Connie M. Remsberg

Pharmacometrics of Stilbenes: Seguing Towards the Clinic

Stilbenes are small molecular weight (approximately 200-300 g/mol), naturally occurring compounds and are found in a wide range of plant sources, aromatherapy products, and dietary supplements. These molecules are synthesized via the phenylpropanoid pathway and share some structural similarities to estrogen. Upon environmental threat, the plant host activates the phenylpropanoid pathway and stilbene structures are produced and subsequently secreted. Stilbenes act as natural protective agents to defend the plant against viral and microbial attack, excessive ultraviolet exposure, and disease. One stilbene, resveratrol, has been extensively studied and has been shown to possess potent anti-cancer, antiinflammatory and anti-oxidant activities. Found primarily in the skins of grapes, resveratrol is synthesized by Vitis vinifera grapevines in response to fungal infection or other environmental stressors. Considerable research showing resveratrol to be an attractive candidate in combating a wide variety of cancers and diseases has fueled interest in determining the disease-fighting capabilities of other structurally similar stilbene compounds. The purpose of this review is to describe four such structurally similar stilbene compounds, piceatannol, pinosylvin, rhapontigenin, and pterostilbene and detail some current pharmaceutical research and highlight their potential clinical applications.

Clinical toxicities of nanocarrier systems.

Toxicity of nanocarrier systems involves physiological, physicochemical, and molecular considerations. Nanoparticle exposures through the skin, the respiratory tract, the gastrointestinal tract and the lymphatics have been described. Nanocarrier systems may induce cytotoxicity and/or genotoxicity, whereas their antigenicity is still not well understood. Nanocarrier may alter the physicochemical properties of xenobiotics resulting in pharmaceutical changes in stability, solubility, and pharmacokinetic disposition. In particular, nanocarriers may reduce toxicity of hydrophobic cancer drugs that are solubilized. Nano regulation is still undergoing major changes to encompass environmental, health, and safety issues. The rapid commercialization of nanotechnology requires thoughtful environmental, health and safety research, meaningful, and an open discussion of broader societal impacts, and urgent toxicological oversight action.

Flip-flop pharmacokinetics - delivering a reversal of disposition: challenges and opportunities during drug development

Flip-flop pharmacokinetics is a phenomenon often encountered with extravascularly administered drugs. Occurrence of flip-flop spans preclinical to human studies. The purpose of this article is to analyze both the pharmacokinetic interpretation errors and opportunities underlying the presence of flip-flop pharmacokinetics during drug development. Flip-flop occurs when the rate of absorption is slower than the rate of elimination. If it is not recognized, it can create difficulties in the acquisition and interpretation of pharmacokinetic parameters. When flip-flop is expected or discovered, a longer duration of sampling may be necessary in order to avoid overestimation of fraction of dose absorbed. Common culprits of flip-flop disposition are modified dosage formulations; however, formulation characteristics such as the drug chemical entities themselves or the incorporated excipients can also cause the phenomenon. Yet another contributing factor is the physiological makeup of the extravascular site of administration. In this article, these causes of flip-flop pharmacokinetics are discussed with incorporation of relevant examples and the implications for drug development outlined.

Effect of dehydration on raspberries: polyphenol and anthocyanin retention, antioxidant capacity, and antiadipogenic activity.

Fresh and dried raspberries prepared by freeze drying (FD), microwave-vacuum (MIVAC), hot-air drying (HAD), and a combination of hot-air drying and microwave-vacuum (HAD/MIVAC) drying methods were evaluated for polyphenol retention, total polyphenol and anthocyanin contents, total antioxidant capacity, and antiadipogenic activity (the inhibition of fat cell development). Ellagic acid and quercetin were present in the largest concentrations in fresh and dehydrated raspberries. Dehydration led to a loss of polyphenols and anthocyanins and antioxidant capacity. Polyphenols (aglycone form) were retained in the greatest amount: 20% (freeze dried) to 30% (HAD/MIVAC) (fresh = 100%). A total of 30% of polyphenols (glycoside form) were retained in raspberries dried by the HAD/MIVAC methods with 5% of retention observed for raspberries dried by FD, HAD, or MIVAC. FD and MIVAC resulted in higher retention of anthocyanins (aglycone form) than other drying methods. It was also observed that antioxidant activity was reduced by dehydration. Adipogenesis was inhibited by polyphenolic glycosides (30%) and aglycones (30% to 40%) in fresh and HAD/MIVAC raspberries. Extracts from dried raspberries by HAD/MIVAC methods were relatively more effective at inhibiting adipogenesis compared to HAD and FD dried raspberries.

Improving Nutritional Value of Dried Blueberries (Vaccinium corymbosum L.) Combining Microwave-Vacuum, Hot-Air Drying and Freeze Drying Technologies

Blueberries (Vaccinium corymbosum L.) were dried combining microwave-vacuum, hot-air drying and freeze drying technologies to retain their nutritional value. Polyphenol retention, total polyphenols, anthocyanins, and antioxidant activity were evaluated in dried blueberries. Glycoside compounds for ellagic acid, quercetin, and kaempferol exhibited a higher retention than phloridzin, and R- and S-naringin in dried blueberries following dehydration. Freeze and HA-MIVAC® dried blueberries had a higher retention of total polyphenols and anthocyanins. Freeze dried blueberries had higher antioxidant activity, followed by the combination of HA-MIVAC®, MIVAC® and HA drying methods. FD, HA-MIVAC® and MIVAC® treated blueberries had a higher retention of individual polyphenols than HA treated blueberries, indicating that the nutritional properties of berries may be retained to a greater extent when these processes are employed.

Vorinostat with sustained exposure and high solubility in poly(ethylene glycol)-b-poly(dl-lactic acid) micelle nanocarriers: Characterization and effects on pharmacokinetics in rat serum and urine

The histone deacetylase inhibitor suberoylanilide hydroxamic acid, known as vorinostat, is a promising anticancer drug with a unique mode of action; however, it is plagued by low water solubility, low permeability, and suboptimal pharmacokinetics. In this study, poly(ethylene glycol)-b-poly(DL-lactic acid) (PEG-b-PLA) micelles of vorinostat were developed. Vorinostats pharmacokinetics in rats was investigated after intravenous (i.v.) (10 mg/kg) and oral (p.o.) (50 mg/kg) micellar administrations and compared with a conventional polyethylene glycol 400 solution and methylcellulose suspension. The micelles increased the aqueous solubility of vorinostat from 0.2 to 8.15 ± 0.60 and 10.24 ± 0.92 mg/mL at drug to nanocarrier ratios of 1:10 and 1:15, respectively. Micelles had nanoscopic mean diameters of 75.67 ± 7.57 and 87.33 ± 8.62 nm for 1:10 and 1:15 micelles, respectively, with drug loading capacities of 9.93 ± 0.21% and 6.91 ± 1.19%, and encapsulation efficiencies of 42.74 ± 1.67% and 73.29 ± 4.78%, respectively. The micelles provided sustained exposure and improved pharmacokinetics characterized by a significant increase in serum half-life, area under curve, and mean residence time. The micelles reduced vorinostat clearance particularly after i.v. dosing. Thus, PEG-b-PLA micelles significantly improved the p.o. and i.v. pharmacokinetics and bioavailability of vorinostat, which warrants further investigation.

Clinical pharmacokinetic and pharmacodynamic profile of etoricoxib.

The NSAID etoricoxib is a selective inhibitor of cyclo-oxygenase 2 (COX-2), approved for treatment of patients with chronic arthropathies and musculoskeletal and dental pain. The rate of absorption of etoricoxib is moderate when given orally (the maximum plasma drug concentration occurs after ∼1 hour), and the extent of absorption is similar with oral and intravenous doses. Etoricoxib is extensively protein bound, primarily to plasma albumin, and has an apparent volume of distribution of 120 L in humans. The area under the plasma concentration-time curve (AUC) of etoricoxib increases in proportion to increasing oral doses between 5 and 120 mg. The elimination half-life of ∼20 hours in healthy subjects enables once-daily dosing. Etoricoxib is eliminated following biotransformation to carboxylic acid and glucuronide metabolites that are excreted in urine and faeces, with little of the drug (<1%) being eliminated unchanged in the urine. Etoricoxib is metabolized primarily by the cytochrome P450 (CYP) 3A4 isoenzyme. Plasma concentrations (AUC) of etoricoxib appear not to be different in patients with chronic renal insufficiency compared with individuals who have normal renal function. Compared with healthy subjects, it has been reported that the AUC is increased by approximately 40% in patients with moderate hepatic impairment. No inhibitory effects on CYP2C9, 2C19, 2D6, 2E1 or 3A4 are expected to occur with etoricoxib. Coadministration of etoricoxib with other drugs has been examined only to a limited extent, thus further assessment is necessary. Etoricoxib has been assessed for the management of several specific disease states, including pain, osteoarthritis, and rheumatoid arthritis, and has shown similar efficacy in comparison with traditional NSAIDs (including naproxen, diclofenac and ibuprofen) in these conditions. Etoricoxib has demonstrated a significant reduction in gastrointestinal toxicity compared with many traditional NSAIDs. The renal adverse effects of etoricoxib appear to be similar to those of other NSAIDs, and the cardiovascular adverse effects of this selective COX-2 inhibitor require further clinical scrutiny. Further study is necessary to delineate the relevance of the pharmacokinetic disposition in terms of the clinical benefits and risks of etoricoxib compared with other options in the clinical arsenal.

High-performance liquid chromatographic analysis: applications to nutraceutical content and urinary disposition of oxyresveratrol in rats

A high-performance liquid chromatographic (HPLC) method was developed for the analysis of the stilbene, oxyresveratrol. This method involves the use of a Luna C(18) column with ultraviolet detection at 320 nm. The mobile phase consisted of acetonitrile, water and formic acid (30 : 70 : 0.04 v/v) with a flow rate of 0.6 mL/min. The calibration curves were linear over the range of 0.5-100.0 microg/mL. The mean extraction efficiency was between 98.9 and 109%. The precision of the assay was 0.069-18.4% (RSD%), and within 20% at the limit of quantitation (0.5 microg/mL). The bias of the assay was <15% and within 15% at the limit of quantitation. This assay was successfully applied to pre-clinical pharmacokinetic samples from rat urine and to nutraceutical product analysis.

Stereospecific analysis of sakuranetin by high-performance liquid chromatography : Pharmacokinetic and botanical applications

A stereospecific method for analysis of sakuranetin was developed. Separation was accomplished using a Chiralpak AD-RH column with UV (ultraviolet) detection at 288 nm. The stereospecific linear calibration curves ranged from 0.5 to 100 microg/mL. The mean extraction efficiency was >98%. Precision of the assay was <12% (relative standard deviation (R.S.D.)%), and within 10% at the limit of quantitation (0.5 microg/mL). Bias of the assay was lower than 10%, and within 5% at the limit of quantitation. The assay was applied successfully to pharmacokinetic quantification in rats, and the stereospecific quantification in oranges, grapefruit juice, and matico (Piper aduncum L.).

High-performance liquid chromatographic analysis of lacosamide in canine serum using ultraviolet detection: Application to pre-clinical pharmacokinetics in dogs

A method for analysis of lacosamide [(R)-2-acetamido-N-benzyl-3-methoxypropionamide] is needed for both human and veterinary pharmacokinetic investigations. While lacosamide is currently used to manage partial-onset seizures in humans suffering from epilepsy, it is also presently being investigated for use in the treatment of canine epilepsy in veterinary medicine. Currently, no dosing regimen for the drug exists in dogs. A novel and simple high-performance liquid chromatography method was developed for determination of lacosamide in dog serum. Serum proteins (0.1 mL) were precipitated with -20.0°C acetonitrile after addition of the internal standard, daidzein. Separation was achieved with a Phenomenex® Luna® C₁₈ (2) (5 µm, 250 × 4.60 mm) column with ultraviolet detection at 210 nm. The calibration curves were linear ranging from 0.5 to 25 µg/mL. Precision of the assay was <13% (RSD) and was within 12% for all points in the calibration curve. The limit of quantitation for this method was 0.5 µg/mL. The assay was applied successfully to a pre-clinical study of lacosamide pharmacokinetics in dogs.