Prevention and treatment of glucocorticoid‐induced osteoporosis

Glucocorticoidinduced osteoporosis is a common clinical problem. This review briefly summarizes the pathogenesis of this disorder. All relevant studies on the prevention and treatment of glucocorticoidinduced osteoporosis are discussed more in detail. As the results of these studies are inconclusive, a proposal for a practical approach of the individual patient is formulated.     

A comparison of medical symptoms reported by cocaine‐, opiate‐, and alcohol‐dependent patients

Substance abuse is frequently associated with adverse medical consequences. The differences in medical symptoms reported by 101 alcohol‐, 113 cocaine‐, and 107 opiate‐dependent individuals receiving outpatient treatment were studied using a 134‐item questionnaire (MILCOM). Data analysis revealed interesting and unexpected findings, with cocaine patients reporting the fewest total symptoms among the three groups. Moreover, cocaine patients reported significantly fewer CNS and musculo‐skeletal symptoms compared to both alcohol and opiate patients and significantly fewer GI and urinary symptoms than the alcohol but not the opiate patients. In addition, there were sex‐ and race‐related differences in the pattern of symptoms reported. Women reported significantly more CVS, mood, nose/throat, CNS, skin, and GI symptoms than men. Similarly, Caucasians reported significantly more mood, CNS, nose/throat, head/neck, musculoskeletal, and GI symptoms than African‐Americans. The study highlights the influence of drug of choice, gender, and race on medical needs of substance‐abusing persons.     

Lyophilised liposome‐based formulations of α‐tocopheryl succinate: Preparation and physico‐chemical characterisation

α‐Tocopheryl succinate (α‐TOS) is a semisynthetic analogue of α‐tocopherol with selective toxicity to the cancer cells and anticancer activity in vivo. Yet, no suitable formulation of α‐TOS for medical application has been reported. Various formulations, for example, solutions in organic solvents, oil emulsions and vesicules prepared by spontaneous vesiculation, polyethylene glycol conjugates and liposomes of various compositions have been tested. We developed and characterised a stable lyophilised liposome‐based α‐TOS formulation. α‐TOS (15 mol%) was incorporated into large oligolamellar vesicles (OLVs) composed of soy phosphatidylcholine (SPC) by the method of lipid film hydration followed by extrusion through polycarbonate filters. Stabilised liposomal formulation was prepared by lyophilisation in the presence of sucrose (molar ratio lipid/sucrose, 1:5). The size distribution of the liposomes (130–140 nm, polydispersity index 0.14) as well as the stable lipid and α‐TOS contents were preserved during storage in the lyophilised form at 2–8°C for at least 6 months. The data indicate good physical and chemical stability of the lyophilised preparation of α‐TOS liposomes that can be used in clinical medicine. © 2009 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 2434–2443, 2010     

Pharmacokinetics of paracetamol and its metabolites in women at delivery and post‐partum

Aim

A recent report on intravenous (i.v.) paracetamol pharmacokinetics (PK) showed a higher total clearance in women at delivery compared with non‐pregnant women. To describe the paracetamol metabolic and elimination routes involved in this increase in clearance, we performed a population PK analysis in women at delivery and post‐partum in which the different pathways were considered.

Methods

Population PK parameters using non‐linear mixed effect modelling were estimated in a two‐period PK study in women to whom i.v. paracetamol (2 g loading dose followed by 1 g every 6 h up to 24 h) was administered immediately following Caesarean delivery and in a subgroup of the same women to whom single 2 g i.v.loading dose was administered 10–15 weeks post‐partum.

Results

Population PK analysis was performed based on 255 plasma and 71 urine samples collected in 39 women at delivery and in eight of these 39 women 12 weeks post‐partum. Total clearance was higher in women at delivery compared with 12th post‐partum week (21.1 vs. 11.7 l h⁻¹) due to higher clearances to paracetamol glucuronide (11.6 vs. 4.76 l h⁻¹), to oxidative metabolites (4.95 vs. 2.77 l h⁻¹) and of unchanged paracetamol (1.15 vs. 0.75 l h⁻¹). In contrast, there was no difference in clearance to paracetamol sulphate.

Conclusion

The increased total paracetamol clearance at delivery is caused by a disproportional increase in glucuronidation clearance and a proportional increase in clearance of unchanged paracetamol and in oxidation clearance, of which the latter may potentially limit further dose increase in this patient group.     

Texture Optimization of Water‐in‐Oil Emulsions

The aim of this research is to demonstrate the effect of variations in certain parameters of the oily phase (OP) in water‐in‐oil (W/O) emulsions on rheological and texture properties of finished products. The formulated emulsions were selected according to an optimal experimental procedure. The applied variations were nature of the OP, its volume fraction, the hydrophilic‐lipophilic balance (HLB) value, and the surfactant proportion. Results are presented for the followed tests carried out on the emulsions: texture analysis, rheology, and particle size analysis. The oils used in the study were sweet almond oil, liquid paraffin, maize oil, cyclomethicone, dimethicone, and wheat germ oil. The resulting data demonstrate a notable influence of the volume fraction oil on hardness, viscosity, adhesiveness, and cohesiveness of W/O emulsions. Emulsion hardness and viscosity increased as the OP percentage increased; this effect being even more pronounced for the vegetable oils. In contrast, emulsion adhesiveness and cohesiveness decreased as the volume fraction oil increased. The HLB value of the surfactant mixture of the emulsion also influenced hardness, adhesiveness, and elasticity, increasing or decreasing as HLB value did.     

Pro‐cognitive activity in rats of 3‐furan‐2‐yl‐N‐p‐tolyl‐acrylamide,a positive allosteric modulator of the α7 nicotinic acetylcholine receptor

Background and Purpose

α7 nicotinic acetylcholine receptors (α7 nAChRs) may represent useful targets for cognitive improvement. The aim of this study is to compare the pro‐cognitive activity of selective α7‐nAChR ligands, including the partial agonists, DMXBA and A‐582941, as well as the positive allosteric modulator, 3‐furan‐2‐yl‐N‐p‐tolyl‐acrylamide (PAM‐2).

Experimental Approach

The attentional set‐shifting task (ASST) and the novel object recognition task (NORT) in rats, were used to evaluate the pro‐cognitive activity of each ligand [i.e., PAM‐2 (0.5, 1.0, and 2.0 mg·kg⁻¹), DMXBA and A‐582941 (0.3 and 1.0 mg·kg⁻¹)], in the absence and presence of methyllycaconitine (MLA), a selective competitive antagonist. To determine potential drug interactions, an inactive dose of PAM‐2 (0.5 mg·kg⁻¹) was co‐injected with inactive doses of either agonist ‐ DMXBA: 0.1 (NORT); 0.3 mg·kg⁻¹ (ASST) or A‐582941: 0.1 mg·kg⁻¹.

Key Results

PAM‐2, DMXBA, and A‐582941 improved cognition in a MLA‐dependent manner, indicating that the observed activities are mediated by α7 nAChRs. Interestingly, the co‐injection of inactive doses of PAM‐2 and DMXBA or A‐582941 also improved cognition, suggesting drug interactions. Moreover, PAM‐2 reversed the scopolamine‐induced NORT deficit. The electrophysiological results also support the view that PAM‐2 potentiates the α7 nAChR currents elicited by a fixed concentration (3 μM) of DMXBA with apparent EC₅₀ = 34 ± 3 μM and E_max = 225 ± 5 %.

Conclusions and Implications

Our results support the view that α7 nAChRs are involved in cognition processes and that PAM‐2 is a novel promising candidate for the treatment of cognitive disorders.

Abbreviations

α7 nAChR

nicotinic acetylcholine receptor with α7 subunit

AD

Alzheimer''s disease

apparent EC₅₀

enhancement potency

ASST

attentional set‐shifting task

CD

compound discrimination

DI

discrimination index

E

exploration time

ED

extra‐dimensional

E_max

ligand efficacy

ID

intra‐dimensional

ITI

inter‐trial interval

MLA

methyllycaconitine

NORT

novel object recognition task

n_H

Hill coefficient

PAM

positive allosteric modulator

PAM‐2

3‐furan‐2‐yl‐N‐p‐tolyl‐acrylamide

Rev

reversal of discrimination

SD

simple discrimination

T1

familiarisation trial

T2

retention trial

     

Pharmacodynamics,pharmacokinetics and safety of GSK2190915, a novel oral anti‐inflammatory 5‐lipoxygenase‐activating protein inhibitor

Aim

To assess the pharmacokinetics, pharmacodynamics, safety and tolerability of the 5‐lipoxygenase‐activating protein inhibitor, GSK2190915, after oral dosing in two independent phase I studies, one in Western European and one in Japanese subjects, utilizing different formulations.

Method

Western European subjects received single (50–1000 mg) or multiple (10–450 mg) oral doses of GSK2190915 or placebo in a dose‐escalating manner. Japanese subjects received three of four GSK2190915 doses (10–200 mg) plus placebo once in a four period crossover design. Blood samples were collected for GSK2190915 concentrations and blood and urine were collected to measure leukotriene B₄ and leukotriene E₄, respectively, as pharmacodynamic markers of drug activity.

Results

There was no clear difference in adverse events between placebo and active drug‐treated subjects in either study. Maximum plasma concentrations of GSK2190915 and area under the curve increased in a dose‐related manner and mean half‐life values ranged from 16–34 h. Dose‐dependent inhibition of blood leukotriene B₄ production was observed and near complete inhibition of urinary leukotriene E₄ excretion was shown at all doses except the lowest dose. The EC₅₀ values for inhibition of LTB₄ were 85 nm and 89 nm in the Western European and Japanese studies, respectively.

Conclusion

GSK2190915 is well‐tolerated with pharmacokinetics and pharmacodynamics in Western European and Japanese subjects that support once daily dosing for 24 h inhibition of leukotrienes. Doses of ≥50 mg show near complete inhibition of urinary leukotriene E₄ at 24 h post‐dose, whereas doses of ≥150 mg are required for 24 h inhibition of blood LTB₄.     

APOM‐project: a first study of pharmacy organization and management

In 1994, a Ph.D.study started regarding pharmacy, organization and management (APOM) in the Netherlands. The APOMproject deals with the structuring and steering of pharmacy organization. This article describes a summary of the theoretical background of the project and the empirical results of a pilot study (n=24). No generalization to the population of pharmacies in the Netherlands was made. Three mixes of objectives in pharmacy organization were theoretically postulated; the product mix, the process mix, and the customer mix. Mainly, the purpose of the pilot study was method selection. Additionally, it was studied if thought and action of pharmacy managers corresponded, and, if theoretical pharmacy mixes corresponded with the empirical pharmacy mixes. Two methods were selected to be applied in a survey. Thought and action did not correspond for most pharmacy managers. Thought related to customer and product mainly, and action related to process and customer mainly.     

An Investigation into the Influence of Counterion on the RS‐Propranolol and S‐Propranolol Skin Permeability

The effects of two contra‐ions, namely benzoate (Bz) and oleate (Ol), on the in vitro human skin permeability of propranolol racemate (RS‐PR) or S‐enantiomer (S‐PR) were studied. Saline solution (SS) or mineral oil (MO) were selected as vehicles. The MO increased the permeability coefficient (K_p) of PR‐Bz (pK_p ≈ 4) of about four times with respect to SS (pK_p ≈ 8) probably due to the ion pair formation. The steady‐state flux of S‐enantiomers resulted about twofold higher than that of racemates according to their lower melting temperatures with the exception of (S)‐PR‐Ol and (RS)‐PR‐Ol vehicled in SS which not resulted statistically different. This anomalous result could be explained considering the behavior of (RS)‐PR‐Ol or (S)‐PR‐Ol in aqueous solutions: these salts formed ion pairs which associated to form aggregates up to a concentration of 20 µg/mL as verified by light scattering. Therefore, their effective concentrations in SS resulted similar and justified the overlapped skin permeation profiles. All three considered variables, namely counterion, vehicle, and chirality, resulted mutually interfering on and deeply influenced the passive diffusion process of PR. © 2009 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 1217–1224, 2010     

Stability and surface activity of lactate dehydrogenase in spray‐dried trehalose

The stability of the model protein lactate dehydrogenase (LDH) during spray‐drying and also on subsequent dry storage was examined. Trehalose was used as a carrier. The spray‐drying temperatures T_inlet and T_outlet have a measurable effect on LDH inactivation. Low T_inlet produced the least process inactivation, but gave a high residual moisture content making the protein's storage stability poor. High T_inlet reduced residual moisture and improved storage stability, but at the cost of high process inactivation. As already found for other systems, addition of a surfactant (in this case polysorbate 80) could ameliorate process inactivation of LDH at T_inlet = 150 °C. Surfactant had, however, a deleterious effect on storage stability of LDH, the vital factor being the molar ratio of surfactant/protein in the dried product. By using electron spectroscopy it was shown that LDH has a 10 times higher surface concentration in the dried trehalose particles than expected for a homogeneous distribution. Surface tension measurements at the water/air interface proved that LDH is surface active, although the Gibbs equation appeared to be inapplicable. Calculations of spray‐droplet formation time and drying time indicate than the extent of diffusion‐driven LDH adsorption to the liquid/air interface is sufficient to account for the measured amount of LDH inactivation during spray‐drying. The presence of 0.1% polysorbate 80 to the spray solution prevents LDH from appearing at the surface of the dried particles. As a negative control, the phosphatide Lipoid E 80 does not prevent the appearance of LDH in the surface according to electron spectroscopy and does not therefore prevent LDH inactivation during spray‐drying at T_inlet = 150 °C.     

Long‐term stability of morphine and bupivacaine mixture for spinal use

From clinical studies it has been proven that morphine in combination with bupivacaine is applicable in cancer pain. The availability of a ready to use parental dosage form of morphine and bupivacaine is comfortable for health care workers. Stability of a morphine or a bupivacaine preparation or a combination of both in a PVC cassette or polypropylene syringe for spinal use is examined in several studies. Apart from one study no data on longterm stability of morphinebupivacaine mixture is available. A forced degradation study and a shelflife study at room temperature (2025 °C) were started on morphine hydrochloride 0.2 mg/ml and bupivacaine hydrochloride 7.5 mg/ml in 50 ml sterilized glass bottles type II. The results of the stability study showed that this mixture was stable up to 18 months at room temperature, whereafter morphine showed a slight degradation (5 %) and bupivacaine remained stable.     

Solid‐State Characterization and Transformation of Various Creatine Phosphate Sodium Hydrates

Creatine phosphate sodium (CPS) salt is a first‐line cardiovascular drug for severe diastolic heart failure. The drug exists in different hydrate forms. The marketed drug form was determined as CPS·4.5H₂O (H1); however, the reference standard was supplied as CPS·6H₂O (H2). In this work, we present two newly identified hydrate forms: a thermodynamically stable low hydrate form, CPS·1.5H₂O (H3), and a pressure‐sensitive transit form, CPS·7H₂O (H4). The hydrate forms were discovered through a comprehensive solid‐state screening experiment and fully characterized using a range of analytical techniques including X‐ray powder diffraction (XRPD), FTIR, Raman spectroscopy, hot‐stage microscopy (HSM), thermogravimetric analysis, and differential scanning calorimetry. Stability tests revealed that H3 was the most stable hydrate under thermal stimulation. H4 is a pressure‐sensitive hydrate and easily transforms to H2 and then H1 upon grinding. The form transformation process was closely monitored using the HSM, variable‐temperature XRPD (VT‐XRPD), and VT‐Raman spectroscopy techniques. Specifically, the transformation of H4 to H1 is characterized in a single‐crystal‐to‐single‐crystal transformation process. The newly discovered hydrate form H3 has superior physicochemical properties than the marketed forms and is worthy of further development. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:3688–3695, 2014     

Neutrophil elastase induces inflammation and pain in mouse knee joints via activation of proteinase‐activated receptor‐2

Background and Purpose

Neutrophil elastase plays a crucial role in arthritis. Here, its potential in triggering joint inflammation and pain was assessed, and whether these effects were mediated by proteinase‐activated receptor‐2 (PAR2).

Experimental Approach

Neutrophil elastase (5 μg) was injected into the knee joints of mice and changes in blood perfusion, leukocyte kinetics and paw withdrawal threshold were assessed. Similar experiments were performed in animals pretreated with the neutrophil elastase inhibitor sivelestat, the PAR2 antagonist GB83, the p44/42 MAPK inhibitor U0126 and in PAR2 receptor knockout (KO) mice. Neutrophil elastase activity was also evaluated in arthritic joints by fluorescent imaging and sivelestat was assessed for anti‐inflammatory and analgesic properties.

Key Results

Intra‐articular injection of neutrophil elastase caused an increase in blood perfusion, leukocyte kinetics and a decrease in paw withdrawal threshold. Sivelestat treatment suppressed this effect. The PAR2 antagonist GB83 reversed neutrophil elastase‐induced synovitis and pain and these responses were also attenuated in PAR2 KO mice. The MAPK inhibitor U0126 also blocked neutrophil elastase‐induced inflammation and pain. Active neutrophil elastase was increased in acutely inflamed knees as shown by an activatable fluorescent probe. Sivelestat appeared to reduce neutrophil elastase activity, but had only a moderate anti‐inflammatory effect in this model.

Conclusions and Implications

Neutrophil elastase induced acute inflammation and pain in knee joints of mice. These changes are PAR2‐dependent and appear to involve activation of a p44/42 MAPK pathway. Blocking neutrophil elastase, PAR2 and p44/42 MAPK activity can reduce inflammation and pain, suggesting their utility as therapeutic targets.

Linked Articles

This article is part of a themed section on Inflammation: maladies, models, mechanisms and molecules. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2016.173.issue-4

Abbreviations

IVM

intravital microscopy

LASCA

laser speckle contrast analysis

PAR

proteinase‐activated receptor

TRPV

transient receptor potential vanilloid

VCAM

vascular cell adhesion molecule

Tables of Links

Formulation and in vitro/in vivo correlation of a drug‐in‐adhesive transdermal patch containing azasetron

The aim of the present study was to develop a transdermal drug delivery system for azasetron and evaluate the correlation between in vitro and in vivo release. The effects of different adhesives, permeation enhancers, and loadings of azasetron used in patches on the penetration of azasetron through rabbit skin were investigated using two‐chamber diffusion cells in vitro. For in vivo studies, azasetron pharmacokinetic parameters in Bama miniature pigs were determined according to a noncompartment model method after topical application of transdermal patches and intravenous administration of azasetron injections. The best permeation profile was obtained with the formulation containing DURO‐TAK 87‐9301 as adhesive, 5% of isopropyl myristate as penetration enhancer, and 5% of azasetron. The optimal patch formulation exhibited sustained release profiles in vivo for 216 h. The in vivo absorption curve in Bama miniature pigs obtained by deconvolution approach using WinNonlin® program was correlated well with the in vitro permeation curve of the azasetron patch. These findings indicated that the developed patch for azasetron is promising for the treatment of delayed chemotherapy‐induced nausea and vomiting, and the in vitro skin permeation experiments could be useful to predict the in vivo performance of transdermal azasetron patches. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:4540–4548, 2012     

Beating the odds: efficacy and toxicity of dihydropyrimidine dehydrogenase‐driven adaptive dosing of 5‐FU in patients with digestive cancer

Aims

5‐FU is the backbone of most regimens in digestive oncology. Administration of standard 5‐FU leads to 15–30% of severe side effects, and lethal toxicities are regularly reported with fluoropyrimidine drugs. Dihydropyrimidine dehydrogenase (DPD) deficiency is a pharmacogenetic syndrome responsible for most cases of life‐threatening toxicities upon 5‐FU intake, and pre‐treatment checking for DPD status should help to reduce both incidence and severity of side effects through adaptive dosing strategies.

Methods

We have used a simple method for rapidly establishing the DPD phenotype of patients with cancer and used it prospectively in 59 routine patients treated with 5‐FU‐based therapy for digestive cancers. No patient with total DPD deficiency was found but 23% of patients exhibited poor metabolizer phenotype, and one patient was phenotyped as profoundly deficient. Consequently, 5‐FU doses in poor metabolizer patients were cut by an average 35% as compared with non deficient patients (2390 ± 1225 mg vs. 3653 ± 1371 mg, P < 0.003, t‐test).

Results

Despite this marked reduction in 5‐FU dosing, similar efficacy was achieved in the two subsets (clinical benefit: 40 vs. 43%, stable disease: 40 vs. 37%, progressive disease: 20% in both subsets, P = 0.893, Pearson''s chi‐square). No difference in toxicities was observed (P = 0.104, Fisher''s exact test). Overall, only 3% of early severe toxicities were recorded, a value markedly lower than the 15‐30% ones usually reported with 5‐FU.

Conclusions

This feasibility study shows how simplified DPD‐based adaptive dosing of 5‐FU can reduce sharply the incidence of treatment‐related severe toxicities while maintaining efficacy as part of routine clinical practice in digestive oncology.