Preventing Post Dural Puncture Headache after Intrathecal Drug Delivery System Implantation Through Preventive Fibrin Glue Application: A Retrospective Study.

BACKGROUND: Cerebrospinal fluid (CSF) leakage resulting in post dural puncture headache (PDPH) is a frequent adverse effect observed after intrathecal drug delivery system (IDDS) implantation. CSF leakage symptoms negatively affect patient quality of life and can result in additional complications. Fibrin glue was used to treat CSF leakage syndrome. We developed a procedure to reduce the incidence of PDPH by preventing CSF leakage with the use of fibrin glue during surgery. OBJECTIVES: The main outcome criterion for this study was the incidence of PDPH syndrome after IDDS implantation with or without preventive fibrin glue application during the procedure. STUDY DESIGN: We designed a monocentric retrospective cohort study to compare the incidence of PDPH due to CSF leakage syndrome after lumbar puncture in patients with an implanted intrathecal pump, with or without preventive fibrin glue application during the procedure. SETTING: The study was held in the Anesthesiology and Pain department of the  Integrative Cancer Institute (ICO), Angers - France. METHODS: The study compared 2 patient cohorts over 2 successive periods. Fibrin glue was injected into the introducer needle puncture pathway after placement of the catheter immediately following needle removal. RESULTS: The no-glue group included 107 patients, whereas the glue group included 92 patients.Two application failures were observed (2.04%). Fibrin glue application results in a significant decrease in PDPH incidence, from 32.7% in the no-glue group to 10.92 % (P < 0.001) in the glue group. In regard to severity, in the no-glue group, 37.1% of PDPH syndromes were mild, 34.3% were moderate, and 28.6% were severe. In the fibrin glue group, 80% of PDPH syndromes were mild, and 20% were moderate. No severe PDPHs were reported after fibrin glue application. Duration of symptoms was also statistically shorter in the fibrin glue group (maximum of 3 days vs. 15 days in the no-glue group). In a univariate analysis, preventive fibrin glue application and age are significant to prevent PDPH. In multivariate analysis, only fibrin glue application was statistically significant (odds ratio, 0.26; P = 0.0008). No adverse effects linked to fibrin glue were observed. LIMITATIONS: The main limitation of this study is its retrospective nature. In addition, this study is from a single center with a potential selection bias and a center effect. CONCLUSIONS: The novel use of fibrin glue is promising in terms of its effect on PDPH and its safety profile. Its moderate cost and reproducibility make it an affordable and efficient technique.

Large-Volume Hyperthermia for Safe and Cost-Effective Targeted Drug Delivery Using a Clinical Ultrasound-Guided Focused Ultrasound Device.

Lyso-thermosensitive liposomes (LTSLs) are specifically designed to release chemotherapy agents under conditions of mild hyperthermia. Preclinical studies have indicated that magnetic resonance (MR)-guided focused ultrasound (FUS) systems can generate well-controlled volumetric hyperthermia using real-time thermometry. However, high-throughput clinical translation of these approaches for drug delivery is challenging, not least because of the significant cost overhead of MR guidance and the much larger volumes that need to be heated clinically. Using an ultrasound-guided extracorporeal clinical FUS device (Chongqing HAIFU, JC200) with thermistors in a non-perfused ex vivo bovine liver tissue model with ribs, we present an optimised strategy for rapidly inducing (5-15 min) and sustaining (>30 min) mild hyperthermia (ΔT <+4°C) in large tissue volumes (≤92 cm3). We describe successful clinical translation in a first-in-human clinical trial of targeted drug delivery of LTSLs (TARDOX: a phase I study to investigate drug release from thermosensitive liposomes in liver tumours), in which targeted tumour hyperthermia resulted in localised chemo-ablation. The heating strategy is potentially applicable to other indications and ultrasound-guided FUS devices.

Challenges in Biomaterial-Based Drug Delivery Approach for the Treatment of Neurodegenerative Diseases: Opportunities for Extracellular Vesicles.

Biomaterials have been the subject of numerous studies to pursue potential therapeutic interventions for a wide variety of disorders and diseases. The physical and chemical properties of various materials have been explored to develop natural, synthetic, or semi-synthetic materials with distinct advantages for use as drug delivery systems for the central nervous system (CNS) and non-CNS diseases. In this review, an overview of popular biomaterials as drug delivery systems for neurogenerative diseases is provided, balancing the potential and challenges associated with the CNS drug delivery. As an effective drug delivery system, desired properties of biomaterials are discussed, addressing the persistent challenges such as targeted drug delivery, stimuli responsiveness, and controlled drug release in vivo. Finally, we discuss the prospects and limitations of incorporating extracellular vesicles (EVs) as a drug delivery system and their use for biocompatible, stable, and targeted delivery with limited immunogenicity, as well as their ability to be delivered via a non-invasive approach for the treatment of neurodegenerative diseases.

Intravitreous delivery of melatonin affects the retinal neuron survival and visual signal transmission: in vivo and ex vivo study.

Intravitreal delivery can maximize the intensity of therapeutic agents and extend their residence time within ocular tissue. Melatonin is a lipophilic molecule that crosses freely biological barriers and cell membranes. This study intends to investigate the effects of intravitreally delivered melatonin on mouse retina. The visual function of administered mice is assessed by electrophysiological and behavior examinations three weeks after intravitreal delivery. Moreover, multi-electrode array (MEA) was used to assess the electrical activities of retinal ganglion cells (RGCs). We found that intravitreal delivery of high dosage melatonin (400-500 µg/kg) destroyed the retinal architecture and impaired the visual function of mice. Conversely, the melatonin administration at low dose (100-300 µg/kg) did not have any significant effects on the photoreceptor survival or visual function. As shown in the MEA recording, the photoreceptors activity of the central region was more severely disturbed by the high dose melatonin. A pronounced augment of the spontaneous firing frequency was recorded in these mice received high dosage melatonin, indicating that intravitreal delivery of high dosage melatonin would affect the electrical activity of RGCs. Immunostaining assay showed that the vitality of cone photoreceptor was impaired by high dose melatonin. These findings suggest that intravitreal melatonin is not always beneficial for ocular tissues, especially when it is administered at high dosage. These data add new perspectives to current knowledge about melatonin delivery at the ocular level. Further therapeutic strategies should take into consideration of these risks that caused by delivery approach.

Development and evaluation of novel topical gel of neem extract for the treatment of bacterial infections.

BACKGROUND: The microspheres are one of the major formulations in the novel drug delivery systems. These days' scientists are predominantly focusing on natural plant products because of the poisonous effect of synthetic drug molecules. From olden days itself, neem has some excellent antibacterial activities. AIMS: The main objective of the research work was to formulate microspheres containing methanolic extract of neem and incorporate it into a gel. The optimized gel was evaluated for its antibacterial activity. METHODS: The methanolic extract of the neem leaves was prepared by maceration process. The microspheres prepared were evaluated for shape, size of particles, and in vitro drug release. Out of all the formulations, the F5 formulation was found to be optimized; therefore, it was incorporated into the gel and evaluated for the in vitro permeation studies, in vivo skin irritation test, in vitro antibacterial activity studies, and accelerated stability studies. RESULTS: The prepared gel formulation showed an acceptable zone of inhibition when compared to the pure drug in in vitro antibacterial activity studies. The skin irritation study on albino Wistar rats showed that the prepared gel formulation was compatible. Based on the stability studies, the gel formulation was found to be stable during the study period. CONCLUSION: The optimized formulation of containing neem extract showed better antibacterial activity, and it could be promising one in the topical delivery of neem for treatment of bacterial infections.

Comprehensive Evaluation of the Effectiveness and Safety of Placenta-Targeted Drug Delivery Using Three Complementary Methods.

No effective treatments currently exist for placenta-associated pregnancy complications, and developing strategies for the targeted delivery of drugs to the placenta while minimizing fetal and maternal side effects remains challenging. Targeted nanoparticle carriers provide new opportunities to treat placental disorders. We recently demonstrated that a synthetic placental chondroitin sulfate A binding peptide (plCSA-BP) could be used to guide nanoparticles to deliver drugs to the placenta. In this protocol, we describe in detail a system for assessing the efficiency of drug delivery to the placenta by plCSA-BP that employs three separate methods used in combination: in vivo imaging, high-frequency ultrasound (HFUS), and high-performance liquid chromatography (HPLC). Using in vivo imaging, plCSA-BP-guided nanoparticles were visualized in the placentas of live animals, while HFUS and HPLC demonstrated that plCSA-BP-conjugated nanoparticles efficiently and specifically delivered methotrexate to the placenta. Thus, a combination of these methods can be used as an effective tool for the targeted delivery of drugs to the placenta and development of new treatment strategies for several pregnancy complications.

Preparation of an efficient and safe polymeric-magnetic nanoparticle delivery system for sorafenib in hepatocellular carcinoma.

AIMS: Superparamagnetic iron oxide nanoparticles (SPIONs), as drug delivery vehicles, offer to eliminate the concerns associated with hydrophobic anti-cancer agents. The current study was intended to fabricate a SPION based delivery system for sorafenib that can simultaneously enable targeted delivery of sorafenib and expand its therapeutic index against hepatocellular carcinoma (HCC). MAIN METHODS: Co-precipitation and physical entrapment methods were employed for the synthesis of sorafenib loaded PVA coated SPIONs. Physicochemical characterizations were done using TEM, XRD, FTIR, Raman spectra and VSM measurements. The superior activity of nanoconjugate was demonstrated by AO/EB staining, FACS, immunofluorescence and Western blot. The safety of the sorafenib conjugated nanoparticles were verified in Wistar rats. KEY FINDINGS: The synthesized nanoparticles were in the size range of 5-15 nm. The adsorption of PVA to the SPIONs and the conjugation of sorafenib to the nanocarrier were confirmed by XRD, FTIR and Raman spectra analyses. VSM study ascertained the superparamagnetic nature of the nanoconjugate. Cellular uptake studies suggested its efficient entrapment in HepG2 cells. MTT assay showed that the cytotoxicity of sorafenib loaded PVA/SPIONs was comparable or higher than free sorafenib. The activation of apoptosis and autophagy pathways in HepG2 by the nanoconjugate was evidenced. Acute toxicity testing in Wistar rats supported the safe administration of the nanoconjugate and established its localization in animal tissues by Perl's Prussian Blue reaction. SIGNIFICANCE: The novel combination of sorafenib with PVA/SPIONs showed better anticancer efficiency than free sorafenib demonstrative of its potential in cancer chemotherapy.

Preclinical Pharmacology and Pharmacokinetics of Inhaled Hexadecyl-Treprostinil (C16TR), a Pulmonary Vasodilator Prodrug.

This article describes the preclinical pharmacology and pharmacokinetics (PK) of hexadecyl-treprostinil (C16TR), a prodrug of treprostinil (TRE), formulated in a lipid nanoparticle (LNP) for inhalation as a pulmonary vasodilator. C16TR showed no activity (>10 µM) in receptor binding and enzyme inhibition assays, including binding to prostaglandin E2 receptor 2, prostaglandin D2 receptor 1, prostaglandin I2 receptor, and prostaglandin E2 receptor 4; TRE potently bound to each of these prostanoid receptors. C16TR had no effect (up to 200 nM) on platelet aggregation induced by ADP in rat blood. In hypoxia-challenged rats, inhaled C16TR-LNP produced dose-dependent (0.06-6 µg/kg), sustained pulmonary vasodilation over 3 hours; inhaled TRE (6 µg/kg) was active at earlier times but lost its effect by 3 hours. Single- and multiple-dose PK studies of inhaled C16TR-LNP in rats showed proportionate dose-dependent increases in TRE Cmax and area under the curve (AUC) for both plasma and lung; similar results were observed for dog plasma levels in single-dose PK studies. In both species, inhaled C16TR-LNP yielded prolonged plasma TRE levels and a lower plasma TRE Cmax compared with inhaled TRE. Inhaled C16TR-LNP was well tolerated in rats and dogs; TRE-related side effects included cough, respiratory tract irritation, and emesis and were seen only after high inhaled doses of C16TR-LNP in dogs. In guinea pigs, inhaled TRE (30 µg/ml) consistently produced cough, but C16TR-LNP (30 µg/ml) elicited no effect. These results demonstrate that C16TR-LNP provides long-acting pulmonary vasodilation, is well tolerated in animal studies, and may necessitate less frequent dosing than inhaled TRE with possibly fewer side effects.

Zebrafish models for functional and toxicological screening of nanoscale drug delivery systems: promoting preclinical applications.

Preclinical screening with animal models is an important initial step in clinical translation of new drug delivery systems. However, establishing efficacy, biodistribution, and biotoxicity of complex, multicomponent systems in small animal models can be expensive and time-consuming. Zebrafish models represent an alternative for preclinical studies for nanoscale drug delivery systems. These models allow easy optical imaging, large sample size, and organ-specific studies, and hence an increasing number of preclinical studies are employing zebrafish models. In this review, we introduce various models and discuss recent studies of nanoscale drug delivery systems in zebrafish models. Also in the end, we proposed a guideline for the preclinical trials to accelerate the progress in this field.

Stability of (-)-epigallocatechin gallate and its activity in liquid formulations and delivery systems.

(-)-Epigallocatechin gallate (EGCG) has become a popular disease-preventive supplement worldwide because it may aid in slowing down the onset of age-related diseases such as cancer, diabetes and tissue degeneration. As largely demonstrated in cell culture studies, EGCG possesses antioxidant properties and exhibits favorable effects on gene expression, signal transduction and other cell functions. However, only limited effects have been observed in experimental animals and human epidemiological studies. The inconsistency between the biological activity of EGCG in cell cultures and in vivo can be attributed to its low stability, which not only decreases its bioavailability but also leads to the formation of degradation products and prooxidant molecules with possible side-effects. Understanding EGCG degradation kinetics in solution and in vivo is crucial for its successful clinical application. Ambient conditions (pH, temperature, oxygen) can either enhance or decrease the stability of EGCG, thus influencing its biological activity. Usage of stabilizers and/or encapsulation of EGCG into particulate systems such as nanoparticles or microparticles can significantly increase its stability. In this review, the effects of ambient conditions, stabilizers and encapsulation systems on EGCG stability, activity and degradation rate are illustrated.

Transdermal Delivery of Iron Using Soluble Microneedles: Dermal Kinetics and Safety.

Currently, the iron compounds are administered via oral and parenteral routes in patients of all ages, to treat iron deficiency. Despite continued efforts to supplement iron via these conventional routes, iron deficiency still remains the most prevalent nutritional disorder all over the world. Transdermal replenishment of iron is a novel, potential approach of iron replenishment. Ferric pyrophosphate (FPP) was found to be a suitable source of iron for transdermal replenishment. The safety of FPP was assessed in this project by challenging the dermal fibroblast cells with high concentration of FPP. The cell viability assay and reactive oxygen species assay were performed. The soluble microneedle array was developed, incorporated with FPP and the kinetics of free iron in the skin; extracellular fluid following dermal administration of microneedle array was investigated in hairless rats. From the cell based assays, FPP was selected as one of the potential iron sources for transdermal delivery. The microneedles were found to dissolve in the skin fluid within 3 hours of administration. The FPP concentration in the dermal extracellular fluid declined after complete dissolution of the microneedle array. Overall, the studies demonstrated the safety of FPP for dermal delivery and the feasibility of soluble microneedle approach for transdermal iron replenishment therapy.

Polymeric Nanostructured Systems for Liquid Formulation of Praziquan-tel: Development and in vitro Assessment.

Praziquantel (PZQ) is widely used in the treatment of several parasitic infections in both humans and animals, and is the first choice in the treatment of Schistosomiasis in humans. However, PZQ is a hydrophobic drug, and its low aqueous solubility has been a significant barrier to the development of oral liquid formulations that may provide improved bioavailability, pharmacokinetic profile, and compliance. The aim of this study was thus (i) to develop an oil-in-water (O/W) nanoemulsion(NE)-based platform for the delivery of PZQ in liquid form; (ii) to study the transport of PZQ formulated in NEs across an in vitro model of the intestinal epithelium; and (iii) to determine the toxicity profile of the NEs and their individual components on the model epithelium. We also sought to compare the toxicity and transport profiles of the proposed formulations, with those of PZQ in a solid nanostructured particle system - PZQ encapsulated within poly(lactic acid-co-glycolic acid) (PLGA) nanoparticles (NPs). Two essential oils were selected as the oil phase in the NEs, namely clove and orange. The NEs were prepared with selected non-ionic surfactants and had high solubilization capacity towards PZQ, and average diameters well below 100nm. The NEs also showed long term physical stability at both simulated physiological and gastric conditions. NEs with clove oil (NEC-PZQ) were observed to have a lower cytotoxic profile when compared to the orange oil NEs (NEO-PZQ). The results also showed that the transport of PZQ formulated within such nanostructured systems was much greater and larger rates across confluent and polarized Caco-2 monolayers when compared to free PZQ. Interestingly, little difference in PZQ transport between the NEs and NPs was observed. These results point to NEs as potentially viable strategies for the liquid formulation of PZQ in particular, and more broadly to the formulation of other hydrophobic therapeutics that may be employed in the fight against important neglected diseases such as Schistosomiasis, which alone affects more than 240 million people worldwide.

Enhanced delivery of daidzein into fibroblasts and neuronal cells with cationic derivatives of gamma-cyclodextrin for the control of cellular glycosaminoglycans.

Two cationic derivatives of γ-cyclodextrin (GCD) were synthesized by functionalization with glycidyltrimethylammonium chloride (GTMAC) and ethylenediamine (EDA). Both these derivatives (GCD-GTMAC and GCD-EDA) have been shown to interact strongly with anionic biopolymers, unfractionated heparin (UFH) and mucin, the latter showing their mucoadhesive properties. They form inclusion complexes with daidzein (DAI), an isoflavone displaying a multitude of physiological effects, much more efficiently than the unmodified GCD. It was also shown that the complexes of these GCD derivatives with DAI and Nile Red penetrate human fibroblasts and murine hippocampal neuronal cells indicating that cationic GCD derivatives can be considered as potential delivery systems for isoflavones and other poorly water soluble compounds. Moreover, it was found that DAI delivered in cationic GCD complexes decreased the level of the cellular glycosaminoglycans (GAGs) in normal fibroblasts suggesting their possible application in the control of GAGs in mucopolysaccharidoses, lysosomal storage diseases caused by pathological accumulation of GAGs in the cells.

Preclinical safety and efficacy models for pulmonary drug delivery of antimicrobials with focus on in vitro models.

New pharmaceutical formulations must be proven as safe and effective before entering clinical trials. Also in the context of pulmonary drug delivery, preclinical models allow testing of novel antimicrobials, reducing risks and costs during their development. Such models allow reducing the complexity of the human lung, but still need to reflect relevant (patho-) physiological features. This review focuses on preclinical pulmonary models, mainly in vitro models, to assess drug safety and efficacy of antimicrobials. Furthermore, approaches to investigate common infectious diseases of the respiratory tract, are emphasized. Pneumonia, tuberculosis and infections occurring due to cystic fibrosis are in focus of this review. We conclude that especially in vitro models offer the chance of an efficient and detailed analysis of new antimicrobials, but also draw attention to the advantages and limitations of such currently available models and critically discuss the necessary steps for their future development.

Characterization of anastrozole effects, delivered by an intravaginal ring in cynomolgus monkeys.

STUDY QUESTION: Is it feasible to deliver anastrozole (ATZ), an aromatase inhibitor (AI), by a vaginal polymer-based drug delivery system in the cynomolgus monkey (Macaca fascicularis) to describe the pharmacokinetic profile? SUMMARY ANSWER: The present study showed the effective release of ATZ into the systemic circulation from intravaginal rings in cynomolgus monkeys. WHAT IS KNOWN ALREADY: ATZ is a marketed drug with well documented pharmacological and safety profiles for oral administration. Aromatase is the key enzyme catalyzing estrogen biosynthesis and is overexpressed in endometriotic lesions. AIs show therapeutic efficacy in endometriosis in exploratory clinical trials. STUDY DESIGN, SIZE, DURATION: The pharmacokinetics of the in vivo release and the pharmacodynamic activity of ATZ released by intravaginal rings (IVR) were investigated in healthy cycling female cynomolgus monkeys in three different dose groups (n = 5) for one menstrual cycle. PARTICIPANTS/MATERIALS, SETTING, METHODS: IVRs for the cynomolgus monkey, releasing three different doses of ATZ were designed and tested for in vitro/in vivo release for up to 42 days. For pharmacokinetic and pharmacodynamic evaluation, plasma samples were taken once daily from Day 1 to 3 and then every third day until menses occurred (17-42 days). MAIN RESULTS AND THE ROLE OF CHANCE: ATZ was shown to be compatible with the IVR drug delivery system. An average in vivo release of 277 µg/day/animal of ATZ for one menstrual cycle was effective in causing a decrease of systemic estradiol (E2) levels by ∼30% without inducing counter regulation such as the elevation of FSH or the formation of ovarian cysts. LIMITATIONS, REASONS FOR CAUTION: The study was limited to three dose groups in which only the highest dose decreased the E2 level. Hence, additional research with IVRs releasing higher amounts of ATZ is required to define the threshold for an ATZ-dependent ovarian stimulation in cynomolgus monkeys. WIDER IMPLICATIONS OF THE FINDINGS: The release rate administered from IVRs is sufficient and in a range that supports feasibility of IVR administration of ATZ as a new approach for long-term therapy of estrogen-dependent diseases such as endometriosis in human.

Abdominal and scrotal wall emphysema in a patient with severe ulcerative colitis.

Severe ulcerative colitis can be associated with bowel perforation. Bowel perforation rarely leads on to abdominal wall and scrotal wall emphysema. Bowel perforation in such cases can be spontaneous or iatrogenic (colonoscopy-related). We report a rare scenario where a patient presented with abdominal wall and scrotal emphysema after topical corticosteroid enema-induced traumatic rectal perforation. Topical corticosteroids were stopped immediately after identification of rectal perforation. The patient was managed conservatively with intravenous antibiotics. With this report we intend to sensitise clinicians and topical enema manufacturers regarding this rare complication.

Infectious complications related to intrathecal drug delivery system and spinal cord stimulator system implantations at a comprehensive cancer pain center.

BACKGROUND: Intrathecal drug delivery (IDD) and spinal cord stimulator (SCS) systems are implantable devices for the management of both chronic and cancer pain. Although these therapies have favorable long-term outcomes, they are associated with occasional complications including infection. The incidence of infectious complications varies from 2 - 8% and frequently requires prolonged antibiotics and device revision or removal. Cancer patients are particularly susceptible to infectious complications because they are immunocompromised, malnourished, and receiving cytotoxic cancer-related therapies. OBJECTIVE: Determine if cancer pain patients have a higher incidence of infectious complications following implantation of IDD or SCS systems than non-cancer pain patients. STUDY DESIGN: Retrospective chart review. SETTING: Single tertiary comprehensive cancer hospital. METHODS: Following local Institutional Review Board (IRB) approval, we collected data on infectious complications for IDD and SCS systems implanted at MD Anderson Cancer Center for the treatment of cancer and chronic pain. The examined implants were performed from July 15, 2006, to July 14, 2009. In addition, we obtained data regarding patient comorbidities and perioperative risk factors to assess their impact on infectious complications. RESULTS: One hundred forty-two devices were implanted in 131 patients during the examined period. Eighty-three of the devices were IDD systems and 59 were SCS systems. Eighty percent of the patients had a diagnosis of cancer. Four infectious complications were noted with an overall infectious risk of 2.8%. The infection rate was 2.4% for IDD systems versus 3.4% for SCS systems (P = 1). All infections were at the implantable pulse generator (IPG) or pump pocket site. The rate of infection was 2.7% for cancer patients and 3.3% for non-cancer patients (P = 1). Neither the perioperative administration of prophylactic antibiotics (P = 0.4) nor the National Nosocomial Infection Surveillance (NNIS) risk level for individual patients (P = 0.15) were statistically associated with infectious complication. The mean surgical time was longer for cases with infection at 215 ± 93 minutes versus 132 ± 52 minutes for those without infection which was statistically significant (P = 0.02). LIMITATIONS: The major limitation of this study is that it was a retrospective analysis. An additional limitation is that 51(38.9%) of our patients either died or were lost to follow-up during the year following implantation which may have led to an underestimation of our infection rates. CONCLUSIONS: The experience of this tertiary cancer pain center demonstrates that infectious complications following implantation of IDD and SCS systems are relatively rare events in cancer patients. Contrary to our initial hypothesis, no difference was found in the infection rate between cancer and non-cancer patients. The main factor associated with increased risk of infectious complications was increased surgical time, indicating a need to minimize patient time in the operating room. The low infectious complication rate seen in this series compared to previous reports in non-cancer patients is likely multifactorial in nature.

Peripheral neuropathy in Parkinson's disease: levodopa exposure and implications for duodenal delivery.

In advanced Parkinson's disease (PD) patients, continuous intra-duodenal infusion of levodopa/carbidopa intestinal gel (LCIG) is an established approach in the management of motor complications that cannot be further improved by conventional oral therapy. In general, tolerability of LCIG has resembled that of oral dopaminergic therapy; however, cases of symptomatic peripheral neuropathy (PN), sometimes severe, have been reported in patients receiving LCIG. Cases are generally a sensorimotor polyneuropathy with both subacute and chronic onsets, often associated with vitamin B12 and/or B6 deficiency. Rare cases clinically resemble Guillain-Barré syndrome. In the absence of prospectively collected data on possible associations between LCIG and PN, it is prudent to explore potential mechanisms that may explain a possible relationship. The PN may be linked to use of high-dose levodopa, promoting high levels of homocysteine and methylmalonic acid or reduced absorption of vitamins essential for homocysteine metabolism. Cases of LCIG-associated PN often have responded to vitamin supplementation without need for LCIG cessation, although LCIG cessation is sometimes necessary. It may be advisable to monitor vitamin B12/B6 status before and after patients start LCIG and be vigilant for signs of PN. Prospective, large-scale, long-term studies are needed to clarify whether vitamin supplementation and routine use of a catechol-O-methyltransferase inhibitor may help prevent PN in LCIG recipients and whether these measures should be routine practice in patients with PD on high-dose oral levodopa.

Therapeutic nanoparticles in clinics and under clinical evaluation.

This article reviews nanoparticulate-chemotherapeutic systems that have been developed for human therapy, considering the components of the nanoparticles, the therapeutic agents associated with the nanoparticles and the clinical indications these therapeutic nanoparticles have been developed for. In this evaluation we have put into perspective the types of nanomaterials and their therapeutic indications. We have reviewed the nanoparticulate-chemotherapeutic systems that have been published, approved and marketed and that are currently in clinical use. We have also analyzed the nanoparticulate-chemotherapeutic systems that are in clinical trials and under preclinical development.

S-protected thiolated chitosan: synthesis and in vitro characterization.

Purpose of the present study was the generation and evaluation of novel thiolated chitosans, so-named S-protected thiolated chitosans as mucosal drug delivery systems. Stability of all conjugates concerning swelling and disintegration behavior as well as drug release was examined. Mucoadhesive properties were evaluated in vitro on intestinal mucosa. Different thiolated chitosans were generated displaying increasing amounts of attached free thiol groups on the polymer, whereby more than 50% of these thiol groups were linked with 6-mercaptonicotinamide. Based on the implementation of this hydrophobic residue, the swelling behavior was 2-fold decreased, whereas stability was essentially improved. Their mucoadhesive properties were 2- and 14-fold increased compared to corresponding thiolated and unmodified chitosans, respectively. Release studies out of matrix tablets comprising the novel conjugates revealed a controlled release of a model peptide. Accordingly, S-protected thiomers represent a promising type of mucoadhesive polymers for the development of various mucosal drug delivery systems.