Pharmacokinetic-Pharmacodynamic Modelling of Morphine Transport Across the Blood-Brain Barrier as a Cause of the Antinociceptive Effect Delay in Rats—A Microdialysis Study

Purpose. To quantify the contribution of distributional processes across the blood-brain barrier (BBB) to the delay in antinociceptive effect of morphine in rats. Methods. Unbound morphine concentrations were monitored in venous blood and in brain extracellular fluid (ECF) using microdialysis (MD) and in arterial blood by regular sampling. Retrodialysis by drug was used for in vivo calibration of the MD probes. Morphine was infused (10 or 40 mg/kg) over 10 min intravenously. Nociception, measured by the electrical stimulation vocalisation method, and blood gas status were determined. Results. The half-life of unbound morphine in striatum was 44 min compared to 30 min in venous and arterial blood (p < 0.05). The BBB equilibration of morphine, expressed as the ratio of areas under the curve between striatum and venous blood, was less than unity (0.28 ± 0.09 and 0.22 ± 0.17 for 10 and 40 mg/kg), respectively, indicating active efflux of morphine across the BBB. The concentration-effect relationship exhibited a clear hysterisis with an effect delay half-life of 32 and 5 min based on arterial blood and brain ECF concentrations, respectively. Conclusions. Eighty five percent of the effect delay was caused by morphine transport across the BBB, indicating possible involvement of rate limiting mechanisms at the receptor level or distributional phenomena for the remaining effect delay of 5 min.     

Biodegradable Nanoparticles Improve Oral Bioavailability of Amphotericin B and Show Reduced Nephrotoxicity Compared to Intravenous Fungizone®

Purpose

Amphotericin B (AMB), an effective antifungal and antileishmanial agent associated with low oral bioavailability (0.3%) and severe nephrotoxicity, was entrapped into poly(lactide-co-glycolide) (PLGA) nanoparticles to improve the oral bioavailability and to minimize the adverse effects associated with it.

Materials and Methods

The AMB-nanoparticles (AMB-NP) were prepared by nanoprecipitation method employing Vitamin E-TPGS as a stabilizer. In vitro release was carried out using membrane dialysis method. The in vitro hemolytic activity of AMB-NP was evaluated by incubation with red blood cells (RBCs). The acute nephrotoxicity profile and oral bioavailability of AMB-NP were evaluated in rats.

Results

The prepared AMB-NP formulation contained monodispersed particles in the size range of 165.6?±?2.9 nm with 34.5?±?2.1% entrapment at 10% w/w initial drug loading. AMB-NP formulation showed biphasic drug release, an initial rapid release followed by a sustained release. The AMB-NP formulation exerted lower hemolysis and nephrotoxicity as compared to Fungizone®. The relative oral bioavailability of the AMB-NP was found to be ～800% as compared to Fungizone®.

Conclusion

Together, these results offer a possibility of treating systemic fungal infection and leishmaniasis with oral AMB-NP, which could revolutionize the infectious disease treatment modalities.

     

Delivery of Nasal Powders of β-Cyclodextrin by Insufflation

Purpose. Delivery of nasal powders of granulated -cyclodextrin by insufflation was studied in order to find the relationship between powder properties and delivery behavior. Methods. Three nasal powder formulations, prepared by granulating -cyclodextrin with different binders, were delivered from a powder insufflation device, in which the dose to be emitted was loaded in a gelatin capsule. The delivery sequence of powder was recorded and characterized using an image analysis program. Results. Particle size was the main parameter affecting nasal powder delivery, both as to the amount of dose sprayed and the aspect of cloud produced. Between 50–150 µm of particle size a substantial change in delivery behavior of powders was observed. Powder of around 100 µm in size showed useful insufflation characteristics for nasal delivery. Bioavailability of nasal formulations of progesterone/-cyclodextrin powders was discussed in term of delivery behavior. Conclusions. The formulation approaches for improving nasal delivery of powders require the use of size optimized carriers. Insufflation of powders over 50 µm can favour the particle deposition by impaction, whereas for powders below 50 µm, deposition by sedimentation is moved. -cyclodextrin is a suitable carrier for achieving high systemic availability following nasal administration of powder formulations.     

Reversal of Morphine Tolerance and Dependence by Passiflora incarnata – A Traditional Medicine to Combat Morphine Addiction

This paper describes the use of Passiflora incarnata Linneaus in reversing the development of dependence and tolerance of morphine in mice. A fraction (BZF) derived from the methanol extract of P. incarnata that had exhibited good anxiolytic activity, delayed the development of tolerance to the analgesic effect of morphine when administered at 10, 50 and 100 mg/kg doses along with 10 mg/kg dose of morphine for 9 days. A single dose of P. incarnata bioactive fraction (BZF) also decreased the naloxoneprecipitated withdrawal jumps in mice that had already been rendered tolerant due to chronic treatment with 10mg/kg of morphine.     

Antidepressant effect of Stillen™

Archives of Pharmacal Research - Stillen™ has been used to treat patients with gastric mucosal ulcers and has an anti-inflammatory effect. It is well-known that neuro-inflammatory reactions...     

Morphine enhancement of shuttle avoidance prevented by α-methyltyrosine

250 mg/kg of l-alpha-methyl-Dopa (-m-Dopa) or saline were administered to rats for three weeks after birth. Subsequent tests revealed an increased locomotor activity and greater rate of acquisition but no disturbance in shuttle-box conditioning. The whole brain content of norepinephrine, dopamine and serotonin was not affected.With IUPHAR fellowship.     

Investigation of the Therapeutic Efficacy of Codelivery of psiRNA–Vascular Endothelial Growth Factor and pIL-4 into Chitosan Nanoparticles in the Breast Tumor Model

Angiogenesis has been known to increase tumor growth and for its metastatic potential in human tumors. Vascular endothelial growth factor (VEGF) plays an important role in tumor angiogenesis and is a promising therapeutic target for breast cancer. VEGF is an essential target for RNAi-based gene therapy of breast cancer. Interleukin-4 (IL-4) may act as an anti-angiogenic molecule that inhibits tumor growth and migration in rats. The purpose of the present study was to improve therapeutic efficacy in breast cancer with the codelivery of siRNA-expressing plasmid targeting VEGF and IL-4-expressing plasmid encapsulating into chitosan nanoparticles (NPs). The codelivery of psiVEGF and pIL-4 plasmids greatly enhanced in vitro and in vivo gene-silencing efficiency. For the in vitro study, when psiVEGF and pIL-4 into chitosan NPs were combined (81%), the gene-silencing effect was higher than psiVEGF and pIL-4 NPs alone. The in vivo study breast tumor model demonstrated that the administration of coencapsulation of psiVEGF and pIL-4 into chitosan NPs caused an additive effect on breast tumor growth inhibition (97%), compared with containing NPs psiVEGF or pIL-4 alone. These results indicate that chitosan NPs can be effectively used for the codelivery of pIL-4 and siVEGF-expressing plasmid in a combination therapy against breast cancer.     

Antinociceptive activity of the monoterpene α-phellandrene in rodents: possible mechanisms of action

Objectives The aim of this work was to investigate the antinociceptive property of α‐phellandrene (α‐PHE) in experimental nociception models and possible mechanisms involved. Methods Mass spectrometry was used to evaluate the purity and molecular mass of α‐PHE. Macrophages from mice peritoneal cavity were used in an MTT test. Rodents were used in tests of chemical and mechanical nociception. In the study of the mechanisms, the animals were treated with pharmacological tools and then submitted to the glutamate test. Key findings α‐PHE purity was 98.2% and molecular mass 136.1 Da. α‐PHE did not show cytotoxicity. In the writhing and capsaicin tests, α‐PHE promoted the antinociceptive effect in all evaluated doses (minimum dose 3.125 mg/kg). In the formalin test, α‐PHE (50 mg/kg) was effective in inhibiting both phases. In the glutamate test, the monoterpene (12.5 mg/kg) decreased the nociceptive response. In carrageenan‐induced hyperalgesia, α‐PHE (50 mg/kg) decreased the hypernociception index. In the study of the mechanisms involved, pretreatment with naloxone reversed the α‐PHE antinociceptive effect, the same occurred with glibenclamide, l ‐arginine, atropine and yohimbine. α‐PHE did not show muscle relaxant activity or central depressant effects in open field and rota rod tests. Conclusions α‐PHE has an antinociceptive effect and it possibly involves the glutamatergic, opioid, nitrergic, cholinergic and adrenergic systems.     

Consideration of dosimetry in evaluation of ToxCast™ data

The US Environmental Protection Agency (US EPA) Toxcast? program has the stated goal of predicting hazard, characterizing toxicity pathways and prioritizing the toxicity testing of environmental chemicals through the use of in vitro high‐throughput screening (HTS) assays. This analysis integrates data from biomonitoring and from in vivo toxicity and pharmacokinetic studies to examine the physiological relevance of the tested and responding in vitro concentrations for five case study chemicals: triclosan, 2,4‐dichlorophenoxyacetic acid, perfluorooctanoic acid, monobutyl phthalate and mono‐2(ethylhexyl)phthalate. This analysis also examines the ToxCast? phase 1 data set for approximately 50 chemicals belonging to four ‘common mechanism groups’ which have been the subject of cumulative risk assessments by the US EPA for both the pattern of key responses and the relative potencies of included chemicals compared with the in vivo relative potencies. Responding concentrations in vitro were generally in the range of serum or plasma concentrations associated with no‐observed to lowest‐observed effect levels for the case study chemicals, while available biomonitoring data demonstrating actual exposures were generally lower. ToxCast? assay endpoints related to acetylcholinesterase (AChE) inhibition had low sensitivity for detecting organophosphate pesticides but good sensitivity for detecting N‐methyl carbamates. However, in vitro relative potencies did not correlate with in vivo potency. Both qualitative and quantitative predictive power is probably affected by the lack of comprehensive metabolic activity in most current in vitro systems explored in the ToxCast? program, and this remains a fundamental challenge for high‐throughput toxicity screening efforts. Copyright © 2011 John Wiley & Sons, Ltd.     

Antinociceptive and anti-inflammatory effects of the monoterpene α,β-epoxy-carvone in mice

α,β-Epoxy-carvone (EC) is a monoterpene found in the essential oils of many species of plants. It can also be obtained by organic synthesis. EC exerts a depressant effect on the central nervous system and is also known to have anticonvulsant, antimicrobial and antioxidant effects. The present study investigated the antinociceptive and anti-inflammatory effects of EC. Intraperitoneal administration of EC at doses of 100, 200 or 300 mg/kg promoted a significant antinociceptive effect, as shown in the acetic acid-induced abdominal writhing test. EC also provoked a reduction in formalin-induced nociception in the first (300 mg/kg) and second phases (200 and 300 mg/kg). In the hot-plate test, an increase in response latency was found at 30 min (at 100, 200 and 300 mg/kg), and at 60 and 120 min (at 300 mg/kg) following administration of EC, an effect that was reversed by naloxone. Intraperitoneal administration of EC (300 mg/kg) inhibited the increased vascular permeability provoked by acetic acid. These findings suggest that EC inhibited the acute inflammatory reaction, with a pronounced peripheral and central antinociceptive effect in mice that is probably associated with activation of the opioidergic system, which appears to play a role in the antinociceptive activity induced by EC.     

Antinociceptive activity and chemical composition of Wei–Chang–An–Wan extracts

Abstract

Context: Currently, famous traditional Chinese medicine formulas have undergone re-evaluation and development in China. Wei–Chang–An–Wan (WCAW) as one of them has been used for treating various gastrointestinal diseases for several decades. The secondary development of WCAW is in progress so as to interpret the effective material basis or find new pharmacological activity.

Objective: To evaluate the antinociceptive effect of methanol extract of WCAW (ME) as well as four fractions (P.E., EtOAc, n-BuOH, H₂O) and obtain information on the correlation between the contents of the fractions and antinociceptive effect.

Materials and methods: ME was divided into four parts extracted by petroleum ether, ethyl acetate and n-butanol. Antinociceptive activity was evaluated by three models of acetic acid–induced writhing, formalin and hot-plate test in mice after repetitive administration of ME at 200, 400 or 800?mg/kg, P.E. 132?mg/kg, EtOAc 106?mg/kg, n-BuOH 176?mg/kg and H₂O 176?mg/kg for six days. The chemical compounds were analyzed by HPLC-ESI-MS.

Results: ME at 800?mg/kg inhibited acid-induced writhing by 84.69%, and reduced the licking time of second phase in formalin test by 53.23%. The inhibition rates in acid-induced writhing of P.E., EtOAc, n-BuOH and H₂O were 27.79, 33.85, 38.97 and 37.69%, respectively, and in formalin test about 50%. They had no effect on the hot-plate test. HPLC-ESI-MS analysis showed that 68 chemical compounds were detected and 41 compounds were identified from ME.

Discussion and conclusion: The results obtained herein indicate that WCAW possesses the antinociceptive activity that provides a new aspect in clinical application.     

Efficacy of α-lipoic acid in diabetic neuropathy

Introduction: Neuropathy is a serious complication of diabetes. Its management focuses on glycaemic control, multifactorial cardiovascular risk intervention, pathogenesis-oriented therapy, and analgesics where needed.

Areas covered: The objective of this review is assessment of efficacy and safety of α lipoic acid (ALA, also thioctic acid) in pathogenesis-oriented treatment of diabetic neuropathy. The mechanisms of action of ALA in experimental diabetic neuropathy include reduction of oxidative stress along with improvement in nerve blood flow, nerve conduction velocity, and several other measures of nerve function. There is ample evidence from randomised, double-blind, placebo-controlled clinical trials and meta-analyses, suggesting that ALA is efficacious and safe for the diabetic neuropathy, accomplishing clinically meaningful improvements.

Expert opinion: ALA is a valuable therapeutic option for diabetic neuropathy. When compared with currently licensed analgesic drugs, it is better tolerated, has a more rapid onset of action, and improves paraesthesiae, numbness, sensory deficits, and muscle strength in addition to neuropathic pain. In clinical practice, ALA may be chosen in patients with early neuropathic deficits and symptoms, in whom clinical improvement is more likely. ALA should also be considered when comorbidities render other analgesics less appropriate or in the presence of cardiovascular autonomic neuropathy.     

In Situ Blood–Brain Barrier Transport of Nanoparticles

PURPOSE: Two novel types of nanoparticles were evaluated as poten tial carriers for drugs across the blood-brain barrier (BBB). METHODS: Nanoparticles were composed of biocompatible materials including emulsifying wax (E. Wax) or Brij 72. Brij 78 and Tween 80 were used as surfactants for E. Wax nanoparticles (E78 NPs) and Brij 72 nanoparticles (E72 NPs), respectively. Both nanoparticle formulations were prepared from warm microemulsion precursors usin melted E. Wax or Brij 72 as the oil phase. Nanoparticles were radio-labeled by entrapment of [3H]cetyl alcohol, and entrapment efficiency and release of radiolabel were evaluated. The transport of E78 and E72 NPs across the BBB was measured by an in situ rat brai perfusion method. RESULTS: Both formulations were successfully radiolabeled by entrapment of [3H]cetyl alcohol; -98% of radiolabel remained associated with nanoparticles at experimental conditions. The transfer rate (Kin) of E78 NPs from perfusion fluid into the brain was 4.1 +/- 0.5 x 10(-3) ml/s/g, and the permeability-surface area product (PA) was 4.3 +/- 0.7 x 10(-3) ml/s/g. The values for Kin and PA for E72 NPs were 5.7 +/- 1.1 x 10(-3) ml/s/g and 6.1 +/- 1.4 x 10(-3) ml/s/g, respectively. CONCLUSIONS: For both nanoparticle types, statistically significant uptake was observed compared to [14C]sucrose, suggesting central nervous system uptake of nanoparticles. The mechanism underlying th nanoparticle brain uptake has yet to be fully understood.     

Nasal delivery of H5N1 avian influenza vaccine formulated with GenJet™ or in vivo-jetPEI® induces enhanced serological,cellular and protective immune responses

Avian influenza virus infection is a serious public health threat and preventive vaccination is the most cost-effective public health intervention strategy. Unfortunately, currently available unadjuvanted avian influenza vaccines are poorly immunogenic and alternative vaccine formulations and delivery strategies are in urgent need to reduce the high risk of avian influenza pandemics. Cationic polymers have been widely used as vectors for gene delivery in vitro and in vivo. In this study, we formulated H5N1 influenza vaccines with GenJet? or in vivo-jetPEI^®, and showed that these formulations significantly enhanced the immunogenicity of H5N1 vaccines and conferred protective immunity in a mouse model. Detailed analyses of adaptive immune responses revealed that both formulations induced mixed T_H1/T_H2 antigen-specific CD4 T-cell responses, antigen-specific cytotoxic CD8 T-cell and memory B-cell responses. Our findings suggest that cationic polymers merit future development as potential adjuvants for mucosal delivery of poorly immunogenic vaccines.     

Does Registration of Professionals Improve the Quality of Travelers' Health Advice?

Background.  The objectives of the Dutch National Coordination Center for Travelers' Health Advice (LCR) are to improve the uniformity of travelers' health advice in the Netherlands and to enhance its quality. The LCR offers national guidelines and quality criteria, as well as a telephone consultation service, where health professionals can pose questions regarding travel medicine. Since 2005, a register for qualified travel health professionals has been in place. We studied the quality and relevance of the telephone consultations, to see whether there was a difference between registered as qualified and nonregistered health professionals.
Methods.  Telephone questions regarding pretravel advice were logged in September 2007. The questions were categorized as basic or advanced and compared by the profession of the caller, type of institution, and LCR registration of the responsible physician.
Results.  In 2007, 85% of travel clinic physicians, 42% of general practitioners, and 31% of travel clinic nurses were registered with the LCR. A total of 146 telephone consultations were included in the analysis. Significantly more callers from travel clinics posed advanced questions than those from general practices [odds ratio (OR) 7.6; 95% confidence interval (CI): 3.6–16.1; p = 0.000]. More callers who were registered asked advanced questions, although this difference was not significant (OR 1.7; 95% CI: 0.9–3.3; p = 0.124). Assistants from general practices asked significantly less advanced questions than physicians or nurses.
Conclusions.  Opening a register for travel health professionals has led to a large increase of professionals who follow courses and register as travel health professionals. A positive association was found between the quality of the questions and the registration of the responsible physician. The quality of travel health advice given in general practices needs increased attention.     

Development of an inhaled dry-powder formulation of tobramycin using PulmoSphere™ technology

Abstract At present, the only approved inhaled antipseudomonal antibiotics for chronic pulmonary infections in patients with cystic fibrosis (CF) are nebulized solutions. However, prolonged administration and cleaning times, high administration frequency, and cumbersome delivery technologies with nebulizers add to the high treatment burden in this patient population. PulmoSphere? technology is an emulsion-based spray-drying process that enables the production of light porous particle, dry-powder formulations, which exhibit improved flow and dispersion from passive dry powder inhalers. This review explores the fundamental characteristics of PulmoSphere technology, focusing on the development of a dry powder formulation of tobramycin for the treatment of chronic pulmonary Pseudomonas aeruginosa (Pa) infection in CF patients. This dry powder formulation provides substantially improved intrapulmonary deposition efficiency, faster delivery, and more convenient administration over nebulized formulations. The availability of more efficient and convenient treatment options may improve treatment compliance, and thereby therapeutic outcomes in CF.     

Nebulization of NanoCrystals™: Production of a Respirable Solid-in-Liquid-in-Air Colloidal Dispersion

Pharmaceutical Research -