presence of physiological albumin concentrations.