Pharmacokinetic interaction of garlic and atorvastatin in dyslipidemic rats

Objective:

To assess pharmacokinetic interaction of garlic with atorvastatin in dyslipidemic rats.

Materials and Methods:

Sprague Dawley rats with induced dyslipidemia were divided into five groups of eight rats each. Group 1 was given atorvastatin (10 mg/kg body weight (b.wt) orally), group 2 was given atorvastatin (10 mg/kg b.wt orally)+garlic (1% w/w in feed), group 3 was maintained on atorvastatin (5 mg/kg b.wt orally)+garlic (0.5% w/w in feed), group 4 was maintained on atorvastatin (7.5 mg/kg b.wt orally)+garlic (0.25% w/w in feed), and group 5 was maintained on atorvastatin (2.5 mg/kg b.wt orally)+garlic (0.75% w/w in feed) for 12 weeks. Blood samples were collected at predetermined time intervals for kinetic analysis after the first and last oral dosing of atorvastatin for single and multiple dose studies, respectively. Plasma samples were assayed for atorvastatin concentration by High-Performance Liquid Chromatography (HPLC) and then the concentration-time data were analyzed.

Results:

Maximum observed plasma concentration (C_max), half-life, Area Under Plasma Concentration Time Curve (AUC), and Mean Resident Time (MRT) were significantly (P<0.05) increased during multiple dose kinetic study and elimination rate constant was significantly (P<0.05) decreased in comparison with their respective single-dose values, while there was no significant difference in time to achieve maximum concentration (t_max) in all groups during both phases of the study. The highest values for kinetic parameters were observed in group 2 with correspondingly low activity of Cytochrome P₄₅₀ (CYP₄₅₀).

Conclusion:

The study revealed higher values [C_max, AUC, Area Under The Moment Curve (AUMC), MRT, and half-life] of atorvastatin in garlic-treated groups.KEY WORDS: Atorvastatin, garlic, pharmacokinetics     

Does progression through the stages of physical addiction indicate increasing overall addiction to tobacco?

Rationale  

With physical addiction to tobacco, abstinence triggers a desire to smoke. As physical addiction advances, the desire to smoke changes in quality and intensity from wanting, to craving, to needing. A prior study in adolescents suggested that this progression signifies increasing addiction.     

Impact of CYP2D6 polymorphisms on the pharmacokinetics of lovastatin in Chinese subjects

Purpose

Although CYP3A4/5 enzymes play the predominant role in the metabolism of simvastatin and lovastatin, polymorphisms in CYP2D6 were reported to be associated with the cholesterol-lowering effect and/or tolerability of simvastatin. This study was performed to examine whether common CYP2D6 polymorphisms affect the pharmacokinetics of lovastatin, which is taken as the inactive prodrug lovastatin lactone and converted to active lovastatin acid.

Methods

A single-dose pharmacokinetic study was performed with lovastatin in 23 Chinese healthy male subjects. Plasma concentrations of lovastatin lactone and acid were determined by an LC-MS-MS method in samples collected over 24?h after single oral doses of 40-mg lovastatin.

Results

Compared with the CYP2D6 wt/wt group, the area under the plasma concentration–time curve (AUC_0-∞) values for lovastatin lactone increased (P?wt/*10, *10/*10, *10/*5, and *5/*5 groups, and the values of lovastatin lactone plasma clearance (CL/F) were reduced on average (95% CI) by 40.4% (10.2–60.5%), 53.1% (29.3–68.9%), 63.8% (40.2–78.1%) and 84.2% (72.1–91.1%) in these genotype groups respectively. The pharmacokinetics of lovastatin acid did not differ among the genotype groups.

Conclusion

This study demonstrates that CYP2D6 polymorphisms appeared to influence the disposition of lovastatin lactone in these subjects.     

Effects of paroxetine on emotional functioning and treatment awareness: a 4-week randomized placebo-controlled study in healthy clinicians

Objective  

The objective of our study was to evaluate the effects of paroxetine on emotional functioning in three arms: double-blind paroxetine (DBPX), single-blind paroxetine (SBPX), and double-blind placebo (DBPO). Healthy psychologists and psychiatrists were elected for their ability to analyze with correct sensibility changes in their emotions.     

Photolysis of Recombinant Human Insulin in the Solid State: Formation of a Dithiohemiacetal Product at the C-Terminal Disulfide Bond

Purpose  

Exposure of protein pharmaceuticals to light can result in chemical and physical modifications, potentially leading to loss of potency, aggregation, and/or immunogenicity. To correlate these potential consequences with molecular changes, the nature of photoproducts and their mechanisms of formation must be characterized. The present study focuses on the photochemical degradation of insulin in the solid state.     

Pharmacokinetics and biological activity of 2,3,7,8-tetrachlorodibenzo-p-dioxin

Concentrations of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in rat liver and adipose tissue, and hepatic ethoxyresorufin O-deethylase (EROD) activity were studied subsequent to a single subcutaneous injection of TCDD. Two types of experiments were performed to study: (a) time-dependent changes following a single injection of 300 ng TCDD/kg body wt (points 1-4), and (b) dose-dependent changes measurable after 7 days following a single injection (points 5-7). 1. Absorption of TCDD following a single subcutaneous injection was about 90% after 3 days and 98% after 5 days. 2. Following a single dose of 300 ng TCDD/kg body wt peak concentrations were: liver (after 3 days): 4.7 +/- 0.9 ng/g wet wt, and adipose tissue (after 7 days): 0.82 +/- 0.07 ng/g wet wt. 3. T1/2 of TCDD in liver was 13.6 days over the total experimental period (from day 10 to 91 of the study), apparently with an initial faster phase: 11.5 days (from day 10 to 49), and a slower period at the end of the experiment: 16.9 days (from day 49 to 91); in adipose tissue the t1/2 was 24.5 days (from day 14 to 91 of the study). 4. Maximum induction of EROD in the liver was observed (14-fold at 300 ng TCDD/kg body wt) 3-7 days following the injection; the activity was decreased to about one third of the maximum 3 weeks after the injection; increase in total cytochrome P-450 at this dose was only about 1.4-fold at the induction maximum. 5. The ratio of the TCDD concentrations in liver and adipose tissue increased considerably between doses of 3 ng TCDD/kg body wt (ratio: about 0.74) and 3000 ng TCDD/kg body wt (ratio: about 7.7). 6. The extent of EROD induction in the liver increased dose dependently. A significant effect was first observed with a dose of 3 ng TCDD/kg body wt (activity about +32% above control activity). The corresponding tissue concentration was about 10 pg TCDD/g liver wet wt. 7. An almost perfect linear relationship exists (when using a double-log plot) between the hepatic TCDD concentration and the EROD activity for tissue concentrations ranging from 40 to 30,000 pg TCDD/g wet wt.     

A novel method of extraction of bamboo seed oil (Bambusa bambos Druce) and its promising effect on metabolic symptoms of experimentally induced polycystic ovarian disease

Objective:

To evaluate the potential effect of bamboo seed oil in decreasing the major metabolic symptoms associated with letrozole-induced polycystic ovarian disease using female rat model.

Materials and Methods:

A new method of microwave-assisted extraction was developed. Female rats were grouped into four with six animals each. All rats were daily administered with letrozole (1 mg/kg b.wt.) for 21 days except control, and during this period, changes in estrous cycle were observed. After letrozole treatment, Group 2 was considered negative control, Groups 3 and 4 were treated orally with bamboo oil, 0.5 ml/kg b.wt. and 1 ml/kg b.wt., respectively, for 3 weeks (five consecutive estrus cycles). Various parameters such as estrus cycle, blood sugar level, lipid profile, and weights of reproductive system were determined. The characteristics of cystic ovaries were evaluated by histopathological studies.

Results:

The isolated bamboo oil restored estrus cyclicity showed hypoglycemic and hypolipidemic effects. 1 ml/kg b.wt. of bamboo oil showed a marked glucose reduction from 254.04 ± 2.08 to 92.6 ± 1.63, and levels of total cholesterol, very low-density lipoprotein, triglyceride were reduced from 186.45 ± 2.28, 30.07 ± 2.36, 100.36 ± 2.35 to 152.14 ± 2.63, 25.94 ± 1.66, 93.32 ± 1.09, respectively. Histopathological results showed the presence of ovulation and recovery from cystic ovaries.

Conclusion:

A novel and promising drug was isolated in the treatment and maintenance of various metabolic symptoms associated with polycystic ovary disease.KEY WORDS: Bamboo seed oil, Bambusa bambos Druce, cystic ovary, estrus cycle, lipid profile, polycystic ovary disease, polycystic ovary syndrome     

Estimation of the percolation thresholds in ternary lobenzarit disodium–dextran–HPMC hydrophilic matrices tablets: Effects of initial porosity

The aim of this work is to estimate the excipient percolation threshold for a new combined matrix native dextran (DT), series B110-1-2 (Mw 2 × 10⁶): HPMC K4M CR: lobenzarit disodium (LBD) system and demonstrate the advantages of this ternary system with respect to previously reported binary dextran:LBD and HPMC:LBD tablets. The formulations studied were prepared with different amounts of excipient (DT:HPMC, 4:1 (wt/wt) for all tablets and relative polymer/drug particle size of 4.17) in the range of 10–70% (wt/wt). Dissolution studies were carried out using the paddle method (100 rpm) and one face water uptake measurements were performed using a modified Enslin apparatus. The Higuchi's models as well as the non-linear regression were employed as empiric methods to study the released data. Values of diffusion exponent 0.588 < n < 0.784 (Korsmeyer equation) for dissolution profile and water uptake mechanism 0.715 < n < 0.960 (Davidson and Peppas equation) suggests anomalous or complex mechanisms in all cases. The critical points in ternary tablets were reduced from 44.75% (v/v) of excipient (correspond to purely native dextran) to 22.34% (v/v) (corresponding to mixture native dextran:HPMC, 4:1, wt/wt). The initial porosity (IP) of hydrophilic matrices above the values of 20% has an important influence on the percolation threshold as well as on establishment of the gel barrier responsible for the controlled release from the DT:HPMC:LBD tablets.     

Multi‐dose drug dispensing as a tool to improve medication adherence: A study in patients using vitamin K antagonists

Purpose

Multi‐dose drug dispensing (MDD) is a dosing aid that provides patients with disposable bags containing all drugs intended for 1 dosing moment. MDD is believed to increase medication adherence, but studies are based on self‐reported data, and results may depend on socially desirable answers. Therefore, our purpose was to determine the effect of MDD on medication adherence in non‐adherent patients taking vitamin K antagonists (VKAs), and to compare with instructing patients on medication use.

Methods

We conducted a before‐after study in non‐adherent patients where MDD was the exposure and change in adherence after MDD initiation was the outcome (within patient comparison). Time in therapeutic range (TTR) was selected as a measure for adherence, as this reflects stability of VKA treatment. To analyze whether MDD improved adherence as compared with standard care (ie, letters or calls from nurses of the anticoagulation clinic), non‐adherent patients without MDD were also followed to estimate their TTR change over time (between patient comparison).

Results

Eighty‐three non‐adherent VKA patients started using MDD. The median TTR was 63% before MDD and 73% 6 months after MDD. The within patient TTR increased on average by 13% (95%CI 6% to 21%) within 1 month after starting MDD and remained stable during the next 5 months. The TTR of MDD‐patients increased 10% (95%CI 2% to 19%) higher as compared with non‐MDD patients within 1 month but was similar after 4 months (TTR difference 3%, 95%CI –2% to 9%).

Conclusions

Adherence improved after initiation of MDD. Compared with instructing patients, MDD was associated with better adherence within 1 month but was associated with similar improvement after 4 months.     

Buffered lidocaine hydrochloride solution with and without epinephrine: stability in polypropylene syringes

Background:

Pain associated with infiltrating the skin with lidocaine can be reduced by buffering the solution with sodium bicarbonate.

Objectives:

To determine the physical compatibility and chemical stability of lidocaine hydrochloride solution buffered with 8.4% sodium bicarbonate, with and without epinephrine, packaged in polypropylene syringes and stored at 5°C with protection from light.

Methods:

Lidocaine solutions (1% and 2%), with and without epinephrine 1:100 000, were diluted 10:1 with 8.4% sodium bicarbonate, packaged in 3-mL polypropylene syringes, and stored at 5°C (range 3°C to 8°C). On each of days 0, 3, 7, 10, 14, 17, 21, 24, and 28, the contents of 3 syringes for each solution of lidocaine combined with epinephrine were collected separately in glass vials and frozen at −70°C for subsequent analysis. In addition, on days 0, 7, 14, 21, and 28, the contents of 3 syringes for each lidocaine solution without epinephrine were collected separately in glass vials and frozen at −70°C for subsequent analysis. Chemical stability was determined with a validated, stability-indicating high-performance liquid chromatography method. Changes in colour, clarity, and pH were used to determine physical compatibility of the solutions.

Results:

All buffered lidocaine solutions containing epinephrine (1:100 000) retained at least 93.3% of the original concentration of epinephrine and 97.5% of the lidocaine concentration for 7 days when stored at 5°C with protection from light. In contrast, the epinephrine-free solutions retained at least 94.7% of the initial concentration of lidocaine for the duration of the study (28 days). All samples remained clear, colourless, and free of precipitate throughout the study, and there were no significant changes in pH.

Conclusion:

Extemporaneously prepared buffered lidocaine (1% and 2%) packaged in polypropylene syringes remained stable for up to 28 days when properly refrigerated with protection from light. A 7-day expiry date was established for buffered lidocaine solutions containing epinephrine, packaged in polypropylene syringes, and stored with refrigeration and protection from light.     

Stability of ciprofloxacin in polyvinylchloride minibags

Background:

Ciprofloxacin is a fluoroquinolone antibiotic used to treat infections caused by both gram-positive and gram-negative organisms.

Objective:

To determine the physical and chemical stability of ciprofloxacin diluted in 5% dextrose in water (D5W) or 0.9% sodium chloride (normal saline [NS]) and stored in polyvinylchloride (PVC) minibags at various temperatures.

Methods:

Solutions of ciprofloxacin (1 and 2 mg/mL) were prepared by diluting a commercially available concentrate (10 mg/mL) with either D5W or NS. The prepared solutions were then packaged in PVC mini-bags. Three minibags of each concentration–diluent combination were stored at 2°C to 8°C with protection from light, at 21°C to 24°C with exposure to light, and at 29°C to 31°C with protection from light. Samples were collected from each minibag on days 0, 7, 14, and 30 and then analyzed. Colour, clarity, and pH were monitored when the samples were collected. On each day of analysis, the samples were accurately diluted before duplicate analysis with a stability-indicating high-performance liquid chromatography assay. A solution was considered stable if the concentration remained above 90% of the initial values.

Results:

There were no changes in the physical characteristics of any of the solutions. At both concentrations (1 and 2 mg/mL), the ciprofloxacin solutions prepared in D5W remained above 93.9% of the initial concentration over the 30-day study period under all 3 storage conditions. Similarly, at both concentrations, solutions diluted in NS remained above 95.9% of the initial concentration over the 30-day study period under all 3 storage conditions.

Conclusions:

Ciprofloxacin prepared in either D5W or NS and stored in PVC minibags was stable for 30 days under 3 separate storage conditions: 2°C to 8°C with protection from light, 21°C to 24°C with exposure to light, and 29°C to 31°C with protection from light.     

Drug Burden Index and physical function in older Australian men

AIMS

This study evaluated the associations of physical performance and functional status measures with the Drug Burden Index in older Australian men. The Drug Burden Index is a measure of total exposure to anticholinergic and sedative medications that incorporates the principles of dose–response and maximal effect.

METHODS

A cross-sectional survey was performed on community-dwelling older men enrolled in The Concord Health and Ageing in Men Project, Sydney, Australia. Outcomes included chair stands, walking speed over 6 m, 20-cm narrow walk speed, balance, grip strength and Instrumental Activities of Daily Living score (IADLs).

RESULTS

The study population consisted of 1705 men (age 76.9 ± 5.5 years). Of the 1527 (90%) participants who reported taking medications, 21% were exposed to anticholinergic and 13% to sedative drugs. The average Drug Burden Index in the study population was 0.18 ± 0.35. After adjusting for confounders (sociodemographics, comorbidities, cognitive impairment, depression), Drug Burden Index was associated with slower walking speed (P < 0.05), slower narrow walk speed (P < 0.05), balance difficulty (P < 0.01), grip weakness (P < 0.01) and poorer performance on IADLs (P < 0.05). Associations with physical performance and function were stronger for the sedative than for the anticholinergic component of the Drug Burden Index.

CONCLUSIONS

Higher Drug Burden Index is associated with poorer physical performance and functional status in community-dwelling older Australian men. The Drug Burden Index has broad applicability as a tool for assessing the impact of medications on functions that determine independence in older people.     

Pharmacokinetic and pharmacodynamic evaluation of linagliptin in African American patients with type 2 diabetes mellitus

Aim

This was an open label, multicentre phase I trial to study the pharmacokinetics and pharmacodynamics of the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin in African American patients with type 2 diabetes mellitus (T2DM).

Methods

Forty-one African American patients with T2DM were included in this study. Patients were admitted to a study clinic and administered 5 mg linagliptin once daily for 7 days, followed by 7 days of outpatient evaluation.

Results

Primary endpoints were area under the plasma concentration–time curve (AUC), maximum plasma concentration (C_max) and plasma DPP-4 trough inhibition at steady-state. Linagliptin geometric mean AUC was 194 nmol l⁻¹ h (geometric coefficient of variation, 26%), with a C_max of 16.4 nmol l⁻¹ (41%). Urinary excretion was low (0.5% and 4.4% of the dose excreted over 24 h, days 1 and 7). The geometric mean DPP-4 inhibition at steady-state was 84.2% at trough and 91.9% at maximum. The exposure range and overall pharmacokinetic/pharmacodynamic profile of linagliptin in this study of African Americans with T2DM was comparable with that in other populations. Laboratory data, vital signs and physical examinations did not show any relevant findings. No safety concerns were identified.

Conclusions

The results of this study in African American patients with T2DM support the use of the standard 5 mg dose recommended in all populations.     

Fertility, developmental toxicity and teratogenicity in albino rats treated with methanol sub-fraction of Carica papaya seeds

Objective:

To evaluate the status of fertility, developmental stages during gestation and teratological changes, if any, following oral administration of methanol sub-fraction (MSF) of the benzene chromatographic fraction of the chloroform extract of the seeds of Carica papaya in rats.

Materials and Methods:

The MSF was administered at the doses of 50 mg contraceptive dose (CD), 100 mg (2× CD), 250 mg (5× CD) and 500 mg (10× CD)/kg body wt/day along with vehicle-treated control using 10 male and 20 female Wistar rats in each group. Necropsies were performed one day before the expected parturition. Status of gravid/non-gravid uterus, the number of corpora lutea in the ovary, implantation status, fetal wellbeing, fetal resorption, fetal body weight, external, visceral and skeletal malformations were recorded.

Results:

Pregnancies were recorded in vehicle-treated control animals and in the animals treated with 50 mg/kg body wt/day. The animals treated with 2× CD, 5× CD and 10× CD did not get pregnant. The fetuses and the status of the ovary, uterus and implantation, fetal body weight, soft tissues and skeletal structures were recorded normal. Data were comparable to those of control.

Conclusion:

The results suggest that the test substance had no developmental toxicity and teratogenicity which could affect pregnancy, implantation and gestation.     

Effectiveness of risk minimization measures for the use of cilostazol in United Kingdom,Spain, Sweden,and Germany

Purpose

The purpose of the study is to evaluate the effectiveness of risk minimization measures—labeling changes and communication to health care professionals—recommended by the European Medicines Agency for use of cilostazol for the treatment of intermittent claudication in Europe.

Methods

Observational study of cilostazol in The Health Improvement Network (United Kingdom), EpiChron Cohort (Spain), SIDIAP (Spain), Swedish National Databases, and GePaRD (Germany). Among new users of cilostazol, we compared the prevalence of conditions targeted by the risk minimization measures in the periods before (2002‐2012) and after (2014) implementation. Conditions evaluated were prevalence of smoking, cardiovascular conditions, concurrent use of ≥2 antiplatelet agents, concurrent use of potent CYP3A4/CYP2C19 inhibitors and high‐dose cilostazol, early monitoring of all users, and continuous monitoring of users at high cardiovascular risk.

Results

We included 22 593 and 1821 new users of cilostazol before and after implementation of risk minimization measures, respectively. After implementation, the frequency of several conditions related to the labeling changes improved in all the study populations: prevalence of use decreased between 13% (EpiChron) and 57% (SIDIAP), frequency of cardiovascular contraindications decreased between 8% (GePaRD) and 84% (EpiChron), and concurrent use of high‐dose cilostazol and potent CYP3A4/CYP2C19 inhibitors decreased between 6% (Sweden) and 100% (EpiChron). The frequency of other conditions improved in most study populations, except smoking, which decreased only in EpiChron (48% reduction).

Conclusions

This study indicates that the risk minimization measures implemented by the EMA for the use of cilostazol have been effective in all European countries studied, except for smoking cessation before initiating cilostazol, which remains an area of improvement.     

Compatibility and Stability of Morphine Sulphate and Naloxone Hydrochloride in 0.9% Sodium Chloride for Injection

Background

Naloxone may be administered in conjunction with morphine to reduce the risk of opioid-induced pruritis. Combining these drugs for coadministration may be beneficial, but little is known about their physical compatibility and stability in combined solutions.

Objective:

To describe the physical compatibility and stability of morphine sulphate and naloxone hydrochloride (at various concentrations) in IV admixtures.

Methods:

The physical compatibility and stability of admixtures of morphine 1000 μg/mL and naloxone 4 μg/mL, 12.5 μg/mL, and 25 μg/mL in 0.9% sodium chloride were studied. For each concentration of naloxone, one bag was stored at room temperature (22°C) for 72 h and one bag was stored under refrigeration (4°C) for 30 days. For all preparations, physical characteristics, including pH, colour, and formation of precipitate, were evaluated. The samples were also analyzed by a stability-indicating high-performance liquid chromatographic method. Stability was defined as the retention of at least 90% of the initial concentration.

Results:

No notable changes in pH or colour and no macroprecipitation were observed in any of the preparations after storage at 22°C for up to 72 h or at 4°C for up to 30 days. All preparations maintained more than 90% of the initial concentrations of morphine and naloxone at the end of the respective study periods. The calculated lower limit of the 95% confidence interval also indicated that 90% or more of the initial concentration remained at the end of each study period.

Conclusion:

Admixtures of morphine sulphate and naloxone hydrochloride were stable for 72 h at room temperature and for 30 days with refrigeration.     

Identifying missed opportunities to curtail antimicrobial therapy for presumed ventilator-associated pneumonia using the clinical pulmonary infection score

Background:

Early discontinuation of antimicrobial therapy for ventilator-associated pneumonia can reduce the emergence of antimicrobial resistance, the occurrence of adverse drug events, and the cost of therapy. Evidence suggests that discontinuation of therapy by day 3 may be appropriate for patients with a clinical pulmonary infection score of 6 or less at baseline and on day 3.

Objectives:

To determine the proportion of patients eligible for antimicrobial discontinuation on day 3 and day 7 of therapy and to determine the proportion of eligible patients for whom antimicrobials were discontinued within these timeframes.

Methods:

A 6-month observational study was conducted from October 3, 2005, to March 31, 2006, in a 27-bed medical–surgical tertiary care intensive care unit. Clinical pharmacists attended daily rounds and prospectively identified patients for inclusion in the study. A study pharmacist retrospectively calculated clinical pulmonary infection scores. Other data were obtained from the quality-improvement database and patient health records for the intensive care unit.

Results:

Ninety-two patients were treated for ventilator-associated pneumonia during the study period, of whom 49 were included in the analysis. At day 3, 17 (35%) of the 49 patients were eligible for early discontinuation of antimicrobial therapy, but therapy was discontinued for only 2 (12%) of these 17 patients. At day 7, 10 (32%) of 31 patients were eligible for antimicrobial discontinuation, but therapy was discontinued for only 1 (10%) of these 10 patients.

Conclusions:

A significant opportunity exists at the authors’ institution to develop and implement an antimicrobial discontinuation policy that uses the clinical pulmonary infection score to guide antimicrobial use for patients with ventilator-associated pneumonia.     

Multiclass mycotoxins in lotus seeds analysed by an isotope‐labelled internal standard‐based UPLC‐MS/MS

Objectives

This study aimed to explore the residue levels of multiclass mycotoxins in medicinal and edible lotus seeds.

Methods

A rapid and reliable isotope‐labelled internal standard‐based UPLC ‐MS /MS method was developed and validated for sensitive and accurate analysis of multiclass mycotoxins including aflatoxins (AFB ₁, AFB ₂, AFG ₁ and AFG ₂), ochratoxin A (OTA ), zearalenone (ZEN ), deoxynivalenol (DON ), fumonisins (FB ₁ and FB ₂), T‐2 and HT ‐2 toxins in lotus seeds. Some critical conditions such as extract solution with the addition of isotope‐labelled internal standard, type of mobile phase and the elution condition were scientifically optimized. The 11 mycotoxins obtained satisfactory resolution and sensitive detection in multiple reactions monitoring scanning mode combined with the ion switching technology in positive and negative ion switching mode.

Key findings

The developed isotope‐labelled internal standard‐based UPLC ‐MS /MS method exhibited an approving linearity (r  ≥  0.9984), high sensitivity (limit of detection in the range of 0.015–30.05 μg/kg), acceptable precision (RSD s ≤6.3%) and good recovery (76.0–116.0%) for 11 analytes, respectively. Ten batches of real lotus seed samples were tested, and three batches out of which were contaminated with AFB ₁, FB ₂, T‐2 and ZEN . AFB ₁ showed the highest occurrence rate (30%) with contents of 10.50 and 8.32 μg/kg in two samples over the official limit (5.0 μg/kg).

Conclusions

The monitoring of multiclass mycotoxins in Chinese herbal medicines is in great urgency to ensure the security of consumers. The proposed method could be further utilized for simple, sensitive and rapid detection of more mycotoxins in other complex matrices to compensate for matrix effects.

     

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.     

Influence of SLCO1B3 haplotype-tag SNPs on docetaxel disposition in Chinese nasopharyngeal cancer patients

AIMS

To completely screen the SLCO1B3 gene in three distinct healthy Asian populations (Chinese, Malay and Indian, n = 168) and investigate the influence of haplotype-tag SNPs (htSNPs) on docetaxel disposition in 50 nasopharyngeal carcinoma patients.

METHODS

Genomic DNA of individuals was screened for SLCO1B3 polymorphisms by direct sequencing. htSNPs were derived based on the sequence clustering algorithm and profiled in the patients. Population based genetic association analysis was performed using Haplostats package implemented in R and PLINK.

RESULTS

A strong linkage disequilibrium pattern was detected across a total of 88 polymorphisms and 15-htSNPs were identified. The SLCO1B3 haplotypic region comprising seven htSNPs was found to be significantly associated with docetaxel clearance (P = 0.003). Conditional haplotype analyses revealed that the haplotypic constructs comprising the IVS4+76G>A, 699G>A(Met233Ile), IVS12-5676A>G, and *347_*348insA polymorphisms were critical determinants of variability in docetaxel disposition [clearance and area under the plasma concentration−time curve (AUC(0,∞)): r² = 29% and 22%, respectively]. Patients harbouring the GAG*347insA haplotype were significantly associated with a 30% decrease in clearance and a 40% increase in AUC(0,∞) of docetaxel compared with patients harbouring the reference haplotype, GGA*347wt (P = 0.025 and 0.018, respectively). In contrast, a 50% higher clearance was observed in patients carrying the GAG*347wt haplotype compared with those with the reference haplotype (P = 0.002). The functional SLCO1B3 haplotypic constructs included the widely studied Met233Ile variant and *347_*348insA located in the putative miR-890 binding site in the 3′-untranslated region which may influence the transport characteristics of SLCO1B3.

CONCLUSIONS

This study highlights the importance of SLCO1B3 polymorphic variations in influencing docetaxel disposition in nasopharyngeal carcinoma patients.