Synthesis of 18F‐labelled biotin analogues

A one‐step ¹⁸F‐labelling strategy was used to prepare three labelled analogues of the vitamin biotin, which can be useful as tracers because of biotin's high affinity for avidin. The labelled compounds were obtained in decay‐corrected yields of up to 35% and specific radioactivity of 320 GBq/µmol. When evaluated in situ, the analogues showed good affinity for avidin: 60–75% of the radiolabelled compounds were bound to avidin within 5 minutes. The binding was site‐specific, as shown by blocking experiments with native biotin.     

SD大鼠使用舒泰®50和盐酸塞拉嗪麻醉比较研究

目的：比较SD大鼠经肌肉注射和腹腔注射舒泰^® 50或盐酸塞拉嗪后的麻醉效果,并比较腹腔注射后对血液学、血清生化指标及主要脏器的病理学影响。方法：以腹腔注射给予戊巴比妥钠作为对照,设置低、中、高3个剂量的舒泰^® 50或盐酸塞拉嗪肌肉注射和腹腔注射麻醉SD大鼠,观察其麻醉诱导时间、 维持时间和苏醒时间。大鼠腹腔注射舒泰^® 50(50 mg·kg^-1)和盐酸塞拉嗪(25 mg·kg^-1)麻醉后约 20 min采血并分离主要脏器,比较血液学、血清生化指标及组织病理学检查结果。结果：舒泰^® 50的2种给予方式的麻醉效果无明显差异,且诱导时间较盐酸塞拉嗪短而维持时间更长;腹腔注射舒泰^® 50或盐酸塞拉嗪对血液学、血清生化指标及组织病理学均无明显影响。结论：与盐酸塞拉嗪相比,舒泰^® 50对SD 大鼠的麻醉效果更好,可应用于大鼠的毒理学评价研究。     

Brain Delivery of Biotin Bound to a Conjugate of Neutral Avidin and Cationized Human Albumin

The delivery of pharmaceuticals through the brain capillary endothelial wall, which makes up the blood-brain barrier (BBB) in vivo, may be facilitated by conjugation of therapeutics to brain drug delivery vectors. Since cationized albumin has been shown to undergo absorptive-mediated transcytosis through the BBB in vivo, cationized human serum albumin (cHSA) is a potential brain drug delivery vector in humans. Conjugation of biotinylated therapeutics to brain drug delivery vectors is facilitated by the preparation of vector/ avidin conjugates. Therefore, the present studies describe the preparation of a cHSA-avidin conjugate and the delivery of ³H-biotin bound to this conjugate through the BBB in vivo in anesthetized rats. Since the cationic nature of avidin (AV) accelerates the removal of avidin-based conjugates from blood in vivo, the present studies also describe the preparation and the pharmacokinetics of ³H-biotin bound to a conjugate of cHSA and neutral avidin (NLA). The bifunctional nature of the conjugate was retained: the cHSA/ NLA conjugate contained 2.8 to 6.8 biotin binding sites per conjugate, and the BBB permeability-surface area (PS) product for ³H-biotin bound to cHSA/NLA was at least 7-fold greater than the BBB PS product for ³H-biotin bound to a conjugate of NLA and native HSA (nHSA). The systemic clearance of the cHSA conjugate was reduced 10-fold by the use of NLA as opposed to AV. The increased area under the plasma concentration curve (AUC) of the cHSA-NLA conjugate correlated with an increase in brain delivery of ³H-biotin as compared to the brain delivery achieved with the cHSA/AV conjugate. In conclusion, these studies demonstrate that cHSA serves as a brain drug delivery vector and that the use of neutral forms of avidin increases the plasma AUC of the conjugate and enhances the brain delivery of biotin.     

Hepatoprotective Activity of Polyherbal Formulation (Normeta®) in Oxidative Stress Induced by Alcohol,Polyunsaturated Fatty Acids and Iron in Rats

Abstract: In recent years, oxidative stress has been implicated in the pathophysiology of a large number of diseases or disorders which are initiated and/or exacerbated by pro‐oxidants such as various drugs including alcohol and food additives. The present study was carried out to evaluate the effects of oral treatment with polyherbal formulation Normeta^® (2 ml and 4 ml/kg) on hepatic damage induced by alcohol 10–30% (blood alcohol was maintained at levels between 150 and 350 mg/dl), thermally oxidized oil (polyunsaturated fatty acids) (15% of diet) and carbonyl iron (1.5–2% of diet) for 30 days in rats. In vitro studies with 1, 1‐Diphenyl, 2‐Picrylhydrazyl (DPPH), Nitric oxide and Ferric chloride (Fe⁺³ ions) showed that Normeta^® possesses antioxidant and metal chelating activity. Alcohol, polyunsaturated fatty acids and iron feeding produced an increase in serum levels of iron, serum glutamate pyruvate transaminase and decrease in serum proteins. It was also associated with elevated lipid peroxidation (thiobarbituric acid reactive substances) and disruption of antioxidant defence mechanism in liver, decreased body weight and increased liver to body weight ratio. Oral administration of Normeta^® along with alcohol, polyunsaturated fatty acids and iron decreased the serum iron, serum glutamate pyruvate transaminase levels and increased serum protein levels. The levels of liver thiobarbituric acid reactive substances were decreased and the activities of antioxidant enzymes superoxide dismutase and catalase were increased. Improvement in body weight and liver to body weight ratio was also observed. The effects of Normeta^® on physico‐metabolic parameters were comparable with silymarin. This indicates that Normeta^® has favourable effect in bringing down the severity of hepatotoxicity.     

Biological evaluation of avidin-based tumor pretargeting with DOTA-Triazole-Biotin constructed via versatile Cu(I) catalyzed click chemistry

Background: The biotin-avidin interaction remains a gold standard for the two-step pretargeting approach to image tumor sites. We aim to develop two-step pretargeting systems utilizing ^99mTc labeled biotin functionalized macrocyclic chelating agents synthesized using the highly efficient Cu(I) catalyzed azide–alkyne cycloaddition for potential radioimaging applications.

Methods: A facile synthesis of DOTA-Triazole-Biotin, radiocomplexation with ^99mTc and the pretargeting protocol is described. The synthesis features Cu(I) catalyzed click conjugation between biotinylated azide and propynyl functionalized DO3A. ^99mTc radiolabeling was performed to detect the accumulation of avidin as the pretargeting agent. Cytotoxicity was determined using the trypan blue exclusion assay, macrocolony, and MTT assay. Cell uptake studies were performed using radiolabeled DOTA-Triazole-Biotin and compared with avidin treated cells for 2?h. Tumor imaging was performed in U-87MG cell line implanted tumor bearing nude mice and uptake of the radiotracer was estimated.

Results: All compounds have been successfully characterized by NMR and MS spectroscopy. More than 96% radiolabeling efficiency was obtained and the radioconjugate exhibited sufficient stability under physiological conditions.

Conclusion: To summarize, a new candidate for avidin based two-step pretargeting of tumors has been synthesized and evaluated for potential imaging and diagnostic applications. The chelate possesses high stability under physiological conditions, exhibits effective interaction with its avidin target, and low nonspecific retention in vivo.     

Drug targeting to the brain using avidin-biotin technology in the mouse; (blood-brain barrier, monoclonal antibody, transferrin receptor, Alzheimer's disease)

A beta1-40 peptide radiopharmaceuticals could be used to image A beta brain amyloid in transgenic mouse models of Alzheimer's disease should the A beta peptide radiopharmaceutical be made transportable through the blood-brain barrier (BBB) in vivo. The present studies used the RI7-217 rat monoclonal antibody to the mouse transferrin receptor as a BBB drug targeting vector for the delivery to brain of A beta1-40 radiolabeled with either 125-Iodine or 111-Indium. The A beta peptide radiopharmaceutical is conjugated to the RI7 MAb using avidin biotin technology, wherein the A beta1-40 peptide radiopharmaceutical is monobiotinylated (bio) and bound to a conjugate of the RI7 MAb and streptavidin (SA). The [125 I]-bio-A beta1-40 or the [111 In]-bio-A beta1-40 either free or bound to the RI7/SA conjugate was injected intravenously into anesthetized adult mice and plasma pharmacokinetics and organ uptake were measured over the next 60 minutes. The A beta1-40 peptide radiopharmaceutical radiolabeled with 111-Indium was the preferred formulation, compared to peptide labeled with 125-Iodine, because there was a greater metabolic stability and reduced artifactual organ uptake of metabolites associated with the use of the 111-Indium nuclide. However, biotinylated A beta1-40 peptide radiopharmaceuticals conjugated to the RI7/SA brain drug targeting system were metabolically unstable in mice in vivo owing to active biotinidase activity. Future work involving brain drug targeting in mice that utilizes avidin biotin technology will need to incorporate biotin analogues that are resistant to biotinidase.     

Effects of Platelet-Activating Factor Antagonists WEB 2086 and BN 50730 on Digoxin-Induced Arrhythmias *

Abstract: Effects of platelet-activating receptor antagonists WEB 2086 (1.0-30.0 mg · kg^–1 intravenously) and BN 50730 (10.0 mg · kg^–1 intravenously) alone or in combination with CGS 8515 (a specific 5-lipoxygenase inhibitor, 0.3 mg · kg^–1 intravenously) and Dazmegrel® (a thromboxane synthase inhibitor, 1.0 mg · kg^–1 · hr^–1 intravenous infusion) on digoxin-induced arrhythmias were investigated in anaesthetised guinea-pigs. ECG, mean arterial blood pressure, heart rate and arrhythmias were recorded, starting 30 min. before digoxin administration and continuing for 60 min. afterwards. WEB 2086 (10.0 mg · kg^–1 intravenously) reduced the mortality rate and arrhythmia score significantly compared to the control values. However, in combination with CGS 8515, it did not affect the mortality rate. BN 50730 (10.0 mg · kg^–1) reduced the incidence of ventricular fibrillation and also arrhythmia score. BN 50730 in combination with Dazmegrel® was reduced the arrhythmia score, incidence of ventricular fibrillation and mortality rate significantly, compared to control values. Digoxin-induced acute rise in mean arterial blood pressure was not affected by any of drug treatment except WEB 2086 (10.0 mg · kg^–1) in combination with CGS 8515. Heart rate values did not differ between groups. However, pressure-rate index was reduced by WEB 2086 alone or in combination with CGS 8615. Results showed that although two different platelet-activating factor antagonists have different effects on the incidence of ventricular fibrillation and mortality, they improved the digoxin-induced arrhythmias when they were used either separately or in combination with CGS 8515 or Dazmegrel® by implicating that platelet-activating factor has a role on digoxin-induced arrhythmias.     

Bioavailability of 99mTc‐Ha‐paclitaxel complex [99mTc‐ONCOFID‐P] in mice using four different administration routes

Paclitaxel, an anti‐tumour drug, shows good results against breast and ovarian cancer. However, its therapeutic response is associated with toxic side‐effects caused by the agent used to dissolve it. Recently paclitaxel was linked to the linear polysaccharide hyaluronic acid (HA), showing good solubility, stabilization, localization and a reduction of cytotoxic side‐effects. To study potential therapeutic applications, HA‐paclitaxel bioconjugate (ONCOFID‐P) was labelled with ^99mTc by the addition of ^99mTc‐pertechnetate, SnCl₂ and sodium gluconate. The reaction mixture was incubated for 90 min at 65°C and purified by size exclusion chromatography. The obtained ^99mTc‐ONCOFID‐P had 100% radiochemical purity and was stable in a phosphate buffer dilution 1:100 for 6 h at 37°C. ^99mTc‐ONCOFID‐P bioavailability studies were carried out in healthy mice using four different administration pathways. The analysis showed that after intravenous administration more than 80% of the injected radiopharmaceutical was found in liver and spleen. Intraperitoneal, intravesical and oral administrations showed that all the ^99mTc‐ONCOFID‐P remained at the administration site. These results demonstrate that ONCOFID‐P administered intravenously could be used for liver metastasis therapy due to its high physiological and receptor‐specific liver uptake, while intravesical, intraperitoneal and oral administration of ONCOFID‐P could be used for local treatment of superficial cancers. Copyright © 2006 John Wiley & Sons, Ltd.     

Optimization and Application of In Vitro and Ex Vivo Models for Vaginal Semisolids Safety Evaluation

Preclinical safety assessment of vaginal products includes cytotoxicity assays upon cell lines. Furthermore, tissue explants have been considered for application on ex vivo models. In this study, traditional and renewed methods were studied for toxicity assessment of vaginal semisolids upon products currently used in clinical practice as antimicrobials (Gino-Canesten^®, Sertopic^®, Dermofix^®, Gyno-Pevaryl^®, Lomexin^®, Gino Travogen^®, Dalacin V^®), containing estrogens (Ovestin^®, Blissel^®, Colpotrophine^®), and reference formulations (Replens^®, Universal Placebo). Two in vitro cytotoxicity tests were performed: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and neutral red uptake upon uterine (HEC-1A), cervical (HeLa) and vaginal (VK2 E6/E7) cells, according to ISO/EN 10993-5 (in vitro evaluation of medical devices). Similarly, a strategy to determine tissue viability on ex vivo porcine vaginal model (through MTT reduction assay and histological analysis) was developed and optimized. The vaginal cell line VK2 E6/E7 conducted to the most accurate calculation of half-maximal toxic concentration among all cells on the MTT assay. However, it was shown not be sensitive to the neutral red uptake assay. Tissues from the porcine model were collected with approx. 15% variability in thickness and variation coefficients lower than 25% when testing negative and positive controls were achieved. These models can improve cost-efficiency in early steps of product development.     

Metabolism of the plasticizer and phthalate substitute diisononyl-cyclohexane-1,2-dicarboxylate (DINCH®) in humans after single oral doses

Hexamoll^® DINCH^® (diisononyl-cyclohexane-1,2-dicarboxylate) is a new high-molecular-weight plasticizer and a phthalate substitute. In this study, the metabolism of DINCH^® was investigated by oral dosage of three male volunteers with approximately 50 mg Hexamoll^® DINCH^® (resulting in individual doses between 0.552 and 0.606 mg/kg body weight). Their urine samples were consecutively collected over 48 h. In analogy to di-iso-nonylphthalate (DINP) metabolism, we quantified the simple monoester mono-isononyl-cyclohexane-1,2-dicarboxylate (MINCH) and its secondary oxidized metabolites with HPLC–MS/MS via isotope dilution analysis. Additionally, we quantified the unspecific full breakdown product, cyclohexane-1,2-dicarboxylic acid (CHDA), via standard addition. All postulated metabolites were present in all samples analyzed. The unspecific CHDA was identified as the major urinary metabolite representing 23.7 % of the dose as the mean of the three volunteers (range 20.0–26.5 %). 14.8 % (11.3–16.7 %) of the dose was excreted as monoesters with oxidative modifications, in particular OH-MINCH 10.7 % (7.7–12.9 %), oxo-MINCH 2.0 % (1.5–2.6 %) and carboxy-MINCH 2.0 % (1.8–2.3 %). Less than 1 % was excreted as the simple monoester MINCH. In sum, 39.2 % (35.9–42.4 %) of the DINCH^® dose was excreted as these metabolites in urine within 48 h. Over 90 % of the metabolites investigated were excreted within 24 h after application. The secondary oxidized metabolites, with elimination half-times between 10 and 18 h, proved to be apt and specific biomarkers to determine DINCH^® exposure. With this study, we provide reliable urinary excretion factors to calculate DINCH^® intakes based on these metabolites in environmental and occupational studies.     

Biotin/Folate‐decorated Human Serum Albumin Nanoparticles of Docetaxel: Comparison of Chemically Conjugated Nanostructures and Physically Loaded Nanoparticles for Targeting of Breast Cancer

Docetaxel (DTX) is a widely used chemotherapeutic agent with very low water solubility. Conjugation of DTX to human serum albumin (HSA) is an effective way to increase its water solubility. Attachment of folic acid (FA) or biotin as targeting moieties to DTX‐HSA conjugates may lead to active targeting and specific uptake by cancer cells with overexpressed FA or biotin receptors. In this study, FA or biotin molecules were attached to DTX‐HSA conjugates by two different methods. In one method, FA or biotin molecules were attached to remaining NH₂ residues of HSA in DTX‐HSA conjugate by covalent bonds. In the second method, HSA‐FA or HSA‐biotin conjugates were synthesized separately and then combined by DTX‐HSA conjugate in proper ratio to prepare nanoparticles containing DTX‐HSA plus HSA‐FA or HSA‐biotin. Cell viability of different nanoparticle was evaluated on MDA‐MB‐231 (folate receptor positive), A549 (folate receptor negative), and 4T1 (biotin receptor positive) and showed superior cytotoxicity compared with free docetaxel (Taxotere^®). In vivo studies of DTX‐HSA‐FA and DTX‐HSA‐biotin conjugates in BULB/c mice, tumorized by 4T1 cell line, showed the conjugates prepared in this study were more powerful in the reduction in tumor size and increasing the survival rate when compared to free docetaxel.     

Investigating the pharmacokinetics and biological distribution of silver‐loaded polyphosphoester‐based nanoparticles using 111Ag as a radiotracer

Purified ¹¹¹Ag was used as a radiotracer to investigate silver loading and release, pharmacokinetics, and biodistribution of polyphosphoester‐based degradable shell crosslinked knedel‐like (SCK) nanoparticles as a comparison to the previously reported small molecule, N‐heterocyclic silver carbene complex analog (SCC1) for the delivery of therapeutic silver ions in mouse models. Biodistribution studies were conducted by aerosol administration of ¹¹¹Ag acetate, [¹¹¹Ag]SCC1, and [¹¹¹Ag]SCK doses directly into the lungs of C57BL/6 mice. Nebulization of the ¹¹¹Ag antimicrobials resulted in an average uptake of 1.07 ± 0.12% of the total aerosolized dose given per mouse. The average dose taken into the lungs of mice was estimated to be 2.6 ± 0.3% of the dose inhaled per mouse for [¹¹¹Ag]SCC1 and twice as much dose was observed for the [¹¹¹Ag]SCKs (5.0 ± 0.3% and 5.9 ± 0.8% for [¹¹¹Ag]aSCK and [¹¹¹Ag]zSCK, respectively) at 1 h post administration (p.a.). [¹¹¹Ag]SCKs also exhibited higher dose retention in the lungs; 62–68% for [¹¹¹Ag]SCKs and 43% for [¹¹¹Ag]SCC1 of the initial 1 h dose were observed in the lungs at 24 h p.a.. This study demonstrates the utility of ¹¹¹Ag as a useful tool for monitoring the pharmacokinetics of silver‐loaded antimicrobials in vivo.     

Spinal cord injury and neural repair: focus on neuroregenerative approaches for spinal cord injury

Background: This review discusses the urgent need for improved therapeutic approaches aimed at restoring function following traumatic spinal cord injury (SCI). The focus of this paper is neuroregenerative approaches for SCI, with a highlighted comparison of recent advances in the field and comparisons to that made by Cethrin^® (Alseres Pharmaceuticals, Inc.), the leading nerve repair product. Objective: This review first provides the reader with an understanding of SCI. The market for promising therapeutics that can either intervene in secondary etiological mechanisms or ameliorate symptoms associated with SCI are then discussed. The reader will also learn about Cethrin^® and its current status in clinical evaluation. Methods: Review of the preclinical literature and clinical SCI trials relevant to the discovery and current development of Cethrin^®. Results/conclusion: In a recently concluded Phase I/IIa clinical trial involving 37 patients with either cervical or thoracic SCIs, the evidence for Cethrin^® indicates that topical administration of either 0.3, 1, 3 or 6 mg of the recombinant rho inhibitor following surgical decompression is safe. Alseres has announced that planning is underway for a Phase IIB trial of Cethrin^® to include a placebo arm to assess better the drugs' clinical efficacy.     

90Y/177Lu‐labelled Cetuximab immunoconjugates: radiochemistry optimization to clinical dose formulation

Radiolabelled monoclonal antibodies (mAbs) are increasingly being utilized in cancer theranostics, which is a significant move toward tailored treatment for individual patients. Cetuximab is a recombinant, human–mouse chimeric IgG₁ mAb that binds to the epidermal growth factor receptor with high affinity. We have optimized a protocol for formulation of clinically relevant doses (~2.22 GBq) of ⁹⁰Y‐labelled Cetuximab and ¹⁷⁷Lu‐labelled Cetuximab by conjugation of the mAb with a suitable bifunctional chelator, N‐[(R)‐2‐amino‐3‐(paraisothiocyanato‐phenyl)propyl]‐trans‐(S,S)‐cyclohexane‐1,2‐diamine‐N,N,N′,N″,N″‐pentaacetic acid (CHX‐A″‐DTPA). The radioimmunoconjugates demonstrated reasonably high specific activity (1.26 ± 0.27 GBq/mg for ⁹⁰Y‐CHX‐A″‐DTPA‐Cetuximab and 1.14 ± 0.15 GBq/mg for ¹⁷⁷Lu‐CHX‐A″‐DTPA‐Cetuximab), high radiochemical purity (>95%) and appreciable in vitro stability under physiological conditions. Preliminary biodistribution studies with both ⁹⁰Y‐CHX‐A″‐DTPA‐Cetuximab and ¹⁷⁷Lu‐CHX‐A″‐DTPA‐Cetuximab in Swiss mice bearing fibrosarcoma tumours demonstrated significant tumour uptake at 24‐h post‐injection (p.i.) (~16%ID/g) with good tumour‐to‐background contrast. The results of the biodistribution studies were further corroborated by ex vivo Cerenkov luminescence imaging after administration of ⁹⁰Y‐CHX‐A″‐DTPA‐Cetuximab in tumour‐bearing mice. The tumour uptake at 24 h p.i. was significantly reduced with excess unlabelled Cetuximab, suggesting that the uptake was receptor mediated. The results of this study hold promise, and this strategy should be further explored for clinical translation.     

The immunomodulatory effects of a commercial antiviral homeopathic compound in C57BL/6 mice,pre and post vaccine challenge

Homeopathic remedies have been selectively employed in human medicine since Hahneman introduced the concept in 1828. While the use of homeopathy is regionally popular in both human and veterinary medicine, there is still a significant lack of scientific evidence supporting its efficacy. This is likely due to an absence of studies evaluating the mechanism of action of these compounds. Engystol® an FDA-approved antiviral agent, is a popular homeopathic commercial product. In select in vivo and in vitro observational studies, the drug showed a measureable innate immune therapeutic efficacy. The focus of the present study was to evaluate the innate and adaptive immunomodulatory effects of oral Engystol^® (1 or 10 tablets/L water consumed), prior to and post antigenic challenge in a mouse model with a well-characterized and clinically measureable immune system. We first evaluated the murine immune response when oral Engystol^® was given alone for 28 days. Mice were then challenged with an antigen-specific H5N1 HA vaccine while on Engystol^® for an additional 33 days. Serum and supernatants from cultured splenic lymphocytes were collected and screened with a 32-cytokine panel. Serum vaccine epitope-specific IgG titers plus T cell and B cell phenotypes from splenic tissue were also evaluated. Preliminary results showed that Engystol^® alone did not alter immunity; however, upon vaccine challenge, Engystol^® decreased CD4⁺/CD8⁺ ratios, altered select cytokines/chemokines, and anti-H5N1 HA IgG titers were increased in the 10 tablet/L group. Collectively, these data suggest that Engystol^® can modulate immunity upon antigenic challenge.     

Formulation of sustained release bioadhesive minitablets containing solid dispersion of levofloxacin for once daily ocular use

This study aimed to increase ocular residence time of levofloxacin by formulation into zero-order sustained release mucoadhesive minitablets for once daily administration using a hydrophobic–hydrophilic polymeric matrix. Levofloxacin was first formulated into solid dispersion with different ratios of Eudragit^® RS then the resulting solid dispersion was mixed with different concentrations of Carbopol^® and other excipients to be finally compressed into minitablets. A 2⁴ full factorial design was employed to estimate the effects and interactions of two formulation factors, and to establish their relationships with selected responses in the developed minitablets. The studied factors were: drug to Eudragit^® RS ratio, and percent of Carbopol^® in the minitablets. Sixteen ocular minitablets formulations were prepared and evaluated for the cumulative percentages drug release at 6, 12, and 24?h, as well as mucoadhesion time, mucoadhesive strength, and swelling index as response variables. After optimizing the responses, the optimized formulation was found to be stable on sterilization using gamma-irradiation and storage at 40?°C/75% RH for six months. In vivo testing of the optimized formulation showed that the minitablets extended levofloxacin release up to 24?h without causing any ocular irritation. The optimized formulation exhibited superior microbiological activity compared to the commercial product.     

A new self-emulsifying formulation of mefenamic acid with enhanced drug dissolution

To enhance the dissolution of poorly soluble mefenamic acid, self-emulsifying formulation (SEF), composing of oil, surfactant and co-surfactant, was formulated. Among the oils and surfactants studied, Imwitor^® 742, Tween^® 60, Cremophore^® EL and Transcutol^® HP were selected as they showed maximal solubility to mefenamic acid. The ternary phase diagram was constructed to find optimal concentration that provided the highest drug loading. The droplet size after dispersion and drug dissolution of selected formulations were investigated. The results showed that the formulation containing Imwitor^® 742, Tween^® 60 and Transcutol^® HP (10:30:60) can encapsulate high amount of mefenamic acid. The dissolution study demonstrated that, in the medium containing surfactant, nearly 100% of mefenamic acid were dissolved from SEF within 5 min while 80% of drugs were dissolved from the commercial product in 45 min. In phosphate buffer (without surfactant), 80% of drug were dissolved from the developed SEF within 5 min while only about 13% of drug were dissolved in 45 min, from the commercial product. The results suggested that the SEF can enhance the dissolution of poorly soluble drug and has a potential to enhance drug absorption and improve bioavailability of drug.     

Pharmacokinetics and bioavailability of oral and intramuscular artemether

Objective: The pharmacokinetics and bioavailability of artemether and dihydroartemisinin were investigated in eight Thai males following the administration of single oral and intramuscular doses of artemether (300 mg) in a randomized two-way cross-over study. Results: Both oral and intramuscular artemether were well-tolerated. In most cases, artemether and dihydroartemisinin were detected in plasma after 30 min and declined to levels below the limit of detection within 18–24 h. Compared with intramuscular administration, oral administration of artemether resulted in a relatively rapid but incomplete absorption [C_max: 474 vs 540 ng · ml⁻¹; t _max: 2.0 vs 3.9 h; AUC: 2.17 vs 5.20 μg · h · ml⁻¹]. Geographic means of lag-time and absorption half-life (t _1/2a) of oral vs intramuscular artemether were 0.28 and 1.1 h vs 0.30 and 2 h, respectively. t _1/2z was significantly shortened after the oral dose [2.8 vs 6.9 h]. Mean oral bioavailability relative to intramuscular administration was 43.2%. The ratio of the AUCs of artemether to dihydroartemisinin was significantly lower after the oral than after the intramuscular dose (geometric mean: 0.29 vs 0.60). Received: 18 October 1996 / Accepted in revised form: 28 January 1997     

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.     

New formulations of drugs in epilepsy

The advent of numerous new treatment options in epilepsy therapy over the last decade is enabling a more flexible and individualised approach to patients with seizures. For some patients, these products offer added efficacy, reduction of troublesome side effects associated with standard anticonvulsants, and control over acute seizure exacerbations. This review profiles new formulations of anti-epileptic drugs. Tegretol-XR^® (TXR) and Carbatrol^® (CBTL), two extended-release preparations of carbamazepine (CBZ), which allow twice daily administration, minimising drug toxicity and improving efficacy. Topiramate sprinkles and lamotrigine chewable dispersible tablets allow easier administration in children. The rectal gel preparation of diazepam (Diastat^®) is useful for parents of patients with acute seizure exacerbations. Intravenous valproate (Depacon^®) and fosphenytoin (Cerebyx^®) provide parenteral treatment of acute seizures, without sedation or significant peripheral venous side effects. All of these new formulations expand treatment options for patients with epilepsy, who will benefit from them.