Slow-release Depot Research Articles

Non-Prescribed Substance Use during the First Month of Treatment by People Receiving Depot Buprenorphine for Opioid Use Disorder

Background: Non-prescribed substance use (NPSU) during the treatment of opioid use disorder (OUD) is a recognized phenomenon. The use of non-prescribed substances is associated with discontinuing treatment and drop-out can occur within the early weeks of treatment, before benefit from treatment occurs. Recent developments in treatment include long-acting, slow-release depot buprenorphine injections. This article focuses on NPSU during the first month of treatment with depot buprenorphine, addressing the frequency with which it occurs, the substances used, and reasons for use. Methods: 70 semi-structured interviews (held at three time-points) were conducted with 26 patients initiating depot buprenorphine as part of a longitudinal qualitative study. Analysis prioritized content and framework analyses. Findings: 17/26 participants self-reported NPSU at various times during the first month of treatment. NPSU typically involved heroin, crack-cocaine and some use of benzodiazepines and/or cannabis. Participants’ reasons for heroin use were connected to their subjective accounts of opioid withdrawal symptoms, the management of pain, and experimentation (to test the blockade effect of buprenorphine). Frequency of heroin use was typically episodic rather than sustained. Participants associated crack-cocaine use with stimulant-craving and social connections, and considered their use of this substance to be difficult to manage. Conclusions: Patients’ initial engagement with treatment for OUD is rarely examined in qualitative research. This study highlights how NPSU amongst patients receiving new forms of such treatment continues to be a challenge. As such, shared decision-making (between providers and patients) regarding treatment goals and NPSU should be central to the delivery of depot buprenorphine treatment programmes.

Treatment of opioid dependence with depot buprenorphine (CAM2038) in custodial settings.

Background and aimsOpioid agonist treatment is effective but resource intensive to administer safely in custodial settings, leading to significant under‐treatment of opioid dependence in these settings world‐wide. This study assessed the safety of subcutaneous slow‐release depot buprenorphine in custody.DesignOpen‐label, non‐randomized trial.SettingCorrectional centres in New South Wales, Australia.ParticipantsSixty‐seven men and women, aged ≥ 18 years of various security classifications with a diagnosis of moderate to severe DSM‐5 opioid use disorder currently serving a custodial sentence of ≥ 6 months were recruited between November 2018 and July 2019. Patients not in opioid agonist treatment at recruitment commenced depot buprenorphine; patients already stable on oral methadone treatment were recruited to the comparison arm.Intervention and comparatorDepot buprenorphine (CAM2038 weekly for 4 weeks then monthly) and daily oral methadone.MeasurementsSafety was assessed by adverse event (AE) monitoring and physical examinations at every visit. Participants were administered a survey assessing self‐reported diversion and substance use at baseline and weeks 4 and 16.FindingsRetention in depot buprenorphine treatment was 92.3%. Ninety‐four per cent of patients reported at least one adverse event, typically mild and transient. No diversion was identified. The prevalence of self‐reported non‐prescribed opioid use among depot buprenorphine patients decreased significantly between baseline (97%) and week 16 (12%, odds ratio = 0.0035, 95% confidence interval = 0.0007–0.018, P < 0.0001).ConclusionsThis first study of depot buprenorphine in custodial settings showed treatment retention and outcomes comparable to those observed in community settings and for other opioid agonist treatment used in custodial settings, without increased risk of diversion.

Abstract 5243: Averting tumor growth in rodent breast cancer models with a liquid ablation approach

Abstract In low-resource settings, surgery or radiation are inaccessible to 90% of cancer patients due to inadequate infrastructure and lack of trained personnel. Resource appropriate technologies must be developed to make cancer treatments accessible. Ablative techniques, such as radiofrequency ablation are often used as a minimally invasive alternative to surgery. However, energy-based ablation techniques require expensive machinery and a steady supply of electricity and expensive consumables. To address these shortcomings, we have developed a low-cost ablation technique that stabilizes tumor growth with a simple injection of ethanol in combination with a polymer, ethylcellulose (EC). The EC injected with ethanol creates a slow-release depot of ethanol at the injection site by undergoing a solvent induced phase-transition initiated by water in tissues. EC-ethanol improves upon traditional ethanol ablation by providing increased precision while remaining low-cost and simple to administer. We evaluated the precision of EC-ethanol as well as its vascular sclerosing capabilities as a strategy to avert tumor growth in rodent models of breast cancer. EC-ethanol injected at 1 mL/hr with 6% w/w EC was used as this demonstrated to be the optimal formulation and rate for causing tumor necrosis (Morhard et al., Scientific Reports, 2017) and enhanced the anti-tumor immunostimulatory response (Nief et al., 2019, Under Review). We demonstrate the precision delivery of EC-ethanol in orthotopic 67NR mammary tumor as with small-animal MRI. Further, ethanol devascularization is monitored with photoacoustic imaging 24 hours post ablation. Local tumor control was demonstrated both in 67NR mammary tumor and in 7,12-Dimethylbenz[a]anthracene (DMBA) induced rat mammary tumor models. Repeated ablations on significantly decrease primary tumor growth compared to untreated tumors in both the mouse and rat models (P&amp;lt;0.05). In rats weekly 200 µL EC-ethanol injections began when tumors reached 2 mL in volume (n=5), and in 30 days tumors decreased 20% ± 3% untreated controls grew an average of 721%. For mice (n=5), 50 µL was given daily for 6 days on day 3 after tumor implantation to account for small body weight and rapidly growing tumors. Mice treated with EC-ethanol lived significantly longer (P&amp;lt;0.05 log-rank test) than untreated mice and mice injected with the same volume of pure ethanol. EC-ethanol is a low-cost, non-invasive tumor destruction method that shows a clear control of tumor growth when applied as a fractionated dose. We utilized a mouse and rat tumor model to ensure that the EC-ethanol's success is not dependent on the model. Ongoing studies will examine the impact of varying injected volumes at well-defined fractionation schedules on ethanol distribution, necrosis, tumor growth, and survival. Citation Format: Corrine A. Nief, Erika Chelales, Robert Morhard, Maomao Chem, Jeffrey Everitt, Jenna Mueller, Junjie Yao, Mark W. Dewhirst, Nirmala Ramanujam. Averting tumor growth in rodent breast cancer models with a liquid ablation approach [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5243.

Disease-Triggered Drug Release Effectively Prevents Acute Inflammatory Flare-Ups, Achieving Reduced Dosing.

For conditions with inflammatory flare-ups, fast drug-release from a depot is crucial to reduce cell infiltration and prevent long-term tissue destruction. While this concept has been explored for chronic diseases, preventing acute inflammatory flares has not been explored. To address this issue, a preventative inflammation-sensitive system is developed and applied to acute gout, a condition where millions of inflammatory cells are recruited rapidly, causing excruciating and debilitating pain. Rapid drug release is first demonstrated from a pH-responsive acetalated dextran particle loaded with dexamethasone (AcDex-DXM), reducing proinflammatory cytokines in vitro as efficiently as free drug. Then, using the air pouch model of gout, mice are pretreated 24 h before inducing inflammation. AcDex-DXM reduces overall cell infiltration with decreased neutrophils, increases monocytes, and diminishes cytokines and chemokines. In a more extended prophylaxis model, murine joints are pretreated eight days before initiating inflammation. After quantifying cell infiltration, only AcDex-DXM reduces the overall joint inflammation, where neither free drug nor a conventional drug-depot achieves adequate anti-inflammatory effects. Here, the superior efficacy of disease-triggered drug-delivery to prevent acute inflammation is demonstrated over free drug and slow-release depots. This approach and results promise exciting treatment opportunities for multiple inflammatory conditions suffering from acute flares.

Cold isostatic pressing of hydrating calcium sulfate as a means to produce parenteral slow-release drug formulations

In the present study, cold isostatic pressing of hydrating biocompatible inorganic materials was used to encapsulate active substance in a highly dense microstructure of bioresorable/biodegradable material. This forms the basis in the NanoZolid® technology. It was shown that such microstructures can be used to produce slow-release parenteral formulations for long-term drug release.The described novel principle to produce slow-release depot powder formulations was explored to manufacture a water-solvable calcium sulfate formulation encapsulating the anti-androgen substance 2-hydroxyflutamide (2-HOF) in a microstructurally designed calcium sulfate matrix. The microstructure of the solidified depot consisted of a composite of porous and dense material providing a combination of faster and slower release features. By mixing the drug loaded powder, consisting of densified and non-densified granular components, with an aqueous sodium carboxymethyl cellulose solution, an injectable suspension was formulated, which is injectable and which solidifies in vivo as a result of the ability of calcium sulfate to solidify by hydration.The NanoZolid powder was characterised regarding pharmaceutical process parameters and the microstructure of the solidified formulation was evaluated with scanning electron microscopy and elemental mapping. The in vitro drug release was evaluated with a specially designed dissolution method with convection only at sampling occasions.

40P - Antitumoral effect and reduced systemic toxicity in mice after intra-tumoral injection of an in vivo solidifying calcium sulfate formulation with docetaxel

Background: Docetaxel is a cytostatic agent approved for treatment of non-small cell lung cancer as well as other cancers. Its effectiveness in clinical practice is associated with a variety of acute and long term side effects. To reduce the systemic side effects, a local slow-release depot formulation based on calcium sulfate with docetaxel for intra-tumoral administration was developed. Methods: Two formulations with a twofold difference in docetaxel drug load (corresponding to 12.5 and 25.0 mg/kg body weight) were manufactured with the calcium sulfate based NanoZolid™ technology. The formulations were injected intra-tumorally as a paste which solidified within the tumor. The effects of the two local depot formulations were tested in female mice (n = 60) inoculated with subcutaneous Lewis lung carcinoma cells. The slow-release depots were compared to systemic intraperitoneal injections of docetaxel (25.0 mg/kg) and a calcium sulfate placebo formulation. Tumor volumes were measured and systemic side effects were evaluated using body weight and cell counts from whole blood as well as plasma concentrations. In addition, a histological evaluation was performed. Results: Both docetaxel formulations showed a significantly higher antitumor efficacy compared to placebo, which was comparable to that of systemic administration of docetaxel. Moreover, the intra-tumoral depot formulations with docetaxel showed reduced systemic toxicity compared to systemic treatment, including less weight loss and no decrease in blood cell counts. The extracellular deposits of calcium sulfate, observed in all groups with intra-tumoral injections, did not lead to significant inflammatory changes. Conclusions: It was shown that intra-tumoral slow-release depots of calcium sulfate with docetaxel were well tolerated and released docetaxel at amounts sufficient for satisfactory local antitumor effect and for a low level plasma detection. The use of such depots can be an alternative to intravenous injection as an efficient antitumoral treatment with reduced systemic toxicity. Legal entity responsible for the study: Uppsala University, Department of Immunology, Genetics and Pathology, Marie Jeansson Funding: This study was supported by an IGP Young Investigator grant (MJ), the Swedish Research Council (521-2012-865, MJ), Åke Wiberg Foundation (738866289, MJ), Magnus Bergvalls Foundation (24942-1-2013, 2014-00055, MJ), and Ture Stenholms Foundation for Surgical Research (MS) Disclosure: S. Grudén: Consultant for LIDDS AB. N. Axén: Consultant for LIDDS AB and have equity interests in LIDDS AB. All other authors have declared no conflicts of interest.

DESIGN AND INVITRO CHARACTERIZATION OF METFORMIN LOADED RESEALED ERYTHROCYTES

Objective: Metformin is an oral antidiabetic drug in the biguanide class. It is the first-line drug of choice for the treatment of type 2 diabetes. The objective of the present study was to retard the release of metformin using carrier erythrocyte for getting a parenteral slow release depot formulation.Methods: The study retards the release of metformin by encapsulating in carier erythrocyte. Endocytosis is the method used for the encapsulation of the drug metormin.Results: The optimized formulation shows 98.34% of drug release within 12 days. From the invitro release data zero order kinetic graph shows the best fit graph. % cell recovered was found to be 73-78% and it suggests that the loading technique was less destructive.Conclusion: The optimized formulation is a perfect carrier for the parenteral slow release depot of metformin.Keywords: Resealed erythrocytes, cross linking, cell recovery, endocytosis, slow release depot formulation

Preliminary study of highly cross-linked hyaluronic acid-based combination therapy for management of knee osteoarthritis-related pain

BackgroundHyaluronic acid has been extensively used for treatment of knee osteoarthritis due to its anti-inflammatory properties and its ability to act as a synovial lubricant. Furthermore, it has found application in combination with other drugs in the dermatological field and in pre-clinical studies in animal models of osteoarthritis. Experimental evidence suggests that a combination of this macromolecule with other drugs may act as a slow-release depot. However, to date, to the best of our knowledge, no one has tested local intra-articular delivery of highly cross-linked hyaluronic acid combined with bisphosphonate or nonsteroidal anti-inflammatory drugs for management of knee osteoarthritis pain in the clinical setting. The aim of the present randomized double-blind study was to investigate, for the first time, the effect of a highly cross-linked hyaluronic acid, Variofill®, alone or in combination with diclofenac sodium or sodium clodronate, for management of bilateral knee osteoarthritis-related pain.MethodsSixty-two patients with symptomatic bilateral medial tibiofemoral knee osteoarthritis (Kellgren–Lawrence grade II and III) and pain in both knees corresponding to a daily visual analog scale (VAS) score ≥ 30 in the month before the beginning of the study were included in this investigation. Patients were divided into three groups: group 1, treated with an injection of hyaluronic acid alone (66 mg) into each knee; group 2, treated with an injection of hyaluronic acid (49.5 mg) plus diclofenac sodium (5 mg) into each knee; group 3, treated with an injection of hyaluronic acid (49.5 mg) plus sodium clodronate (5 mg) into each knee. Patients also underwent blood tests for measurement of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) immediately before and at 6-month follow-up.ResultsHyaluronic acid alone and in combination with sodium clodronate or diclofenac sodium produced a significant improvement in mean VAS pain score at 3 and 6-month follow-up. At 6-month follow-up, therapy with hyaluronic acid plus sodium clodronate was the most beneficial in terms of percentage improvement in VAS pain score. A significant improvement in ESR and CRP was observed at 6-month follow-up in each treatment group. No significant difference was observed when the percentage change from baseline related to these parameters was compared among the groups. No dropout was observed in any group. No serious adverse events were observed.ConclusionFurther studies are necessary to determine the effect of a therapy based on hyaluronic acid combined with diclofenac sodium or sodium clodronate in larger cohorts of patients affected by knee osteoarthritis and in longer-term follow-up.

Pharmacokinetics of latanoprost in the cynomolgus monkey. 3rd communication: tissue distribution after topical administration on the eye studied by whole body autoradiography. Glaucoma Research Laboratories.

Latanoprost (13,14-dihydro-15(R)-17-phenyl-18,19,20-trinor-PGF2 alpha-isopropyl ester, CAS 130209-82-4, PhXA41, Xalatan), an antiglaucoma drug, labelled with tritium at carbon 13 and 14 (4.8 micrograms, 20.8 MBq/eye) was administered topically on the eyes of cynomolgus monkeys. After 0.5 h the concentration of radioactivity in the cornea was estimated to be about 0.6 ng eq/mg tissue. The elimination half-life of total radioactivity in the cornea was about 4 h. The corneal epithelium contained a higher concentration of radioactivity than the stroma. Cornea seemed to act as a slow release depot to the anterior part of the eye. In the iris, anterior chamber and ciliary body the maximal concentrations were 217.0 +/- 12.9 pg eq/mg, 99.8 +/- 7.4 pg eq/mg and 54.0 +/- 4.9 pg eq/mg, respectively, 1 h after administration. The elimination half-life of total radioactivity from these tissues was 3-4 h. Trace amounts (0.4-9 pg eq/mg) remained in these tissues 24 h after administration. Initially the radioactivity was present in the conjunctiva, sclera and choroid as well as in the general circulation. Radioactivity passed through the lachrymal ducts and high concentrations were observed in the oesophagus, stomach content, small intestine, bile and urine of a monkey administered latanoprost topical on the eye 0.5 and 1 h before sacrifice. In this animal concentrations of radioactivity were found in the kidney, liver, wall of the small intestine and blood. All other tissues in this animal contained lower concentrations of radioiactivity than the blood. In an animal sacrificed 2 h after administration of tritium labelled latanoprost on one eye and 6 h after administration on the other eye the highest concentrations of radioactivity were found in urine, bile and in the stomach content. Low concentration of radioactivity remained in the kidney and the liver. In a monkey administered latanoprost 12 and 24 h before death low concentrations remained in the colon, bile and urine. The anterior parts of the eyes from the monkey sacrificed 0.5 and 1 h after administration of latanoprost were cut out from the tissue sections for HPLC analysis. The predominating peak present corresponded to acid of latanoprost (PhXA85). In the stomach the radioactivity chromatographed as latanoprost and the acid of latanoprost. In the small intestine and in bile the main radioactive peak corresponded to 1,2-dinor-acid of latanoprost and in addition several more polar metabolites were present. In conclusion, latanoprost penetrated the cornea, was hydrolysed and slowly released into the anterior parts of the eye the site of action. The maximum concentration in the eye was reached after 1 h with an elimination half-life of 3-4 h. In the body the distribution was limited mainly to the gastro-intestinal tract, the kidney, the gall- and urinary bladder.

125I-Iododeoxyuridine for the Treatment of a Brain Tumor Model: Selection of Conditions for Optimal Effectiveness

The intent of this study was to optimise conditions for the use of 125 IUdR in the treatment of cancer. The radiopharmaceutical plus a biomodulator, methotrexate (MTX) was delivered by intra-tumoral injection of a thermosensitive hydrogel forming a slow release depot of 125 IUdR and MTX in the tumor. Methods: The C6 rat glioblastoma was implanted intra-cranially. A chitosan polymer was used to formulate a biodegradable and biocompatible implant for controlled intra-tumoral delivery of 125 IUdR plus MTX. Results: Intratumoral implant of hydrogel loaded with 7.0 -7.4 MBq of 125 IUdR resulted in survival of 20% of treated animals to 180 days after tumor implant. Simultaneous delivery of MTX increased the number of rats that were effectively cured, to 40%. Conclusion: Using an injectable thermolabile hydrogel as vehicle for 125 IUdR delivery a higher level of tumor control was achieved in a rat glioma model than had been previously reported.

Nanostructured lipid carriers as nitroxide depot system measured by electron paramagnetic resonance spectroscopy

Various nanometer scaled transport systems are used in pharmaceutics and cosmetics to increase penetration or storage of actives. Nanostructured lipid carriers (NLCs) are efficient drug delivery systems for dermatological applications. Electron paramagnetic resonance (EPR) spectroscopy was used for the determination of TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) distribution within the carrier and to investigate the dynamics of skin penetration. Results of ex vivo penetration of porcine skin and in vivo data – forearm of human volunteers – are compared and discussed to previously obtained results with invasomes under comparable conditions. W-band measurements show 35% of TEMPO associated with the lipid compartments of the NLC. Application of TEMPO loaded NLC to skin ex vivo increases the observation time by 12min showing a stabilisation of the nitroxide radical. Moreover, stabilisation is also seen with data generated in vivo. Thus, same as invasomes NLCs are a suitable slow release depot system.

Abstract 3982: Deregulation of tumor-suppressive miR-16 through progestin-mediated oncogenic signaling contributes to breast cancer development

Abstract Breast cancer is the commonest type of cancer among women in the US and the second leading cancer-death cause. Understanding its biology will help to design new clinical approaches to achieve a better outcome of the disease. microRNA (miRNA) are short ribonucleic acids with important regulatory functions and with an increasingly acknowledged role in cancer. The present study was designed to characterize progestin-induced miRNA regulation in breast cancer. Primary cultures of the murine breast cancer C4HD were treated or not with 10nM of the synthetic progestin medroxiprogesterone acetate (MPA) for 24 h and total RNA extracted for miRNA profiling using Applied Biosystems low density qPCR arrays. Analysis of data rendered a total of 16 miRNA significantly regulated (P&amp;lt;0.05): miR-378*, miR-376a, miR-224, miR-190b, miR-16, miR-410 and miR-197 were downregulated and miR-191*, miR-17*, miR-470*, miR-451, miR-702, miR-434-3p, miR-493, miR-23a* and miR-485* were upregulated under treatment with MPA. Interestingly, miR-16 has already been shown to be a tumor suppressor in leukemia and so we focused our further study on it. We validated the downregulation of miR-16 by qPCR (0.4 fold against control) and observed that small interference RNA (siRNA) to progesterone receptor (PR) or to signal transducer and activator of signal 3 (STAT3) overcame miR-16 downregulation by MPA. The oncogene c-Myc was a reported negative regulator of miR-16, and we observed that siRNA to PR or STAT3 inhibited MPA-induced c-Myc upregulation. A query for miR-16 targets on miRecords search engine showed that the cell cycle promoter gene Cyclin E has conserved putative target sites on 3′UTR mRNA. Consistently, siRNA to PR and to STAT3 inhibited MPA-induced CCNE mRNA and Cyclin E protein increase as assessed by qPCR and Western blot. In addition, transfection with pre-miR-16 abrogated MPA capacity of inducing Cyclin E upregulation. Most importantly, pre-miR-16 inhibited MPA-induced proliferation, as observed in [3H]-Thymidine incorporation assays and Trypan-blue cell counts. C4HD is a progestin-dependent tumor since it is unable to grow in vivo under exogenous progestin's absence. Therefore, 1 × 106 C4HD cells transfected with a pre-miR-control (CTRL) or with pre-miR-16 were injected s.c. in 8-week female Balb/c mice which had been previously injected with a MPA slow-release depot. Tumors became palpable at day 15 but the ones from pre-miR-16 group grew at a lower rate than the ones from pre-miR-CTRL group, and the mean tumor volume at day 40 was significantly smaller (312.4 ± 42.3 mm3 for CTRL group against 22.2 ± 34.9 mm3 for pre-miR-16 group). To sum up, these results suggest that progestin induce breast cancer growth through a pathway involving PR/STAT3/c-Myc and miR-16 which acts on mRNA targets such as Cyclin E to control cell cycle progression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3982. doi:10.1158/1538-7445.AM2011-3982

Recombinant Gelatin Microspheres: Novel Formulations for Tissue Repair?

Microspheres (MSs) can function as multifunctional scaffolds in different approaches of tissue repair (TR), as a filler, a slow-release depot for growth factors, or a delivery vehicle for cells. Natural cell adhesion-supporting extracellular matrix components like gelatin are good materials for these purposes. Recombinant production of gelatin allows for on-demand design of gelatins, which is why we aim at developing recombinant gelatin (RG) MSs for TR. Two types of MSs (50 < Ø < 100 microm) were prepared by crosslinking two RGs, Syn-RG, and the arginine-glycine-aspartate-containing Hu-RG. The MSs were characterized, and their tissue reaction and degradation in rats was examined. Histological analysis of the explants after 14 and 28 days in vivo also showed that Syn-RG was degraded slower than Hu-RG, which correlated with the in vitro degradation assay. Hu-RG explants displayed more cellular ingrowth (60% vs. 15% for Syn-RG at day 14), which was associated with extracellular matrix deposition and vascularization. The infiltrating cells consisted of mainly macrophages, part of which fused to giant cells locally, and fibroblasts. No differences were found in matrix metalloproteinase mRNA levels, whereas gelatinase activity was clearly higher in Hu-RG explants. In conclusion, the in vitro and in vivo results of these novel formulations pave the way for cell- and/or factor-driven TR by these RG MSs.

Liposomal dexamethasone–diclofenac combinations for local osteoarthritis treatment

Conventional chronic and acute treatments for osteoarthritis (OA) are by oral NSAIDs (such as diclofenac) and intra-articular injected glucocorticosteroids (such as dexamethasone). In free form, diclofenac and dexamethasone generate severe adverse effects with risks of toxicity. To reduce these drawbacks, we investigated local injections of liposomal formulations for diclofenac and dexamethasone (each alone, and their combination). Bioadhesive liposomes carrying hyaluronan (HA-BAL) or collagen (COL-BAL) as their surface-anchored ligand were used for the task. Each drug alone or their combination showed high efficiency encapsulations (≥80%) and performance as slow-release depots (half-lives in the range of 1–3 days under the fastest conditions). Employing RIA and immunoblot assay techniques, it was verified that the encapsulated drugs retained their biological activities: inhibitions of Cyclooxygenases enzyme-activity (diclofenac) and of Cyclooxygenases protein-expression (dexamethasone). Using live-animal MRI, a single intra-articular injection of each liposome-drug(s) formulation sufficed to reduce knee joint inflammation in OA rats over a time span of 17 days, HA-BAL better than COL-BAL. The most effective treatment was by the combination of both drugs in HA-BAL, a single dose reducing the inflammation volume down to 12.9% from initial over that time span. We find all three HA-BAL formulations worthy of further studies.

Latanoprost ophthalmic solution in the treatment of open angle glaucoma or raised intraocular pressure: a review

Latanoprost is a prostaglandin F2-alpha isopropyl ester prodrug which is rapidly hydrolyzed by esterases in the cornea to the biologically active latanoprost acid. When latanoprost is topically administered into the eye, the cornea seems to act like as a slow-release depot to the anterior segment. One hour after administration maximum concentration is found in the iris, followed by the anterior chamber and the ciliary body. Despite extensive research, controversy remains about the real mechanism of action of this drug. Immunohistochemical data have shown that the intraocular pressure (IOP) reduction with topical prostaglandin F2-alpha is associated with a reduction of collagens within the uveoscleral outflow pathway. Evidence from several experimental and clinical studies suggests that latanoprost is a valuable addition first-line treatment alternatives for glaucoma, ocular hypertension and even angle-closure glaucoma. Strong points are its efficacy, which is demonstrated to be higher than that of brimonidine, dorzolamide and timolol with fewer systemic adverse effects; a convenient administration schedule; and the IOP-controlling pattern, which is relatively flat compared with timolol and dorzolamide, and enables better control in glaucoma progression, since large fluctuations may be associated with the risk of developing glaucoma in untreated ocular hypertensive subjects.

Toxicokinetics and Tissue Distribution of Deltamethrin in Adult Sprague–Dawley Rats

The objectives of this study were twofold: (1) to characterize the toxicokinetics and dose-dependent systemic/tissue distribution of deltamethrin (DLM) over a range of doses in adult Sprague-Dawley (S-D) rats; (2) to provide comprehensive time course blood and tissue data for development of a physiologically based toxicokinetic (PBTK) model for DLM. DLM is one of the more neurotoxic members of a relatively new and commonly used class of insecticides, the pyrethroids. Despite widespread exposure of the general population to pyrethroids, there is little basic toxicokinetic (TK) data to use in health risk assessments or in development of PBTK models. Male S-D rats were dosed orally with 0.4, 2, or 10 mg DLM/kg dissolved in glycerol formal (GF). Another group received 2 mg/kg iv. Serial blood and tissue samples were taken at sacrifice and analyzed by high-performance liquid chromatography for their DLM content, in order to obtain comprehensive time course data sets for estimation of classical TK, as well as PBTK parameters (e.g., tissues:blood partition coefficients). Gastrointestinal (GI) absorption of DLM was rapid but incomplete. Bioavailability was just 18%. Some 83% of DLM in blood was present in the plasma. Just 0.1-0.3% of systemically absorbed doses reached the brain, the target organ of the bioactive parent compound. Fat, skin and surprisingly, skeletal muscle, accumulated large amounts of the highly lipophilic chemical and served as slow-release depots. Tissue distribution was dose dependent, though generally not proportional to dose. Clearance was dose independent in this dosage range. The time-profiles were used by A. Mirfazaelian et al. (2006, Toxicol. Sci. 93, 432-442) to construct and adjust a PBTK model. Much remains to be learned about physiological/biochemical processes and barriers that govern the GI absorption, transport, brain deposition, and elimination of DLM and other pyrethroids in laboratory animals and humans.

Making sense of antisense

The specific and rational targeting of key genes, identified to be vital to driving cancer growth, has recently led to the successful development of several small molecule and antibody therapeutics. However, despite considerable efforts, antisense oligonucleotides (ASO) have yet to prove their worth as targeted therapies. However, many important genes cannot be readily targeted by antibodies or small molecules, and could be blocked by ASOs. Moreover, the latest generation of ASOs is safe, well tolerated and able to modulate target protein expression both in surrogate and tumour tissue in the clinic. This review will describe the experience acquired with these agents to date and will raise critical issues relevant to the further optimal development of these agents. Future clinical studies need to evaluate combinations of several different ASO targeting multiple key targets, including strategies that reverse functional redundancy of the key target ( e.g., targeting several Bcl family members including Bcl-2 and Bcl-x). Approaches to maximise the duration of target blockade yet avert the need for prolonged intravenous infusions, with the consequent risk of line infection and thrombosis, are also needed. These may include slow-release depot subcutaneous formulations. Short interfering (Si) RNA therapeutics, which are now being evaluated in early clinical trials, are also envisioned to impact the future utility of this class of therapeutics. The high manufacture cost of these agents, when compared with small chemical molecules, could however, limit their success unless cost-effective manufacturing processes are developed.

Depot local anesthetic in polymethylmethacrylate bone cement: a preliminary study.

Acrylic bone cement has been used successfully as a slow-release depot for antibiotics after orthopaedic surgery. The feasibility of administering local anesthetics in this way was examined in this preliminary in vitro study. Discs weighing approximately 4 g were prepared from five brands of acrylic cement (40 g) containing as much as 2 g of anesthetic base. Elution of the anesthetics into saline was measured during 72 hours. Prilocaine eluted the fastest and bupivacaine the slowest, with lidocaine between them. The elution rates were greatest in the first hour, declining thereafter. Rates also depended on the brand of cement with the quickest elution from CMW3 and the slowest from Surgical Simplex P. Using cement as a depot, therapeutic levels of a drug should be achievable in vivo at a negligible risk of toxicity. Before in vivo trials it is necessary to optimize elution of drugs in relation to the cement (brand, microstructure, method of preparation) and the concentration of a drug in the cement above which the cements' mechanical and adhesive properties are compromised.

Effects of diet and vitamin E supplementation on the distribution of vitamin E in plasma, muscle, liver and adipose tissue in lambs fed on concentrates alone or with grass silage

Vitamin E protects the animal from oxidative stressin vivoand when it is administered at supranutritional levels it enhances the oxidative stability of meat. Studies have shown that poor absorption of vitamin E often occurs when concentrates are fed to lambs. Distribution of vitamin E in plasma, skeletal muscle, liver (short-term and fast release depot) and adipose tissue (long-term and slow release depot) provides useful information about the overall vitamin E status of the animals. This work studied the distribution of vitamin E in the tissues after supplementation in relation to diet and to the dietary level.

The therapeutic potential of somatostatin receptor ligands in the treatment of obesity and diabetes

Since the development of synthetic somatostatin analogues, several therapeutic applications for somatostatin receptor agonist molecules have been defined. Established applications for somatostatin analogue treatment include pituitary tumours (growth hormone and thyrotropin-secreting adenomas), neuroendocrine tumours of the pancreas and gastrointestinal tract (so-called carcinoid tumours, vasoactive intestinal tumours) and gastroenterological conditions (pancreatitis, gastrointestinal bleedings, refractory diarrhoeas, pancreatic and intestinal fistulas, diarrhoea in AIDS). Further areas for development of somatostatin analogue therapy include obesity, polycystic ovary syndrome and diabetes mellitus, dysmetabolic conditions that are often interrelated. The challenge for the future will be to transform results from clinical trials conducted in heterogeneous clinical situations into novel options of somatostatin analogue use. Since obesity and diabetes mellitus both are disorders of marked heterogeneity, the subgroup of patients that will benefit most from somatostatin analogue treatment has yet to be defined. In addition, the development of more universal ligands covering all of the known somatostatin receptor molecules as well as receptor subtype specific agents is currently underway. The establishment of slow-release depot formulations of octreotide and lanreotide has already provided a more acceptable and consistent delivery mechanism. Use of biodegradable polymer microsphere formulations provides the basis for the development of novel applications, which include hyperinsulinaemia, obesity and polycystic ovary syndrome as components of the dysmetabolic syndrome. The most developed thus far is the use of octreotide in hyperinsulinaemic forms of obesity and in distinct stages of diabetic retinopathy.