High Penetration of Paclitaxel in Abdominal Wall of Rabbits after Hyperthermic Intraperitoneal Administration of Nab-Paclitaxel Compared to Standard Paclitaxel Formulation

Purpose

Paclitaxel (PTX) is currently used in combination with cisplatin for Hyperthermic Intraperitoneal Chemotherapy (HIPEC) for the treatment of peritoneal carcinomatosis. Albumin-bound PTX is a promising new drug for HIPEC because of its easy solubility in aqueous perfusion medium and possibly because of the tendency of albumin to cross physiological barriers and accumulate in tumor tissue.

Methods

We tested the feasibility of using nab-paclitaxel in rabbits treated by HIPEC for 60 min compared with the classical formulation at an equivalent PTX dose. Samples of perfusate and blood were collected at different time points and peritoneal tissues were collected at the end of perfusion. PTX concentrations were determined by HPLC. The depth of paclitaxel penetration through the peritoneal barrier was assessed by mass spectrometry imaging.

Results

PTX after nab-paclitaxel treatment penetrated up to 0.63 mm in the peritoneal wall, but after CRE-paclitaxel, it was not detectable in the peritoneum. Moreover, the peritoneal concentration after nab-paclitaxel was five times that after paclitaxel classical formulation. Despite the high levels reached in the peritoneum, systemic exposure of PTX was low.

Conclusions

Our results show that nab-paclitaxel penetrates into the abdominal wall better than CRE-paclitaxel, in terms of effective penetration and peritoneal tissue concentration.

     

Development of a Nanocrystalline Paclitaxel Formulation for Hipec Treatment

Purpose

To develop a nanocrystalline paclitaxel formulation with a high paclitaxel-to-stabilizer ratio which can be used for hyperthermic intraperitoneal chemotherapy (HIPEC).

Methods

Paclitaxel (PTX) nanocrystals were prepared via wet milling using Pluronic F127^? as stabilizer. The suitability of paclitaxel nanosuspensions for HIPEC treatment was evaluated by analyzing the cytotoxicity of both stabilizer and formulation, and by determining the maximum tolerated dose (MTD) and bioavailability. The effect on tumor growth was evaluated by magnetic resonance imaging (MRI) at day 7 and 14 after HIPEC treatment in rats with peritoneal carcinomatosis of ovarian origin.

Results

Monodisperse nanosuspensions (±400?nm) were developed using Pluronic F127^? as single additive. The cytotoxicity and MTD of this nanocrystalline formulation was similar compared to Taxol^?, while its bioavailability was higher. MRI data after HIPEC treatment with a PTX nanocrystalline suspension showed a significant reduction of tumor volume compared to the non-treated group. Although no significant differences on tumor volume were observed between Taxol^? and the nanosuspension, the rats treated with the nanosuspension recovered faster following the HIPEC procedure.

Conclusion

Nanosuspensions with a high paclitaxel-to-stabilizer ratio are of interest for the treatment of peritoneal carcinomatosis of ovarian origin via HIPEC.     

PEGylated Multi-Walled Carbon Nanotubes for Encapsulation and Sustained Release of Oxaliplatin

Purpose

To develop PEGylated multi-walled carbon nanotubes as a sustained release drug delivery system.

Methods

Oxaliplatin was incorporated into inner cavity of PEGylated multi-walled carbon nanotubes (MWCNT-PEG) using nano-extraction. Oxaliplatin release rates from MWCNT-PEG-Oxaliplatin were investigated using dialysis tubing. Cytotoxicity of oxaliplatin, MWCNT-Oxaliplatin and MWCNT-PEG-Oxaliplatin were evaluated in HT29 cell by MTT assay, Pt-DNA adducts formation, γ-H2AX formation and cell apoptosis assay.

Results

Loading of oxaliplatin into MWCNT-PEG was ~43.6%. Sustained release occurred to MWCNT-PEG-Oxaliplatin, with only 34% of oxaliplatin released into medium within 6 h. In MTT assay, MWCNT-PEG-Oxaliplatin showed slightly decreased cytotoxic effect when cell viability was assessed at 12 and 24 h. A drastic increase of cytotoxicity was found when cell viability was assessed at 48 and 96 h. Pt-DNA adducts formation, γ-H2AX formation and cell apoptosis assay results showed the same trend as the MTT assay, suggesting sustained-release for MWCNT-Oxaliplatin and MWCNT-PEG-Oxaliplatin formulations.

Conclusions

PEGylated multi-walled carbon nanotubes can be used as sustained release drug delivery system, thus remarkably improving cytotoxicity of oxaliplatin on HT-29 cells.     

Synthesis and biological evaluation of some N 4-aryl-substituted 5-fluoroisatin-3-thiosemicarbazones

A series of N ⁴-aryl-substituted 5-fluoroisatin-3-thiosemicarbazones 3a–3l was synthesized and evaluated for selected biological activities. The brine shrimp lethality bioassay was carried out to study their in vitro cytotoxicity potential and besides, their antifungal, phytotoxic and urease inhibitory effects were also investigated. Seven compounds i.e. 3a, 3d, 3f, 3g, 3h, 3j and 3k proved to be active in the brine shrimp assay, displaying promising cytotoxicity (LD₅₀ = 6.89 × 10^?5–2.79 × 10^?4 M). Amongst these, 3a and 3h were found to be the most active ones (LD₅₀ = 6.89 × 10^?5 and 9.79 × 10^?5 M, respectively). Compounds 3i, 3j and 3 k displayed moderate (40 %) antifungal activity against one or two fungal strains i.e. A. flavus and/or M. canis. In phytotoxicity assay, all the synthesized compounds, including the reference point 2m showed weak-to-moderate (15–70 %) activity at the highest tested concentration (500 μg/mL). In urease inhibition assay, compounds 3f, 3g and 3j proved to be the most potent inhibitors, demonstrating relatively a higher degree of enzymatic inhibition with IC₅₀ values ranging from 37.7 to 47.3 μM.     

Comparison of nicotine oral soluble film and nicotine lozenge on efficacy in relief of smoking cue-provoked acute craving after a single dose of treatment in low dependence smokers

Rationale

Pilot study results suggested that a new form of nicotine oral soluble film relieved smoking cue-provoked acute craving faster than nicotine lozenge or gum. The new nicotine film may provide smokers another choice to relieve acute craving.

Objectives

This study compared the efficacy of the 2.5 mg nicotine oral soluble film to 2 mg nicotine lozenge for acute relief of smoking cue-provoked craving.

Methods

A randomized, open label, active comparator controlled, parallel group study was conducted with 322 smokers enrolled. After 4 h of abstinence from smoking, eligible subjects were exposed to smoking cues as provocation. Immediately after the post-provocation baseline craving assessment using a 0–100 mm visual analogue scale (VAS), subjects took a randomized single dose of either the 2.5 mg nicotine film or the 2 mg nicotine lozenge. Craving assessments were completed at 50 s, 3 min, 5 min, 7 min, 15 min, 20 min, 25 min and 30 min after drug administration.

Results

Both treatments reduced cue-induced craving and had similar maximum effects on craving relief. However, the 2.5 mg nicotine film relieved cue-induced craving to a greater degree than the 2 mg nicotine lozenge at 50 s (mean difference: ?4.9, p?=?0.014), 3 min (mean difference: ?6.7, p?=?0.011), and 5 min (mean difference: ?5.6, p?=?0.049) post-treatment.

Conclusions

The study confirmed the results from the pilot study. The 2.5 mg nicotine film relieved cue-provoked craving much quicker than the 2 mg nicotine lozenge while both having similar maximum effects. Nicotine film could be useful to provide quick craving relief for low dependence smokers.     

Paliperidone-Loaded Mucoadhesive Microemulsion in Treatment of Schizophrenia: Formulation Consideration

Purpose

This paper describes formulation considerations and in vitro evaluation of a microemulsion drug delivery system designed for intranasal administration of Paliperidone.

Methods

Drug-loaded microemulsions were successfully prepared by a water titration. Prepared formulations were subjected to physicochemical characterization, and evaluated for in vitro diffusion, nasal cilio toxicity, and in vitro mucoadhesion.

Results

The microemulsion, containing 4 % oleic acid, 30 % surfactant mixture of [Labrasol/Cremophor RH 40 (1:1)]/[Transcutol P] (3:1) and 66 % (wt/wt) aqueous phase, that displayed a 99.93 % optical transparency, globule sizes of 20.01?±?1.28 nm, and a polydispersity index of 0.117?±?0.034 was selected for the incorporation of polyelectrolytic polymer (polycarbophil) as the mucoadhesive component. The mucoadhesive microemulsion formulation of Paliperidone that contains 0.5 % by weight of polycarbophil displayed higher in vitro mucoadhesive potential (18.0?±?2.5 min) and diffusion coefficient (3.83?×?10^?6?±?0.019?×?10^?6) than microemulsion. Also, they were found to be free from nasal ciliotoxicity and had stability for 6 months.

Conclusion

The in vitro studies demonstrated the potential of developing mucoadhesive microemulsion formulation for intranasal delivery of Paliperidone.     

Role of CA2+/calmodulin on ethanol neurobehavioral effects

Rationale

The cAMP-dependent protein kinase A (PKA) signaling transduction pathway has been shown to play an important role in the modulation of several ethanol-induced behaviors. Different studies have demonstrated intracellular calcium (Ca²⁺)-dependent activation of the PKA cascade after ethanol administration. Thus, the cAMP cascade mediator Ca²⁺-dependent calmodulin (CaM) has been strongly implicated in the central effects of ethanol.

Objectives

In this study, we assessed the role of the CaM inhibitor W7 on ethanol-induced stimulation, ethanol intake, and ethanol-induced activation of PKA.

Methods

Swiss mice were pretreated with W7 (0–10 mg/kg) 30 min before ethanol (0–3.75 g/kg) administration. Immediately, animals were placed during 20 min in an open-field chamber. Ethanol (10 %, v/v) intake in 2 h was assessed using a limited access paradigm. Experiments with caffeine (0–15 mg/kg), cocaine (0–4 mg/kg), and saccharine (0.1 %, w/v) were designed to compare their results to those obtained with ethanol. Western blot was assayed 45 min after ethanol administration.

Results

Results showed that pretreatment with W7, reduced selectively in a dose-dependent fashion ethanol-induced locomotor stimulation and ethanol intake. The ethanol-induced activation of PKA was also prevented by W7 administration.

Conclusions

These results demonstrate that CaM inhibition resulted in a selective reduction of ethanol-stimulating effects and ethanol intake. The PKA activation induced by ethanol was blocked after the CaM blockade with W7. These results provide further evidence of the key role of cellular Ca²⁺-dependent pathways on the central effects of ethanol.     

Uptake of ANG1005, A Novel Paclitaxel Derivative, Through the Blood-Brain Barrier into Brain and Experimental Brain Metastases of Breast Cancer

Purpose

We evaluated the uptake of angiopep-2 paclitaxel conjugate, ANG1005, into brain and brain metastases of breast cancer in rodents. Most anticancer drugs show poor delivery to brain tumors due to limited transport across the blood-brain barrier (BBB). To overcome this, a 19-amino acid peptide (angiopep-2) was developed that binds to low density lipoprotein receptor-related protein (LRP) receptors at the BBB and has the potential to deliver drugs to brain by receptor-mediated transport.

Methods

The transfer coefficient (K_in) for brain influx was measured by in situ rat brain perfusion. Drug distribution was determined at 30 min after i.v. injection in mice bearing intracerebral MDA-MB-231BR metastases of breast cancer.

Results

The BBB K_in for ¹²⁵I-ANG1005 uptake (7.3?±?0.2?×?10^-3 mL/s/g) exceeded that for ³H-paclitaxel (8.5?±?0.5?×?10^-5) by 86-fold. Over 70% of ¹²⁵I-ANG1005 tracer stayed in brain after capillary depletion or vascular washout. Brain ¹²⁵I-ANG1005 uptake was reduced by unlabeled angiopep-2 vector and by LRP ligands, consistent with receptor transport. In vivo uptake of ¹²⁵I-ANG1005 into vascularly corrected brain and brain metastases exceeded that of ¹⁴C-paclitaxel by 4–54-fold.

Conclusions

The results demonstrate that ANG1005 shows significantly improved delivery to brain and brain metastases of breast cancer compared to free paclitaxel.     

Pharmacokinetics and Metabolism of 2-Aminothiazoles with Antiprion Activity in Mice

Purpose

To discover drugs lowering PrP^Sc in prion-infected cultured neuronal cells that achieve high concentrations in brain to test in mouse models of prion disease and then treat people with these fatal diseases.

Methods

We tested 2-AMT analogs for EC₅₀ and PK after a 40 mg/kg single dose and 40–210 mg/kg/day doses for 3 days. We calculated plasma and brain AUC, ratio of AUC/EC₅₀ after dosing. We reasoned that compounds with high AUC/EC₅₀ ratios should be good candidates going forward.

Results

We evaluated 27 2-AMTs in single-dose and 10 in 3-day PK studies, of which IND24 and IND81 were selected for testing in mouse models of prion disease. They had high concentrations in brain after oral dosing. Absolute bioavailability ranged from 27–40%. AUC/EC₅₀ ratios after 3 days were >100 (total) and 48–113 (unbound). Stability in liver microsomes ranged from 30–>60 min. Ring hydroxylated metabolites were observed in microsomes. Neither was a substrate for the MDR1 transporter.

Conclusions

IND24 and IND81 are active in vitro and show high AUC/EC₅₀ ratios (total and unbound) in plasma and brain. These will be evaluated in mouse models of prion disease.     

Fasting and exercise increase plasma cannabinoid levels in THC pre-treated rats: an examination of behavioural consequences

Rationale

Δ⁹-Tetrahydrocannabinol (THC), the main psychoactive constituent of cannabis, accumulates in fat tissue where it can remain for prolonged periods. Under conditions of increased fat utilisation, blood cannabinoid concentrations can increase. However, it is unclear whether this has behavioural consequences.

Objectives

Here, we examined whether rats pre-treated with multiple or single doses of THC followed by a washout would show elevated plasma cannabinoids and altered behaviour following fasting or exercise manipulations designed to increase fat utilisation.

Methods

Behavioural impairment was measured as an inhibition of spontaneous locomotor activity or a failure to successfully complete a treadmill exercise session. Fat utilisation was indexed by plasma free fatty acid (FFA) levels with plasma concentrations of THC and its terminal metabolite (-)-11-nor-9-carboxy-?⁹-tetrahydrocannabinol (THC-COOH) also measured.

Results

Rats given daily THC (10 mg/kg) for 5 days followed by a 4-day washout showed elevated plasma THC-COOH when fasted for 24 h relative to non-fasted controls. Fasted rats showed lower locomotor activity than controls suggesting a behavioural effect of fat-released THC. However, rats fasted for 20 h after a single 5-mg/kg THC injection did not show locomotor suppression, despite modestly elevated plasma THC-COOH. Rats pre-treated with THC (5 mg/kg) and exercised 20 h later also showed elevated plasma THC-COOH but did not differ from controls in their likelihood of completing 30 min of treadmill exercise.

Conclusions

These results confirm that fasting and exercise can increase plasma cannabinoid levels. Behavioural consequences are more clearly observed with pre-treatment regimes involving repeated rather than single THC dosing.     

Attenuation of anticipatory nausea in a rat model of contextually elicited conditioned gaping by enhancement of the endocannabinoid system

Rationale

Enhancement of the endocannabinoid (EC) system may reduce anticipatory nausea (AN).

Objectives

The experiments evaluated the potential of the dual fatty acid amide hydrolase (FAAH)/monoacylglycerol lipase (MAGL) inhibitor, JZL195, on its own and combined with anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) to reduce contextually elicited gaping, a measure of AN in rats.

Methods

Following four context lithium chloride (LiCl) pairings, rats were injected with vehicle (VEH) or JZL195 (10 mg kg^–1, intraperitoneally) 105 min before an injection of VEH, 2-AG (1.25 mg kg^–1), or AEA (5.0 mg kg^–1). Fifteen minutes later, all rats were placed in the LiCl-paired context for 5 min and in a different context for a 15-min locomotor test. Whole brains were extracted for EC analysis. The potential of the CB₁ antagonist, SR141716, to reverse the suppression of AN by both JZL195 and AEA and of the CB₂ antagonist, AM630, to reverse the suppression of AN by JZL195 was then evaluated.

Results

JZL195 suppressed gaping and elevated AEA, palmitoylethanolamine, and oleoylethanolamide. As the suppression of gaping was reversed by SR141716, but not by AM630, the effect was CB₁ mediated. The suppressive effect of JZL195 on gaping, as well as elevation of AEA and 2-AG, was amplified by pretreatment with either AEA or 2-AG. On its own, AEA, but not 2-AG, also suppressed gaping—an effect that was also prevented by CB₁ antagonism.

Conclusions

JZL195 reduces AN primarily by acting as a FAAH inhibitor, but MAGL inhibition is also indicated.     

Severe Anion Gap Acidosis Associated with Intravenous Sodium Thiosulfate Administration

Introduction

Severe anion gap (AG) acidosis associated with intravenous sodium thiosulfate (STS) administration has not been previously described in nondialysis chronic kidney disease (CKD) patients.

Case Report

We present a CKD patient with a baseline creatinine 1.8 mg/dL (eGFR 28 ml/min/1.73 m²) who developed sustained and life-threatening AG acidosis associated with intravenous STS treatment for calciphylaxis.

Discussion

Although marketed as a safe drug, STS can cause life-threatening acidosis as illustrated in this case. STS-induced AG acidosis should be considered in the differential diagnosis of severe acidosis in patients receiving STS. Dosage adjustment and close follow-up of patients’ acid–base status after STS initiation is necessary.     

Mephedrone pharmacokinetics after intravenous and oral administration in rats: relation to pharmacodynamics

Rationale

Mephedrone (4-methylmethcathinone) is a still poorly known drug of abuse, alternative to ecstasy or cocaine.

Objective

The major aims were to investigate the pharmacokinetics and locomotor activity of mephedrone in rats and provide a pharmacokinetic/pharmacodynamic model.

Methods

Mephedrone was administered to male Sprague–Dawley rats intravenously (10 mg/kg) and orally (30 and 60 mg/kg). Plasma concentrations and metabolites were characterized using LC/MS and LC-MS/MS fragmentation patterns. Locomotor activity was monitored for 180–240 min.

Results

Mephedrone plasma concentrations after i.v. administration fit a two-compartment model (α?=?10.23 h^?1, β?=?1.86 h^?1). After oral administration, peak mephedrone concentrations were achieved between 0.5 and 1 h and declined to undetectable levels at 9 h. The absolute bioavailability of mephedrone was about 10 % and the percentage of mephedrone protein binding was 21.59?±?3.67 %. We have identified five phase I metabolites in rat blood after oral administration. The relationship between brain levels and free plasma concentration was 1.85?±?0.08. Mephedrone induced a dose-dependent increase in locomotor activity, which lasted up to 2 h. The pharmacokinetic–pharmacodynamic model successfully describes the relationship between mephedrone plasma concentrations and its psychostimulant effect.

Conclusions

We suggest a very important first-pass effect for mephedrone after oral administration and an easy access to the central nervous system. The model described might be useful in the estimation and prediction of the onset, magnitude, and time course of mephedrone pharmacodynamics as well as to design new animal models of mephedrone addiction and toxicity.     

Anti-Tuberculosis Bacteriophage D29 Delivery with a Vibrating Mesh Nebulizer,Jet Nebulizer,and Soft Mist Inhaler

Purpose

To compare titer reduction and delivery rate of active anti-tuberculosis bacteriophage (phage) D29 with three inhalation devices.

Methods

Phage D29 lysate was amplified to a titer of 11.8 ± 0.3 log₁₀(pfu/mL) and diluted 1:100 in isotonic saline. Filters captured the aerosolized saline D29 preparation emitted from three types of inhalation devices: 1) vibrating mesh nebulizer; 2) jet nebulizer; 3) soft mist inhaler. Full-plate plaque assays, performed in triplicate at multiple dilution levels with the surrogate host Mycobacterium smegmatis, were used to quantify phage titer.

Results

Respective titer reductions for the vibrating mesh nebulizer, jet nebulizer, and soft mist inhaler were 0.4 ± 0.1, 3.7 ± 0.1, and 0.6 ± 0.3 log₁₀(pfu/mL). Active phage delivery rate was significantly greater (p < 0.01) for the vibrating mesh nebulizer (3.3x10⁸ ± 0.8x10⁸ pfu/min) than for the jet nebulizer (5.4x10⁴ ± 1.3x10⁴ pfu/min). The soft mist inhaler delivered 4.6x10⁶ ± 2.0x10⁶ pfu per 11.6 ± 1.6 μL ex-actuator dose.

Conclusions

Delivering active phage requires a prudent choice of inhalation device. The jet nebulizer was not a good choice for aerosolizing phage D29 under the tested conditions, due to substantial titer reduction likely occurring during droplet production. The vibrating mesh nebulizer is recommended for animal inhalation studies requiring large amounts of D29 aerosol, whereas the soft mist inhaler may be useful for self-administration of D29 aerosol.

     

Pharmacokinetics and pharmacodynamics of moist inhalation epinephrine using a mobile inhaler

Background

Intramuscular (L-)epinephrine is used as self-medication for serious hypersensitivity reactions. Inhalative administration has the theoretical advantage of a more rapid absorption and better controllability.

Objectives

The current trial was conducted to explore pharmacokinetics and pharmacodynamics of two nebulized inhalative epinephrine doses (4 mg and 8 mg in aqueous solution) using a mobile pocket inhaler relative to intramuscular administration (0.3 mg) and placebo.

Methods

This randomized, open-label, change-over pilot study involved eight young healthy men and women. Noncompartmental pharmacokinetic and pharmacodynamic parameters were calculated from epinephrine plasma concentrations and hemodynamic parameters.

Results

Mean exposure to epinephrine decreased from the 8 mg dose to the 4 mg inhalative dose, and further with the 0.3 mg intramuscular dose, with active treatments showing significantly higher concentrations than placebo (geometric mean area under the curve AUC_0-t(last) values: 282, 236, 204 and 81.6 hr*ng/L). Maximal concentrations were reached within approximately 15 min for all active treatments. Epinephrine effects for inhalative administrations on heart rates were significantly higher than those for the intramuscular or placebo administration, while no excessive effects occurred. Pronounced overall variability prohibited a definite assessment of relative bioavailability between treatments. However, results indicated that epinephrine concentrations obtained following the 8 mg inhalative dose were not inferior to those after 0.3 mg i.m.

Conclusions

A relevant fraction of moist inhalation epinephrine doses is absorbed and mediates systemic effects. This suggests that administration of epinephrine via a suitable pocket inhaler device may be beneficial in ambulatory emergency treatment of systemic hypersensitivity reactions. EudraCT number: 2010-021493-11     

Synthesis and anticonvulsant activity of novel quinazolin-4(3H)-one derived pyrazole analogs

Eighteen novel 6,8-(dibromo/unsubstituted)-2-(methyl/phenyl)-3-(4-(5-(substitutedphenyl)-3-phenyl-4,5-dihydro-1H-pyrazole-1-carbonyl)phenyl)-quinazolin-4(3H)-ones 4a–4r were designed and synthesized in good yield. Antiepileptic screening of the title compounds was performed using MES and scPTZ seizures tests while the neurotoxicity was determined by rotorod test. In the preliminary screening, compounds 4d, 4e, 4p, 4q, and 4r were found active in MES model, while 4a, 4d, 4f, 4m, and 4p showed significant antiepileptic activity in scPTZ model. Further, all these eight compounds were administered to rats and compounds 4e, 4p, and 4q showed better activity than Phenytoin in oral route. Among these compounds 4p revealed protection in MES after i.p. administration at a dose of 30 mg/kg (0.5 h) and 100 mg/kg (4 h). The compound 4p also provided protection in the scPTZ at a dose of 100 mg/kg (0.5 h) and 300 mg/kg (4 h).     

Acid-Responsive Polymeric Nanocarriers for Topical Adapalene Delivery

Purpose

The acne skin is characteristic of a relatively lower pH microenvironment compared to the healthy skin. The aim of this work was to utilize such pH discrepancy as a site-specific trigger for on-demand topical adapalene delivery.

Methods

The anti-acne agent, adapalene, was encapsulated in acid-responsive polymer (Eudragit® EPO) nanocarriers via nanoprecipitation. The nanocarriers were characterized in terms of particle size, surface morphology, drug-carrier interaction, drug release and permeation.

Results

Adapalene experienced a rapid release at pH 4.0 in contrast to that at pH 5.0 and 6.0. The permeation study using silicone membrane revealed a significant higher drug flux from the nanocarrier (6.5?±?0.6 μg.cm^?2.h^?1) in comparison to that (3.9?±?0.4 μg.cm^?2.h^?1) in the control vehicle (Transcutol®). The in vitro pig skin tape stripping study showed that at 24 h post dose-application the nanocarrier delivered the same amount of drug to the stratum corneum as the positive control vehicle did.

Conclusions

The acid-responsive nanocarriers hold promise for efficient adapalene delivery and thus improved acne therapy. Figure

pH liable nanocarriers enhance the adapalene delivery to acne skin.     

The Acoustic Features of Inhalation can be Used to Quantify Aerosol Delivery from a Diskus™ Dry Powder Inhaler

Purpose

Some patients are unable to generate the peak inspiratory flow rate (PIFR) necessary to de-agglomerate drug particles from dry powder inhalers (DPIs). In this study we tested the hypothesis that the acoustic parameters of an inhalation are related to the PIFR and hence reflect drug delivery.

Methods

A sensitivity analysis of the relationship of the acoustics of inhalation to simultaneously recorded airflow, in a cohort of volunteers (n?=?92) was performed. The Next Generation Impactor (NGI) was used to assess in vitro drug delivery from salmeterol/fluticasone and salbutamol Diskus? DPIs. Fine particle fraction, FPF, (<5 μm) was measured at 30–90 l/min for 2–6 s and correlated with acoustically determined flow rate (IFRc). In pharmacokinetic studies using a salbutamol (200 μg) Diskus?, volunteers inhaled either at maximal or minimal effort on separate days.

Results

PIFRc was correlated with spirometrically determined values (R ²?=?0.88). In in vitro studies, FPF increased as both flow rate and inhalation duration increased for the salmeterol/fluticasone Diskus? (Adjusted R ²?=?0.95) and was proportional to flow rate only for the salbutamol Diskus? (Adjusted R ²?=?0.71). In pharmacokinetic studies, blood salbutamol levels measured at 20 min were significantly lower when PIFRc was less than 60 l/min, p?Conclusion Acoustically-determined PIFR is a suitable method for estimating drug delivery and for monitoring inhalation technique over time.     

Design, synthesis and biological evaluation of some novel benzylidene-2-(4-phenylthiazol-2-yl) hydrazines as potential anti-inflammatory agents

A series of substituted benzylidene-2-(4-phenylthiazol-2-yl) hydrazines (2a–q) have been synthesized, characterized and evaluated for their anti-inflammatory activity by carrageenin-induced hind paw edema (acute inflammation) and cotton pellet granuloma (chronic inflammation) methods in rats. In carrageenin-induced hind paw edema method, compounds 2a, 2b, 2c, 2d, 2h, 2k and 2p at a dose of 20 mg kg^?1 body weight, p.o. showed excellent inhibitions (51.80–86.74 %) in between 1 and 4 h. Similarly, in cotton pellet granuloma method, compounds 2a, 2b, 2c, 2d, 2h, 2k and 2p at a dose of 20 mg kg^?1 body weight, p.o. inhibited the granuloma formation (71.71–90.19 % inhibition) which was comparable to that of standard drug, ibuprofen (90.36 % inhibition of paw volume at 3 h and 94.02 % inhibition of granuloma formation). Structure activity relationship studies showed excellent activity of the compounds containing electron withdrawing group (fluoro, chloro, bromo or nitro) in phenyl ring at C2 and/or C4 position of thiazole ring.     

Cue-induced resumption of heroin and cocaine seeking in rats using a conflict model of abstinence and relapse

Rationale and objectives

Most animal research on drug relapse involves the reinstatement model where abstinence is a result of drug removal (extinction). However, abstinence in humans often results from the aversive consequences that accompany drug seeking (conflict situation). This study was aimed at using a conflict-based animal model of abstinence/relapse in rats self-administering heroin or cocaine.

Methods

Rats were trained to self-administer heroin (0.05 mg kg^?1 injection^?1) or cocaine (0.5 mg kg^?1 injection^?1) with each injection paired with a light cue. After stable responding was demonstrated, the floor near the levers was electrified, creating a barrier, in order to model the negative consequences of continued drug seeking. Shock intensities were increased over sessions until no responses occurred for three consecutive sessions. During a relapse test, where shock was maintained,the capacity of noncontingent drug cue presentations to induce active lever pressing was assessed.

Results

Ten of ten heroin animals and three of eight cocaine animals exposed to noncontingent cue presentations resumed responding. During the relapse test, for both drug groups, active lever pressing was significantly higher than during abstinence but only in the heroin group was it significantly higher than inactive lever pressing.

Conclusions

The implementation of negative consequences for drug seeking can result in its cessation just as they might in human addicts. Similarly, exposure to drug cues can lead to resumption of drug seeking. This model may be useful for studying the mechanisms underlying abstinence and relapse and for developing strategies to prevent relapse.