Comparison of the pharmacokinetic properties of vancomycin, linezolid, tigecyclin, and daptomycin.

The rapid antibiotic resistance development has created a major demand for new antimicrobial agents that can combat resistant strains such as methicillin-resistant S. aureus (MRSA). Until a short time ago, the glycopeptide vancomycin was the only therapeutic choice in this situation. However, in recent years some newer agents with different mechanisms of actions have been added to the arsenal, and more are on the horizon. For a successful therapy it is of vital importance that these compounds are used judiciously and dosed appropriately. The present article reviews the pharmacokinetic properties of vancomycin, linezolid, tigecycline and daptomycin. The first major difference between these compounds is their oral bioavailability. Only linezolid can be administered orally, whereas vancomycin, daptomycin and tigecycline are limited to parenteral use. Once in the body, they show very different disposition. Daptomycin has a very small volume of distribution of 7L indicating very little tissue distribution whereas tigecycline has a very large volume of distribution of 350-500 L. Vancomycin and linezolid are in-between with volumes of distribution of approximately 30 and 50 L, close to total body water. However, studies have shown that linezolid shows better tissue penetration than vancomycin. Newer studies using microdialysis, a new technique that allows direct monitoring of unbound tissue levels, support this finding. As far as drug elimination, daptomycin and vancomycin are mainly eliminated into the urine and require dosing adjustments in renally impaired patients, whereas tigecycline is eliminated into the bile and linezolid is metabolized so that in renal patients no dosing adjustments are needed for these compounds. Although the elimination pathways are very different, the resulting half-lives of linezolid, vancomycin, and daptomycin are not greatly different and vary from 4-8 h. Tigecycline, however, has a much longer half-life of up to 1-2 days due to the slow redistribution from tissue binding sites.

The efficacy of octreotide in the therapy of severe nonproliferative and early proliferative diabetic retinopathy: a randomized controlled study.

OBJECTIVE: The pilot study examined the ability of octreotide to retard progression of diabetic retinopathy (DR) and delay the need for panretinal photocoagulation (PRP) in patients with advanced stages of retinal disease. RESEARCH DESIGN AND METHODS: Patients with severe nonproliferative DR (NPDR) or early non-high-risk proliferative DR (PDR) were randomly assigned to conventional diabetes management (control group, 12 patients) or to treatment with maximally tolerated doses of octreotide (200-5,000 microg/day subcutaneously; 11 patients). Ocular changes in each eye were assessed at a minimum of every 3 months for 15 months or until disease progressed to high-risk PDR requiring laser surgery. Endocrine assessments occurred at 3-month intervals during the study RESULTS: Only 1 of 22 eyes from patients treated with octreotide reached high-risk PDR requiring PRP, compared with control patients, in whom 9 of 24 eyes required PRP. The decreased incidence of progression requiring laser surgery was statistically significant if events were considered independently (P < 0.006). The incidence of ocular disease progression was only 27% in patients treated with octreotide compared with 42% in patients with conventional diabetes management. This treatment effect on whether the retina worsened approached statistical significance using repeated measures analysis (P = 0.0605). Endocrine management was similar between treatment groups. Thyroxine replacement therapy was administered to maintain a euthyroid state for all octreotide-treated patients and 7 of 12 control patients. CONCLUSIONS: Our results suggest that octreotide treatment in euthyroid patients may retard progression of advanced DR and may delay the time to laser surgery.

Limiting cefotaxime pediatric dosing to adult standards: a pharmacokinetic simulation study.

OBJECTIVE: The recommended cefotaxime dose of 50 mg/kg every six to eight hours for pediatric patients with a body weight greater than 20 kg exceeds the standard 1-gram dose recommended for adult patients. This study estimated whether limiting the cefotaxime dose recommended for children with mild to moderate infections to a standard 1-gram dose would achieve serum concentrations and time above the MIC90 comparable to those in adults. METHODS: Serum concentration profiles were simulated from mean cefotaxime pharmacokinetic parameters that have been published for children and for adults using widely available spreadsheet software. The simulations employed an open, one-compartment, multiple-dose model and were calculated using a common commercial spreadsheet. The model was used to predict serum concentrations using dosage regimens of 1 g or 50 mg/kg administered every six or eight hours in pediatric patients of various weights with pediatric pharmacokinetic parameters and 1 g every six or eight hours for adult patients with adult pharmacokinetic parameters. The time that cefotaxime concentrations exceeded the MIC90 for pediatric pathogens was also calculated. RESULTS: The 50 mg/kg pediatric dosing regimens administered every 8 hours (q8h) or every 6 hours (q6h) consistently produced peak serum concentrations and area under the concentration versus time curve (AUC) values higher than those in adults. Serum concentrations and AUCs generated for the 1-gram regimens for various pediatric weight categories were also above those predicted in adults. The time above the MIC90 for pediatric patients was equivalent to or exceeded those of the adult simulations for all pathogens. CONCLUSIONS: The results support the concept of limiting cefotaxime dosage regimens to 1 g administered every 6 or 8 hours for mild to moderate infections in children weighing more than 20 kg. This dosage regimen could lead to dose standardization procedures, which could produce reductions in drug costs associated with individualized dosage preparation.

Pharmacokinetic overview of oral second-generation H1 antihistamines.

Specific H1 antihistamines have become the standard of treatment for relief of symptoms associated with seasonal allergic rhinitis. First-generation antihistamines are small lipophilic molecules that are associated with numerous adverse events largely because of their propensity to cross the blood-brain barrier and their cholinergic activity. Second-generation antihistamines, being more lipophobic, offer the advantages of a lack of CNS and cholinergic effects such as sedation and dry mouth, which are commonly seen in first-generation antihistamines. Their longer duration of action also enables a more patient-friendly dosing regimen which increases patient compliance. This paper reviews the pharmacokinetic properties of these second-generation agents and is intended to provide comparisons that help explain differences in dosing profiles and drug interactions for members of this class of drugs. With the announced withdrawal of terfenadine from the U.S. market in early 1997, 4 second-generation antihistamines are currently widely available: astemizole, loratadine, cetirizine, and fexofenadine. Terfenadine and astemizole both produce significant cardiac QT interval prolongation that may progress to a rare but fatal cardiac ventricular tachycardia known as torsades de pointes. While only terfenadine has been withdrawn due to its adverse effects profile, significant warnings were recently issued for astemizole. The pharmacokinetic profiles of loratadine and cetirizine are reflective of the advantages of these agents as non-cardiotoxic antihistamines. With respect to the newest agent fexofenadine, the major metabolite of terfenadine, published reports are minimal, but its pharmacokinetics differs from that of terfenadine.

Pharmacokinetic-pharmacodynamic relationships for analgesics.

A major goal of current pain research is to develop scientifically-based guidelines to optimize selection of analgesic drug doses and control pain. Numerous clinical studies have shown that the drug dose required to effectively alleviate pain is often highly variable, both between patients and between pain episodes in individual patients. This high variability makes it difficult to predict appropriate dosing regimens that will adequately control pain in the individual patient. The result is a "trial and error" approach to analgesic therapy. Experimental tools that measure analgesic response and drug disposition after administration of analgesics can be used to better predict the therapeutic effects of analgesics in individual patients. The approach defines factors that contribute to variability in therapeutic response. Pharmacokinetic-pharmacodynamic (PK/PD) modeling involves analysis of drug disposition data and drug efficacy data. Modeling depends on sensitive and reliable methods to quantify both pain and plasma (or other body fluid) levels of analgesic agents. Two major approaches have been used to quantify pain. The first utilizes subjective reports from patients, while the second employs physiological correlates of pain, such as evoked potentials. Results from PK/PD analysis that successfully identify a relationship between drug dose, drug concentration, and effect can be used to predict the effects of drug dose on analgesic effect in individuals. The ultimate goal is to provide patients with better pain relief by understanding variables that affect the analgesic concentration/effect relationship. This review examines the available pharmacokinetic-pharmacodynamic (PK/PD) data for selected opioid and nonopioid analgesics. Even though most analgesics are used clinically in multiple doses, the majority of PK/PD studies conducted to date evaluate single dose effects. Further studies with multiple doses are required to evaluate the validity of PK/PD relationships defined from single dose studies.

Intravenous and oral pharmacokinetic evaluation of a 2-hydroxypropyl-beta-cyclodextrin-based formulation of carbamazepine in the dog: comparison with commercially available tablets and suspensions.

Complexation of carbamazepine with 2-hydroxypropyl-beta-cyclodextrin was performed to provide improved formulations of this widely used antiepileptic drug. Based on this approach, liquid dosage forms were configured for both parenteral and oral use. Intravenous administration of an aqueous carbamazepine x 2-hydroxypropyl-beta-cyclodextrin (CBZ x HPbetaCD) complex at a CBZ dose of 20 mg/kg was well tolerated and generated high initial drug levels that fell monoexponentially as a function of time, yielding a plasma elimination half-life of 38 min. Oral studies were completed with three preparations: a commercially available tablet and suspension, as well as a CBZ x HPbetaCD oral solution. Oral administration of tablets gave erratic and slow absorption, leading to maximum CBZ concentrations (C(max)) of <2 microg/mL, which were manifested only at 2.5 h after drug dosing. The absolute bioavailability of CBZ from the tablets was approximately 25%. Both the suspension and CBZ x HPbetaCD solution gave a significantly improved profile. Thus, the liquid oral dosage forms approximately doubled the oral bioavailability of CBZ compared with the tablets.

Tissue distribution of LY231617, an antioxidant with neuroprotectant activity, in the rat.

The tissue distribution of a butylated phenol antioxidant, LY231617, which has been shown to exert potent neuroprotection action was examined. Preliminary pharmacokinetic examination suggests that LY231617 was eliminated in a biphasic fashion after iv administration to the rat with a distribution half-life of 5 min and an elimination half-life of close to 2.5 h. The volume of distribution of the compound was large (7.4 L), consistent with its lipophilic structure. Dosing paradigms that have historically resulted in pharmacologically relevant activity were examined and were found to generate brain tissue levels of LY231617 of approximately 45 micrograms/g.

A redox-based chemical delivery system that enhances estradiol distribution to the brain: disposition studies in the rat.

The disposition of a chemical delivery system for estradiol (E2-CDS) which is based on a redox dihydropyridine-pyridinium salt conversion was investigated in rats. Tissue and plasma concentrations of E2-CDS and the oxidized metabolite (E2-Q+) were evaluated at times ranging from 1 to 14 days after intravenous administration of E2-CDS formulated as a modified cyclodextrin inclusion complex. While E2-CDS levels were below HPLC assay detection limits for all samples by 1 day postdosing, E2-Q+ was readily quantified. The calculated half-life of E2-Q+ was longest in brain tissue, significantly shorter in heart, lung, and kidney tissues, and shortest in plasma. There was a linear relationship between administered E2-CDS dose and oxidized metabolite measured in brain as well as in other tissues collected 24 hr after drug administration. Coadministration of high doses of a similarly oxidizable dihydropyridine, 1-methyl-1,4-dihydronicotinamide (NMN), in a dimethylsulfoxide (DMSO) vehicle decreased E2-Q+ measured in brain and other tissues without significantly affecting the relative patterns of distribution in these tissues. Brain tissue E2Q+ levels were not detected after dosing with the oxidized metabolite.

Development of aqueous parenteral formulations for carbamazepine through the use of modified cyclodextrins.

The poor aqueous solubility of carbamazepine was dramatically increased via complexation with various chemically modified beta-cyclodextrins and gamma-cyclodextrins. A preparation of carbamazepine and 2-hydroxypropyl-beta-cyclodextrin was found to be stable to steam sterilization and to storage under a variety of conditions. Carbamazepine, when solubilized in this manner, was found to exert potent anticonvulsant effects in various seizure models and the formulation was tolerated in animals at high doses (100 mg/kg carbamazepine and 1200 mg/kg of the cyclodextrin excipient). The onset of anticonvulsant action was rapid and consistent with almost instantaneous in vivo complex dissociation. The low toxicity of 2-hydroxypropyl-beta-cyclodextrin, when administered via the parenteral route, and its ability to enhance the aqueous solubility of carbamazipine highly favor the use of this excipient.

A redox-based system that enhances delivery of estradiol to the brain: pharmacokinetic evaluation in the dog.

The pharmacokinetics of a dihydropyridine-pyridinium salt-type chemical delivery system (CDS) for brain-targeted delivery of estradiol (E2) were examined in dogs. Parameters evaluated in vitro included stability in buffers and biological fluids and plasma protein binding. In vivo studies examined drug and metabolite concentrations in plasma, urine, and cerebrospinal fluid as well as in selected brain regions. The administered lipophilic E2-CDS disappeared very quickly from plasma and was not detected in urine. The oxidized drug form, E2-Q+, was excreted unchanged or as a conjugate in the urine for as long as 2 weeks. Plasma levels were below assay detection limits at later times. Pharmacokinetic analysis of urine E2-Q+ levels allowed estimation of a half-life of 2.2 days. Amounts of E2-Q+ excreted into the urine were proportional to the dose but averaged only 13.9% of the dose, indicating that other routes of excretion must be considered. CSF levels were below the limit of detection for both E2-CDS and E2-Q+, however, brain tissue concentrations of E2-Q+ were similar in several brain regions of individual animals examined 1 or 3 days after drug dosing.

Improved delivery through biological membranes. XXI. Brain-targeted anti-convulsive agents.

A dihydropyridine in equilibrium with pyridinium salt redox system was applied to effect brain delivery of gamma-aminobutyric acid (GABA) derivatives and analogues. The redox system allows the lipophilic dihydropyridine conjugates to penetrate the blood brain barrier, whereas corresponding oxidized pyridinium forms are retained in the brain for an extended period and rapidly eliminated from the periphery. The most promising compound was the GABA benzyl ester-CDS (1a, Scheme I). It had an ED50 of 15.8 mg/kg (i.v.) in protecting mice against maximal electroconvulsive shock-induced tonic hind-leg extension.

Development of a non-surfactant formulation for alfaxalone through the use of chemically-modified cyclodextrins.

The poor water solubility of alfaxalone (less than 5 micrograms/mL), a useful steroid anesthetic agent, was dramatically increased via complexation with a series of four cyclodextrins. The most effective agent was 2-hydroxypropyl-beta-cyclodextrin (2HPCD) which solubilized alfaxalone in a linear manner as a function of concentration. At a 2HPCD concentration of 50% w/v, approximately 80 mg/mL of alfaxalone was dissolved indicating an increase in aqueous solubility of over four orders of magnitude. The cyclodextrin solution was stable to autoclaving and could be conveniently lyophilized to yield a solid product.

Improved delivery through biological membranes. XXXL: Solubilization and stabilization of an estradiol chemical delivery system by modified beta-cyclodextrins.

A dihydropyridine in equilibrium pyridinium salt chemical delivery system (CDS) for estradiol (E2CDS) was complexed with various modified beta-cyclodextrins including hydroxyethyl-beta-cyclodextrin (HECD), hydroxypropyl-beta-cyclodextrin (HPCD), and heptakis(2,6-di-O-methyl)-beta-cyclodextrin (DMCD). Complex formation with all of these cyclodextrins resulted in dramatic increases in the water solubility of E2CDS. Studies on the complex of E2CDS and HPCD (E2CDS-CD) indicated that the encapsulated estrogen was approximately four times more stable than the unmanipulated CDS, producing an estimated half-life of degradation of 4 years compared with 1.2 years for the uncomplexed drug at room temperature. The complexation of E2CDS and HPCD also stabilized the dihydronicotinate in solutions containing potassium ferricyanide. This formulation was shown to be equivalent to E2CDS in dimethyl sulfoxide in delivering the oxidized, estradiol precursor (E2Q+) to the brain, and also produced similar biological responses; these included decreased luteinizing hormone (LH) secretion and a decrease in the rate of weight gain in castrated female rats.

A dihydropyridine conjugate which generates high and sustained levels of the corresponding pyridinium salt in the brain does not exhibit neurotoxicity in cynomolgus monkeys.

Many drugs can be selectively delivered to the brain by using a dihydropyridine in equilibrium pyridinium salt chemical delivery system (CDS). The interaction of these systems with central dopaminergic function was examined in this communication. Castrate female Sprague-Dawley rats when treated with a CDS for estradiol (i.e. 3-hydroxy-17 beta-[( (1-methyl-1,4-dihydropyridin-3-yl)carbonyl]oxy) estra-1,3,5(10)-triene or E2CDS) exhibit sustained and profound suppression of serum levels of leuteinizing hormone (LH). Treatment of rats with pargyline (80 mg/kg) prior to E2CDS (2 mg/kg) did not mitigate the biological effectiveness of this estrogen indicating at least indirectly that monoamine oxidate (MAO) was not involved in the CDS activation. In a more direct examination, cynomolgus monkeys treated with various repeated doses of E2CDS (cumulative doses of 0.2-40.0 mg/kg) demonstrated neither impaired motor function nor depleted striatal dopamine concentrations. The latter parameter was measured using liquid chromatographic-electrochemical analysis. These experiments support the contention that the CDS is not neurotoxic and further strengthens the strict structure-activity requirements for MPTP-induced neurotoxicity.

High-performance liquid chromatographic assay of a central nervous system (CNS)-directed estradiol chemical delivery system and its application after intravenous administration to rats.

A redox-based chemical delivery system for estradiol (E2-CDS) has been shown capable of sustained and brain-selective delivery of estradiol (E2). A reversed-phase high-performance liquid chromatographic (HPLC) method is presented for the analysis of E2-CDS and its oxidized quaternary metabolite (E2-Quat) in biological fluids or tissues. The assay utilized a precolumn enrichment technique and detects plasma levels down to 10 ng/ml E2-Quat and 20 ng/ml E2-CDS. Sample preparation is rapid and simple. Samples are homogenized with acetonitrile, then centrifuged, and the supernatant is directly injected into the HPLC system. A water delivering pump injects the sample on a precolumn where the drug is concentrated. The mobile phase backflushes the retained compound onto the analytical column. At the same time, another sample can be injected onto a second precolumn. This alternating precolumn sample enrichment technique allows the injection of large volumes, up to 1800 microliters. Plasma and tissue samples of rats collected after i.v. administration of a single 15-mg/kg E2-CDS dose were analyzed for E2-CDS and E2-Quat by this procedure. The results show sustained brain levels of E2-Quat and prolonged half-life in brain compared to six peripheral tissues measured. These data support the concept of brain-targeted delivery using redox carrier systems of this type.

Chronic weight loss in lean and obese rats with a brain-enhanced chemical delivery system for estradiol.

Studies were undertaken to determine the effects on body weight and food intake of a chemical delivery system which preferentially delivers estradiol (E2) to the brain and there serves as a source for the sustained release of the steroid. We injected intravenously various doses of this estradiol-chemical delivery system (E2-CDS), E2-valerate (E2-VAL) or the dimethyl sulfoxide (DMSO) vehicle to young lean male rats and monitored body weight and 24 hr food intake for 39 days postinjection. E2-VAL caused a transient reduction in food intake and body weight gain. By contrast, a single injection of E2-CDS caused a chronic, dose-dependent reduction in the rate of body weight gain. In these lean rats, the duration of reduced body weight gain was not correlated with the observed transient reduction in food intake. In aged, obese male rats, E2-CDS caused a marked and chronic dose-dependent reduction in body weight. In contrast to lean rats, E2-CDS caused a long-term reduction in food intake in obese rats. To evaluate the importance of the E2-CDS-induced reduction in food intake in the observed persistent weight loss in obese rats, E2-CDS was administered to a group of obese rats and a second group which received the DMSO vehicle was pair-fed an equivalent amount of food daily. The resulting weight loss in both groups was equivalent. These results show that the enhanced delivery of E2 to the brain with the E2-CDS causes sustained reduction in the rate of body weight gain in lean rats and persistent weight loss in obese animals.

Improved delivery through biological membranes. 32. Synthesis and biological activity of brain-targeted delivery systems for various estradiol derivatives.

Brain-targeted delivery systems based on the dihydropyridine in equilibrium pyridinium salt redox interconversion were synthesized for estradiol, estradiol 3-benzoate, and ethynylestradiol. Initial biological evaluation indicated that while all four compounds synthesized exerted central estrogenic activity as measured by serum LH suppression, only the delivery systems based on the 17-substituted estradiol and ethynylestradiol demonstrated prolonged action (greater than 12 days). The 17-(1-methyl-1,4-dihydronicotinic acid ester) of ethynylestradiol behaved in a similar manner to the previously described estradiol analogue in various assays. Tissue distribution studies in rats showed that administration of the ethynylestradiol derivative resulted in high sustained levels of the corresponding pyridinium salt in the central nervous system (CNS) while blood levels of the oxidized metabolite rapidly fell. The sustained brain levels were associated with a prolonged release of ethynylestradiol. By 24 h, posttreatment, no ethynylestradiol was found by HPLC in the blood while levels of over 20 ng/g of tissue were detected in the CNS. This enhanced central delivery gave a dose- and time-dependent LH suppression, which indicated a three- to fivefold increased potency compared with the corresponding estradiol derivative.

A redox system for brain targeted estrogen delivery causes chronic body weight decrease in rats.

The effects of 2 redox based carriers for brain directed delivery of estradiol (CDS-E2) and ethinyl estradiol (CDS-EE) on body weight were examined in rats. A single dose of CDS-E2 (3 mg/kg) decreased weight gain in castrate rats for at least 24 days. The dose response of weight gain and LH suppression were compared 12 days and 12 to 25 after CDS-E2 and CDS-EE, respectively, in ovariectomized (OVX) rats. Weight decrease was detected at a lower dose and was significant for longer after drug treatment than LH decrease. Both compounds were more potent than equimolar estradiol or estradiol valerate in reducing weight gain. Intact rats also showed decreased weight gain but were less sensitive to CDS-E2 compared to OVX rats. The effects appeared to be estrogen specific as carrier-linked testosterone had no effect on weight. The mechanisms of sustained and potent drug effects on weight are being explored.