Stability of Bortezomib 2.5 mg/mL in Vials and Syringes Stored at 4°C and Room Temperature (23°C)

Background:

Solutions of bortezomib 1.0 mg/mL for IV administration are reportedly stable for up to 42 days. Recent publications have reported that the safety profile of bortezomib is better with subcutaneous administration than with IV administration.

Objective:

To evaluate the stability of higher-concentration bortezomib solutions for subcutaneous administration (i.e., 2.5 mg/mL in 0.9% sodium chloride [normal saline or NS]).

Methods:

On study day 0, twelve 3.5-mg vials of powdered bortezomib were each reconstituted with 1.4 mL of NS to prepare solutions with concentration 2.5 mg/mL. Half of the solutions were subsequently stored in the original vials and half were transferred to syringes. Three of each type of container were stored in the refrigerator (4°C) and the other 3 of each type were stored at room temperature (23°C). Concentration analysis and physical inspection were completed on study days 0, 1, 2, 8, 12, 14, 19, and 21. The concentration of bortezomib was determined by a validated liquid chromatographic method with ultraviolet detection. The expiry date was determined according to the time to achieve 90% of the initial concentration, based on the fastest degradation rate calculated from the 95% confidence interval of the observed degradation rate.

Results:

The analytical method separated degradation products from bortezomib such that the concentration was measured specifically and accurately (with absolute deviations from known concentration averaging 2.99%), with intraday and interday reproducibility averaging 1.51% and 2.51%, respectively. During the study period, all solutions were observed to retain at least 95.26% of the initial concentration in both types of containers at both temperatures.

Conclusions:

Bortezomib (3.5 mg in manufacturer’s vial) reconstituted with 1.4 mL NS is physically and chemically stable for up to 21 days at 4°C or 23°C when stored in either the manufacturer’s original glass vial or a syringe. Subcutaneous injection of bortezomib represents a change in practice, and there is a potential safety concern if a solution of the increased concentration used for subcutaneous administration (2.5 mg/mL) is inadvertently used to prepare a dose intended for IV administration. Therefore, it is recommended that sites switching to subcutaneous administration of bortezomib eliminate 1.0 mg/mL IV solutions altogether or institute substantial barriers to prevent IV administration of the higher concentration of bortezomib.     

Stability of Dabigatran Etexilate in Manufacturer’s Blister Pack,Unit-Dose Packaging,and Community Pharmacy Blister Pack

Background:Dabigatran, a direct thrombin inhibitor, is indicated for the prevention and treatment of venous thromboembolism and for stroke prophylaxis in atrial fibrillation. The manufacturer recommends that dabigatran etexilate be retained in the original packaging until administration. Currently, no information exists about the stability of dabigatran etexilate outside its original packaging.Objective:To evaluate the stability of dabigatran etexilate capsules over 120 days, with storage in the manufacturer’s original packaging, in unit-dose packaging, and in community pharmacy blister packaging.Methods:Commercially available dabigatran etexilate capsules (110 mg) were stored at room temperature (25°C) in the manufacturer’s original blister pack, in unit-dose packaging, or in community pharmacy blister packs. Samples were collected from each container daily for the first 3 days, weekly up to 28 days, every other week until day 98, and at day 120. Suspensions were prepared, pH was evaluated, and samples were stored at −85°C until analysis. Each sample was analyzed in duplicate by a validated, stability-indicating high-performance liquid chromatography – ultraviolet detection method. The capsules were considered stable if they maintained at least 90% of the initial concentration.Results:Dabigatran etexilate capsules maintained 100.4% of the original concentration with 120 days of storage in the manufacturer’s original blister pack, 98.7% with storage in unit-dose packaging, and 98.0% with storage in community pharmacy blister packs. There were no notable changes in appearance, ease of suspension of the capsule content, or pH over the 120-day period.Conclusion:Dabigatran etexilate 110-mg capsules were stable for 120 days with storage at room temperature in 3 types of packaging widely used in hospital and community settings.     

Extended stability of pantoprazole for injection in 0.9% sodium chloride or 5% dextrose at 4°c and 23°c

Background:

The pantoprazole product available in Canada for IV administration has recently been reformulated to include ethylenediaminetetra-acetic acid (EDTA). The purpose of this study was to determine if the chemical stability of pantoprazole for injection containing EDTA (PANTO IV), admixed in polyvinyl chloride (PVC) minibags at concentrations of 0.16 mg/mL and 0.80 mg/mL in 5% dextrose in water (D5W) or 0.9% sodium chloride for injection (normal saline [NS]) and stored at 4°C or 23°C, could be extended beyond the manufacturer’s expiry period of 24 hours.

Methods:

Sodium pantoprazole was reconstituted in NS or D5W, and 32 PVC minibags were prepared, 16 containing pantoprazole at a nominal concentration of 0.16 mg/mL (8 in NS, 8 in D5W) and 16 containing pantoprazole at a nominal concentration of 0.80 mg/mL (8 in NS, 8 in D5W). Half of the minibags for each diluent–concentration combination were stored at 4°C and half at room temperature (23°C). The concentration of pantoprazole in each minibag was determined by a validated, stability-indicating liquid chromatographic method on study days 0, 1, 2, 4, 7, 9, 11, 14, and 21.

Results:

Analysis of variance revealed differences in the percentage of drug remaining in relation to temperature (p < 0.001), study day (p = 0.001), concentration (p = 0.007), and diluent (p = 0.008).

Conclusions:

Solutions of pantoprazole in D5W with concentration between 0.16 mg/mL and 0.80 mg/mL can be stored for a maximum of 11 days at 4°C plus an additional 6 h at 23°C. The saline solutions degraded more slowly, and pantoprazole admixtures in NS with concentration between 0.16 mg/mL and 0.80 mg/mL can be stored for 20 days at 4°C plus an additional 6 h at 23°C. Under these conditions, more than 90% of the initial concentration will remain (with 95% confidence).     

Stability of solutions of doxorubicin and epirubicin in plastic minibags for intravesical use after storage at −20° C and thawing by microwave radiation

Doxorubicin and epirubicin solutions in plastic minibags for intravesical use were stored at ?20° C and thawed at room temperature or by microwave radiation. Concentrations were measured with HPLC and TLC. Doxorubicin and epirubicin solutions could be frozen and stored at ?20° C during at least two and four weeks, respectively, and subsequently thawed without loss of content. When the thawed doxorubicin solutions were refrozen and thawed again five weeks later, only a slight decrease of content was measured.     

Effect of metabolic syndrome and thyroid hormone on efficacy of desvenlafaxine 50 and 100 mg/d in major depressive disorder

Objective This pooled, post hoc analysis evaluated the efficacy of desvenlafaxine vs placebo in adults with major depressive disorder (MDD) with and without metabolic syndrome, and above or at or below median baseline thyroid-stimulating hormone (TSH) levels.

Research design and methods Patients were randomly assigned to receive desvenlafaxine 50 or 100 mg/d or placebo in nine short-term, double-blind studies. Metabolic syndrome was defined as meeting at least three of five criteria based on body mass index, triglycerides, high-density lipoprotein, fasting glucose, blood pressure, current medication, and medical history.

Clinical trial registration NCT00072774; NCT00277823; NCT00300378; NCT00384033; NCT00798707; NCT00863798; NCT01121484; NCT00824291; NCT01432457

Main outcome measures Treatment effects on change from baseline in 17-item Hamilton Rating Scale for Depression (HAM-D₁₇) total score at week 8 (last observation carried forward [LOCF]) were analyzed in four subgroups—metabolic syndrome and no metabolic syndrome, baseline TSH levels above median or at or below median—using analysis of covariance with treatment, study, and baseline in the model. Metabolic syndrome and TSH were examined as predictors of change in HAM-D₁₇ total score using regression analysis.

Results The pooled analysis included 4279 patients; 971 (22.7%) patients had metabolic syndrome. In all subgroups, HAM-D₁₇ total scores improved significantly from baseline to week 8 (LOCF) with desvenlafaxine 50 or 100 mg/d compared with placebo (all p?≤?0.006). There was no significant treatment by metabolic syndrome or by TSH interaction. Neither metabolic syndrome nor TSH above median predicted change in HAM-D₁₇ total scores, response (≥50% reduction in HAM-D₁₇ total score), or remission (HAM-D₁₇ total score?≤7; all p?>?0.05).

Limitations Individual studies included in this analysis were not designed to examine the relationship between metabolic syndrome or TSH and response to desvenlafaxine treatment. Metabolic syndrome status was determined post hoc based on available baseline measures and not diagnosed at study entry. Exclusion criteria were selected to enroll medically healthy patients with a primary diagnosis of MDD (i.e., patients healthier than the general MDD population).

Conclusions Desvenlafaxine 50 and 100?mg/d significantly improved depression compared with placebo in patients with and without metabolic syndrome, and in patients with baseline TSH above median and at or below median levels.     

Mercury levels of Nelson’s and saltmarsh sparrows at wintering grounds in Virginia,USA

Nelson’s and saltmarsh sparrows (Ammodramus nelsoni and A. caudacutus) have recently been recognized as separate species, and because of their limited distributions and the susceptibility of their wetland habitats to climate change, these two new species are of conservation concern. Both species are known to bioaccumulate mercury at breeding sites in New England, USA where their ranges overlap, with the saltmarsh sparrow reported to have twice the concentration of blood total mercury. In this study we sampled both species on their shared wintering grounds, and documented that mercury exposure is lower than that reported for the breeding range, with saltmarsh sparrow blood mercury 2.6 times higher than in Nelson’s sparrow. Feather mercury, which is incorporated on the breeding grounds, confirmed that saltmarsh sparrows had incorporated 2.3 times more mercury than Nelson’s sparrows during the previous breeding season. A comparison of stable isotopes of nitrogen and carbon suggests that the higher exposure of saltmarsh sparrows may be not due to feeding at a higher trophic level, as previously hypothesized, but rather could be related to a difference in the carbon source at the base of each species’ food chain. This study, along with recently published data from both species on additional breeding and wintering grounds, provides a more complete picture of relative mercury exposure. Saltmarsh sparrows are exposed to mercury levels that warrant concern, with the highest exposure being during the breeding season. Areas set aside for the long-term conservation of this species should be carefully assessed for mercury bioaccumulation.     

Solubility prediction of clonazepam in aqueous mixtures of ethanol,polyethylene glycol 200 and propylene glycol at 30 °C

Solubility of clonazepam in aqueous binary mixtures of ethanol, polyethylene glycol 200 and propylene glycol was determined at 30 °C using the shake flask method. The maximum solubility of clonazepam was observed at volume fraction of 0.90 of ethanol, whereas for aqueous mixtures of polyethylene glycol 200 and propylene glycol, the maximum values were observed in the neat cosolvents. The generated data was fitted to the Jouyban-Acree model and its constants were computed, then the back-calculated solubilities were compared with the corresponding experimental values by calculating the mean percentage deviation (MPD) in which the overall MPD for three cosolvent systems was 7.0 %. The solubility data in cosolvent + water mixtures was predicted using previously trained versions of the Jouyban-Acree model and the prediction MPDs were 13.4, 54.2 and 24.9 %, respectively for ethanol, polyethylene glycol 200 and propylene glycol mixtures and the overall MPD was 30.8 %.     

A trial of levofloxacin 750 mg once daily for 5 days versus ciprofloxacin 400 mg and/or 500 mg twice daily for 10 days in the treatment of acute pyelonephritis

ABSTRACT

Objective: A double-blind, noninferiority trial was conducted to establish the safety and efficacy of a once-daily, 5-day course of levofloxacin 750?mg compared to a twice-daily, 10-day course of ciprofloxacin in complicated urinary tract infections (cUTI) and acute pyelonephritis (AP). This report focuses on subjects with AP.

Research design and methods: Adult male and female subjects with clinical signs and symptoms of AP and laboratory confirmation of their diagnosis were randomized to receive one dose of levofloxacin 750?mg once daily intravenously (IV) or orally and one dose of placebo for 5 days, followed by placebo; or ciprofloxacin 400?mg IV and/or 500?mg orally twice daily for 10 days.

Main outcome measures: The primary, prospectively defined end point was microbiologic eradication at post-therapy (study days 15–22). Secondary outcomes included clinical response and safety and tolerability.

Results: In the modified intent-to-treat (mITT) population (levofloxacin 94, ciprofloxacin 98), 83% of levofloxacin-treated and 79.6% of ciprofloxacin-treated subjects achieved microbiological eradication (difference –3.4, 95% CI –14.4%, 7.6%). In the microbiologically evaluable (ME) population (levofloxacin 80, ciprofloxacin 76), 92.5% of levofloxacin-treated vs. 93.4% of ciprofloxacin-treated subjects (difference –0.9, 95% CI –7.1%, 8.9%) achieved microbiologic eradication. Clinical success was achieved in 86.2% vs. 80.6% (mITT) and in 92.5% vs. 89.5% (ME) of levofloxacin-treated and ciprofloxacin-treated subjects, respectively. Escherichia coli was the most commonly isolated uropathogen. Few (2.1%) of the pathogens were fluoroquinolone-resistant. Adverse events (AEs) were similar to those seen previously with both agents. Potential limitations are that this analysis is based on a subset of subjects from a larger study and, because of different durations of therapy, the results may be biased against levofloxacin.

Conclusions: High-dose, short-course therapy with levofloxacin in subjects with AP is at least as effective as standard 10-day therapy with ciprofloxacin.     

Efficacy of etoricoxib 60 mg/day and diclofenac 150 mg/day in reduction of pain and disability in patients with chronic low back pain: results of a 4‐week,multinational, randomized,double-blind study

ABSTRACT

Background and methods: The efficacy and safety of etoricoxib 60?mg/day in patients with established chronic low back pain (CLBP) were compared with those of diclofenac 150?mg/day in a 4‐week, multicentre, randomized, double-blind, parallel-group trial. Four hundred and forty-six adult patients with CLBP (Quebec Task Force on Spinal Disorders Class 1 or 2) and with worsening pain upon discontinuation of pre-study analgesic medication were enrolled in the study.

The study primary efficacy endpoint was change from baseline in Low Back Pain Intensity Scale (LBP‐IS) score over the 4‐week treatment period. Secondary and other efficacy endpoints included: changes in Roland and Morris Disability Questionnaire (RMDQ), Patient Global Assessment of Response to Therapy (PGART) and Low Back Pain Bothersomeness Scale (LBP-BS) scores. Early efficacy was assessed using PGART and LBP‐IS scores 4?h after the first dose on the mornings of Days 1, 2 and 3. The overall safety and tolerability of etoricoxib 60?mg/day during 4 weeks of treatment were also assessed.

Results: The least-squares mean time-weighted change from baseline LBP‐IS score over 4 weeks was –32.94?mm (95% CI –36.25, –29.63) for etoricoxib, indicating substantial efficacy in relief of pain. The treatment difference for the primary outcome was 2.51?mm (95% CI –1.50, 6.51), fulfilling the prespecified equivalence criterion of 95% confidence interval wholly within ± 10?mm. Etoricoxib improved all secondary and other efficacy outcomes.

There were no statistically significant between-group differences in the proportion of patients with one or more clinical adverse events (AEs) (etoricoxib 35%, diclofenac 39%), or the proportion of patients who discontinued due to AEs (etoricoxib 7%, diclofenac 5%).

Conclusions: The results of this study confirm that, for adult patients with CLBP, etoricoxib 60?mg once daily over 4 weeks is effective for relief of pain and improvement of physical function and comparable to high-dose diclofenac 150?mg daily.     

Physico-chemical analysis of several injectable drug in ready-to-use infusion after microwave freeze-thaw treatment and final storage at 5 ± 3 °C

Objective

In hospitals, the majority of the reconstitution of injectable drugs are carried out right before the administration to the patient by the nursing staff. The risks and errors related on their preparation and administration are numerous. The standardization, the centralization of these preparations and reconstitution by the hospital pharmacy make it possible to reduce the various risks and errors To enhance the number of drugs taken in charge, it is necessary to develop the long-term stability of ready-to-use drugs. Freezing seems an easy method but defrosting takes too much time. Some authors develop the concept of microwave treatment and apply this to different drugs. A characteristic of these studies was nevertheless the short period of study after thawing.

Methods

Long-term stability studies were started for different drugs mainly used in the hospital, and verify their stability after freezing at temperature < − 25 °C, long-term storage (1 to 4 months), microwave-thawing and long-term storage at 5 ± 3 °C.

Results

Sixteen molecules were tested and preserve more than 90% of their initial concentration the day of defrosting by microwave oven like this value a certain number of days at 5 ± 3 °C. All the analyses were carried out by HPLC.

Conclusion

The microwave freeze/thawing treatment allows the production of more important batches, makes profit of this technique in workload and material beyond a certain produced quantity. The described results encourage to check the possibilities of taking in charge other molecules regularly used in the Hospital Institutions.     

Long-term stability of temocillin in dextrose 5% and in sodium chloride 0.9% polyolefin bags at 5 ± 3°C after freeze-thaw treatment

Introduction

The aim of this study was to investigate the stability of a mixture of temocillin 20 mg/ml in 5% dextrose and in 0.9% sodium chloride polyolefin bags after freezing, microwave thawing and long-term storage at 5 ± 3 °C.

Methods

The stability of ten polyolefin bags containing 20 mg/ml of temocillin, five bags in 5% dextrose and five bags in 0.9% sodium chloride, prepared under aseptic conditions was studied after freezing for 1 month at –20 °C, thawing in a microwave oven with a validated cycle, and stored at 5 ± 3 °C. Over 30 days, temocillin concentrations were measured by high-pressure liquid chromatography. Visual inspections, microscope observation, spectrophotometric measurements and pH measurements were also performed.

Results and discussion

No precipitation occurred in the preparations but minor colour change was observed. No microaggregate was observed with optical microscopy or revealed by a change of absorbance. Based on a shelf life of 95% residual potency, temocillin infusions were stable at least 11 days in 5% dextrose and 14 days in 0.9% sodium chloride after freezing and microwave thawing (corresponding at the period where 95% lower confidence limit of the concentration-time profile remained superior to 95% of the initial concentration). During this period, the pH values of drug solutions have been observed to decrease without affecting chromatographic parameters.

Conclusion

Within these limits, temocillin in 5% dextrose and in 0.9% sodium chloride infusions may be prepared and frozen in advance by a centralized intravenous admixture service then thawed before use in clinical units.     

Non-oral drug delivery in Parkinson’s disease: a summary from the symposium at the 7th International Congress of Parkinson’s Disease and Movement Disorders

This symposium reviewed the issues of non-oral therapy in the late stage Parkinson’s disease (PD). The accepted standard treatment of PD is oral levodopa or oral dopamine agonists. However, the long-term complications and limitations of this treatment might be improved by changing therapy from the present pulsatile stimulation to a more constant stimulation of central dopamine receptors. Stimulation of these receptors may be possible with non-oral drug delivery treatments. Many of these non-oral options have been evaluated during the last few decades to find a more continuous drug delivery. The non-oral treatment options include invasive measures such as intraduodenal levodopa, subcutaneous apomorphin and most recently, the non-invasive transdermal (patch) delivery system, with the novel dopamine agonist rotigotine (Aderis Pharmaceuticals Inc.). The benefits of the non-oral, more continuous dopaminergic treatment of PD needs to be demonstrated in clinical trials and long-term clinical practice, before they can be considered as potential replacements of the standard oral therapy.     

Investigational drugs in phase I and phase II clinical trials targeting interleukin 23 (IL23) for the treatment of Crohn’s disease

Introduction: Medical therapy for Crohn’s disease (CD) is directed at controlling intestinal inflammation to prevent development of disease-related complications. Not all patients will respond to currently available treatments and thus, novel therapies are needed. The interleukin (IL)-23 cytokine axis is implicated in CD pathogenesis and so targeting this pathway has become an important focus for drug development.

Areas covered: This review summarizes the role of the IL23 cytokine pathway in CD pathogenesis and appraises phase I and II clinical trial data for novel IL23p19 specific monoclonal antibodies for the treatment of CD. The evidence for risankizumab (BI655066/ABBV066), brazikumab (MEDI2070, formerly AMG139), guselkumab (CNTO1959), tildrakizumab (MK3222), and mirikizumab (LY3074828) is reviewed; moreover, future applications for these agents are considered.

Expert opinion: Targeting the specific p19 subunit of IL23 is a promising strategy in CD. Two multicenter, randomized, placebo-controlled phase II clinical trials have evaluated risankizumab and brazikumab. Both studies indicate that IL23-specific blockade is likely to be a safe and effective alternative to current biologics, including the TNF antagonists vedolizumab and ustekinumab. Confirmatory Phase 3 studies are underway. Ultimately, comparative effectiveness trials will be necessary to define the role of IL23-specific antagonists in CD treatment algorithms.     

Social and environmental influences on opioid sensitivity in rats: importance of an opioid’s relative efficacy at the mu-receptor

Rationale Evidence indicates that social and environmental enrichment can influence the functional maturation of the central nervous system and may affect an organism’s sensitivity to centrally acting drugs. Objective The purpose of the present study was to examine the effects of social and environmental enrichment on sensitivity to mu-opioids possessing a range of relative efficacies at the mu-receptor. Methods Rats were obtained at weaning (21 days) and divided into two groups immediately upon arrival. Isolated rats were housed individually in opaque laboratory cages with no visual or tactile contact with other rats; enriched rats were housed socially in groups of four in large cages and given various novel objects on a daily basis. After 6 weeks under these conditions, the effects of morphine, levorphanol, buprenorphine, butorphanol, and nalbuphine were examined in the warm-water, tail-withdrawal procedure and the place-conditioning procedure. Results In the tail-withdrawal procedure, isolated and enriched rats did not differ in sensitivity to morphine (1.0–30 mg/kg) and levorphanol (0.3–10 mg/kg), but enriched rats were more sensitive to buprenorphine (0.03–3.0 mg/kg), butorphanol (0.3–30 mg/kg), and nalbuphine (0.3–30 mg/kg). In drug combination tests, butorphanol and nalbuphine antagonized the effects of morphine in isolated rats under conditions in which they produced high levels of antinociception in enriched rats. In the place-conditioning procedure, doses of 10 morphine and 3.0 levorphanol established a place preference in both groups of rats, whereas doses of 0.3 buprenorphine, 3.0 butorphanol, and 10 nalbuphine established a place preference only in enriched rats. Conclusions These findings may be taken as evidence that enriched rats are more sensitive than isolated rats to the effects of lower-efficacy mu-opioids and that social and environmental enrichment leads to functional alterations in opioid receptor populations.     

What’s in a Name? Correlates of Ecstasy Users Knowing or Agreeing that Molly is Ecstasy/MDMA

Ecstasy (MDMA) has regained popularity in powder and crystalline form, known as Molly. However, it is unknown whether all Molly users are aware that Molly is ecstasy. A total of 1045 nightclub/festival-attending adults in New York City were surveyed about ecstasy/MDMA/Molly use in 2016. Users were asked if they agreed that “Molly is (or is supposed to be) ecstasy/MDMA.” Of the 43.5% reporting lifetime use, 84.6% agreed that Molly is ecstasy, 9.5% disagreed, and 5.9% reported not knowing that Molly is ecstasy. Prevalence of use of other drugs (e.g., ketamine, opioids, methamphetamine, NBOMe, 2C series) was lowest among those not knowing that Molly is ecstasy, and highest among those not agreeing that Molly is ecstasy. Those not knowing that Molly is ecstasy were less likely to have used powder or crystal MDMA and less likely to have used in the past 12 months or to report intention to use again. Those disagreeing or not knowing that Molly is ecstasy were at over six times the odds of obtaining ecstasy from an unknown dealer, and those disagreeing were at four times higher odds of having suspected or found out that their ecstasy was adulterated. Results suggest that knowing or agreeing that Molly is ecstasy/MDMA can help indicate ecstasy-related risk.     

CD4+ Regulatory and Effector/Memory T Cell Subsets Profile Motor Dysfunction in Parkinson’s Disease

Animal models and clinical studies have linked the innate and adaptive immune system to the pathology of Parkinson’s disease (PD). Despite such progress, the specific immune responses that influence disease progression have eluded investigators. Herein, we assessed relationships between T cell phenotype and function with PD progression. Peripheral blood lymphocytes from two separate cohorts, a discovery cohort and a validation cohort, totaling 113 PD patients and 96 age- and environment-matched caregivers were examined by flow cytometric analysis and T cell proliferation assays. Increased effector/memory T cells (Tem), defined as CD45RO+ and FAS+ CD4+ T cells and decreased CD31+ and α4β7+ CD4+ T cells were associated with progressive Unified Parkinson’s Disease Rating Scale III scores. However, no associations were seen between immune biomarkers and increased age or disease duration. Impaired abilities of regulatory T cells (Treg) from PD patients to suppress effector T cell function was observed. These data support the concept that chronic immune stimulation, notably Tem activation and Treg dysfunction is linked to PD pathobiology and disease severity, but not disease duration. The association of T cell phenotypes with motor symptoms provides fresh avenues for novel biomarkers and therapeutic designs.

     

Novel anti-arthritic mechanisms of trans-cinnamaldehyde against complete Freund’s adjuvant-induced arthritis in mice: involvement of NF-кB/TNF-α and IL-6/IL-23/ IL-17 pathways in the immuno-inflammatory responses

Inflammopharmacology - Trans-cinnamaldehyde (TCA), a natural cinnamaldehyde derivative of cinnamon oil, is known for anti-inflammatory, anti-bacterial, anti-fungal, anti-diabetic, and anti-cancer...     

Variability in PXR-mediated induction of CYP3A4 by commercial preparations and dry extracts of St. John’s wort

St. John’s wort (SJW, Hypericum perforatum) is a well-tolerated herbal medicine widely used for the treatment of mild and moderate depressions. In the last 5 years, SJW has been implicated in drug interactions, which are largely mediated by the induction of the drug metabolizing enzymes, especially CYP3A4. There is still some controversy regarding the exact mechanism of induction and the identity of the SJW constituents involved. We investigated in LS174T cells the induction of CYP3A4 by ten SJW extracts, six commercial preparations, and the purified SJW constituent hyperforin. The content of hyperforin among the commercial preparations of SJW varied 62-fold (range 0.49–30.57 mg/dose). The CYP3A4 induction was mediated by PXR, but not by CAR. The magnitude of the induction correlated statistically significantly with the content of hyperforin in commercial SJW preparations (R = 0.87, p = 0.004) and in dry extracts (R = 0.65, p = 0.03), but not with their content of flavonoids or hypericin. Most of the CYP3A4 induction response occurred in the hyperforin range encountered in the blood of patients treated with SJW preparations. A temperature-induced decrease in the hyperforin content of a selected dry SJW extract abolished the induction of CYP3A4. In conclusion, commercial SJW preparations still exhibit an enormous variability in CYP3A4 induction, which is mediated by hyperforin and PXR. SJW preparations with lower hyperforin content should reduce the frequency of clinical interactions involving this herbal drug. This work was partly funded by the Deutsche Forschungsgemeinschaft (DFG) grant WO505/2-2.