Oral inhalation is the main drug delivery route for treating obstructive lung conditions. Thus, many inhaler devices with various design and pharmaceutical formulation have been introduced. The fine ...particle dose (FPD) and mass median aerodynamic diameter (MMAD ≤ 5 μm) of the aerosol delivered dose (DD) dictate the therapeutically effective peripheral lung deposition. This study evaluated the in vitro aerosol emission performance of tiotropium bromide emitted from Spiriva® Respimat® soft mist inhalers (R) after living under patients' real-world, post-dispensing handling environments.
This was a two-stage investigation. In the first clinical stage, research ethical approval was obtained to enrol patients already been using R for at least 3 months. Those who signed consent were given both new R to use and temperature and relative humidity (RH) handheld, portable data loggers to keep in the vicinity of the given R. The participants returned the given R and data loggers after 2 weeks. Patient recruitment took place in Amman, Jordan, during the summer (RS) and winter (RW). Subsequently, in the second laboratory stage, other R were strictly stored at an average of 21.0 °C and 46.9% RH as control (RC). The Next Generation Impactor (NGI) was used to evaluate the RS, RW and RC. The NGI was operated at a flow rate of 30 L/min.
The RS were exposed to an average (range) 23.6 °C (18.2-37.5 °C) and 43.8% RH (21.4-60.0% RH) that were statistically comparable (p > 0.05) to that of the RW; 17.3 °C (13.2-26.7 °C) and 52.8% RH (26.3-69.1% RH). The RW and RC retention environments were statistically different (p < 0.05), whilst the RS and RC had comparable (p > 0.05) conditions. No significant differences (p > 0.05) were found in the tiotropium bromide DD (2.39 vs 2.43 μg), FPD (0.88 vs 0.90 μg) and MMAD (5.1 vs 4.98 μm) between the RS and RW, respectively. Compared to the RC inhalers, both the RS and RW devices had significantly higher FPD and relatively smaller tiotropium bromide particles.
Using the R under the fluctuating summer and winter environments of our patients would not affect its overall tiotropium bromide emission performance. The significant increase in the respirable mass of the RS and RW might be offset by the increase in particles <1 μm particularly in patients with poor inhaler technique.
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Morin (3,5,7,2′,4′-pentahydroxyflavone; MR) is a bioactive plant polyphenol whose therapeutic efficacy is hindered by its poor biopharmaceutical properties. The purpose of this study ...was to develop a nanoparticle (NP) formulation to enhance the bioactivity and oral bioavailability of MR. The nanoprecipitation techniquewas employed to encapsulate MR in lipid-cored poly(lactide-co-glycolide) (PLGA) NPs. The optimal NPs were about 200 nm in size with an almost neutral surface charge and a loading efficiency of 82%. The NPs exhibited sustained release of MR within 24 h. In vitro antioxidant assays showed that MR encapsulation did not affect its antioxidant activity. On the other hand, anti-inflammatory assays in lipopolysaccharide-stimulated macrophages revealed a superior anti-inflammatory activity of MR NPs compared to free MR. Furthermore, oral administration of MR NPs to mice at a single dose of 20 mg/kg MR achieved a 5.6-fold enhancement in bioavailability and a prolongation of plasma half-life from 0.13 to 0.98 h. The results of this study present a promising NP formulation for MR which can enhance its oral bioavailability and bioactivity for the treatment of different diseases such as inflammation.
Study Objectives: The present study aimed to evaluate the comparative bioavailability of a new generic sitagliptin formulation. Methods: This was an open label, randomized, balanced, two-sequence, ...two-treatment, two-period, single oral dose, crossover, bioequivalence (BE) study in 30 healthy male volunteers under fasting conditions. A 100 mg single dose of sitagliptin in the form of sitagliptin hydrochloride monohydrate (test) and sitagliptin phosphate monohydrate (reference) tablets were administered to each volunteer, separated by one week washout period. Twenty-two blood samples were collected at pre-dose and up until 48 hours post-dose. Sitagliptin concentrations were determined via a validated LC-MS/MS method following a protein precipitation step. Pharmacokinetic (PK) parameters were estimated via non-compartmental analysis and then compared between the reference and test formulations by performing a multivariate analysis of variance. Results and Discussion: No statistically significant difference was found between the test and reference formulations in terms of the maximum concentration (C.sub.max), area under the curve (AUC), AUC.sub.0-inf, and AUC.sub.0-48. The 90% confidence intervals of sitagliptin Lntransformed C.sub.max, AUC.sub.0-inf, and AUC.sub.0-48 were within the regulatory BE acceptance range of 80%-125%. Conclusion: The test formulation met regulatory definition of BE to the reference formulation under fasting condition in these healthy male volunteers.
Fructose-1,6-bisphosphatase – hereafter abbreviated as FBPase has been recently implicated in diabetes prompting several attempts to discover and optimize new FBPase inhibitors. Toward this end we ...explored the pharmacophoric space of 136 FBPase inhibitors using three diverse sets of inhibitors. This identified 520 pharmacophores that were subsequently clustered into 104 groups. Cluster centers were evaluated by receiver operating characteristic (ROC) curves analysis and correlation with bioactivities of collected compounds. Pharmacophore model Hypo1/7 illustrated the best combination of classification power (ROC-AUC) and correlation with bioactivity. Two other pharmacophores (Hypo2/1 and Hypo2/6) were found to be mergeable and their combined model (Hypo2-1/2-6) illustrated excellent ROC performance. We employed Hypo1/7 and Hypo2-1/2-6 models to screen the National Cancer Institute (NCI) list of compounds. In silico mining identified 18 FBPase inhibitors out of which six were of sub-micromolar IC50 values.
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► Pharmacophoric space of 136 fructose-1,6-bisphosphatase inhibitors (FBPase) was explored. ► Two pharmacophore models, Hypo1/7 and Hypo2-1/2-6, illustrated the best performance. ► Screening of a National Cancer Institute list and in silico mining identified 18 FBPase inhibitors. ► Six compounds of the investigated list have sub-micromolar IC50 values.
Trigonella foenum-groecum L. is directly related to the traditional use. Trigonella foenum-graecum L, have been reported to be beneficial for treating type 2 diabetes (T2D). The study was conducted ...to investigate the postprandial hypoglycemic effect of fenugreek seeds on patients with T2D. Pretest - posttest control group design was used to test the hypothesis that fenugreek may have a hypoglycemic effect on blood sugar. One hundred sixty--six D2T patients were assigned into three groups: FGO (control group: placebo drink), FG2.5 (2.5g of fenugreek), and FG5 (5g of fenugreek). Participants were instructed to drink the extract and chew the seeds. Postprandial plasma glucose level was measured before and 2-hours after the administration of the treatment. Accounting for gender, age, education, physical activity, body mass index, glycemic control, and medication, patients in FG5 group showed the greatest decrease in postprandial glucose with a pretest-posttest difference (D) of - 41 +- 6.1 mg/dl. Two-hour plasma glucose dropped for patients in FG2.5, however, the drop was not statistically different from that noticed in the placebo group (D = - 24.8 +- 4.9 mg/dl vs. - 9.8 +- 2.2 mg/dl respectively). Fenugreek seeds appear to have a significant hypoglycemic activity in T2D patients.
Medicinal plants are an important element of indigenous systems in Jordan. These resources are usually regarded as part of a culture's traditional knowledge. Therefore, the aim of this study is to ...collect information from local population concerning the use of medicinal plants of the Mujib region; identify the most important medicinal plants used; determine the relative importance of the species surveyed and calculate the informant consensus factor (
F
ic) in relation to medicinal plant use.
Qualitative tools were used for data collection and to record the interviewee's personal information and topics related to the medicinal use of specific plants. The collected data were used to calculate the
F
ic and the plant use values.
Fifty-eight plants were identified to be still in use in traditional practice in Mujib. Our results showed that the highest use values were recorded for the species
Artemisia sieberi Bess. and
Silybum marianum (L.) Gaertn., while the highest
F
ic was cited for digestive problems. Anthropologically, women were the primary gatherers while healers were reported to be both females, predominantly, and males; yet, herbalists are deficient in this local community.
The study of local knowledge about natural resources is becoming increasingly important in defining strategies and actions for conservation of medicinal plants. This study therefore sought to collect ...information from local population concerning the use of Ajloun Heights region medicinal plants; identify the most important species used; determine the relative importance of the species surveyed and calculate the informant consensus factor (ICF) in relation to medicinal plant use. Data collection relied predominantly on qualitative tools to record the interviewee's personal information and topics related to the medicinal use of specific plants. Our results revealed that 46 plant species grown in the study region are still in use in traditional medicine for the treatment of various diseases. Most of the locals interviewed dealt with well-known safe medicinal plants such as
Achillea falcata,
Matricaria aurea,
Majorana syriaca,
Allium sativum and
Allium cepa. The use of moderately unsafe or toxic plants was noted to be practiced by practitioners and herbalists rather than the locals. These plants include
Ecballium elaterium,
Euphorbia hierosolymitana,
Mandragora autumnalis and
Citrullus colocynthis. Kidney problems scored the highest ICF while
Crocus hyemalis was the plant of highest use value. Searching the literature evidenced some concordance with the solicited plant uses mentioned by the informants.
Hydroxychloroquine (HCQ) was repurposed for COVID-19 treatment. Subtherapeutic HCQ lung levels and cardiac toxicity of oral HCQ were overcome by intratracheal (IT) administration of lower HCQ doses. ...The crosslinker-free supercritical fluid technology (SFT) produces aerogels and impregnates them with drugs in their amorphous form with efficient controlled release. Mechanistic physiologically based pharmacokinetic (PBPK) modeling can predict the lung’s epithelial lining fluid (ELF) drug levels. This study aimed to develop a novel HCQ SFT formulation for IT administration to achieve maximal ELF levels and minimal cardiac toxicity. HCQ SFT formulation was prepared and evaluated for physicochemical,
in vitro
release, pharmacokinetics, and cardiac toxicity. Finally, the rat HCQ ELF concentrations were predicted using PBPK modeling. HCQ was amorphous after loading into the chitosan-alginate nanoporous microparticles (22.7±7.6 μm). The formulation showed a zero-order release, with only 40% released over 30 min compared to 94% for raw HCQ. The formulation had a tapped density of 0.28 g/cm
3
and a loading efficiency of 35.3±1.3%. The IT administration of SFT HCQ at 1 mg/kg resulted in 23.7-fold higher bioavailability, fourfold longer MRT, and eightfold faster absorption but lower CK-MB and LDH levels than oral raw HCQ at 4 mg/kg. The PBPK model predicted 6 h of therapeutic ELF levels for IT SFT HCQ and a 100-fold higher ELF-to-heart concentration ratio than oral HCQ. Our findings support the feasibility of lung-targeted and more effective SFT HCQ IT administration for COVID-19 compared to oral HCQ with less cardiac toxicity.
Graphical abstract
Early in the coronavirus disease 2019 (COVID-19) pandemic, hydroxychloroquine (HCQ) drew substantial attention as a potential COVID-19 treatment based on its antiviral and immunomodulatory effects
. ...However, HCQ showed a lack of efficacy
, and different groups of researchers attributed this failure to the insufficient drug concentration in the lung following oral administration (HCQ is only available in the market in the tablet form). Delivering HCQ by inhalation represents a more efficient route of administration to increase HCQ exposure in the lungs while minimizing systemic toxicity. In this pilot study, the safety, tolerability, and pharmacokinetics of HCQ nebulizer solution were evaluated in healthy volunteers.
Twelve healthy participants were included in this study and were administered 2 mL of HCQ01 solution (equivalent to 25 mg of HCQ sulfate) through Aerogen
Solo, a vibrating mesh nebulizer. Local tolerability and systemic safety were assessed by forced expiratory volume in the first and second electrocardiograms, clinical laboratory results (e.g., hematology, biochemistry, and urinalysis), vital signs, and physical examinations. Thirteen blood samples were collected to determine HCQ01 systemic exposure before and until 6 hours after inhalation.
The inhalation of HCQ01 was well tolerated in all participants. The mean value of
for the 12 participants was 9.66 ng/mL.
occurred at around 4.8 minutes after inhalation and rapidly decreased thereafter. The reported systemic exposure was very low with a mean value of 5.28 (0.6-15.6) ng·h/mL.
The low systemic concentrations of HCQ01 of 9.66 ng/mL reported by our study compared with 1 μg/mL previously predicted after 200 mg BID oral administration, and the safety and tolerability of HCQ01 administered as a single dose through nebulization, support the assessment of its efficacy, safety, and tolerability in further studies for the treatment of COVID-19.
Mass production of low-cost, generic direct-acting antivirals (DAAs) will be required to achieve targets of eliminating hepatitis C (HCV) by 2030. The pharmaceutical companies Gilead and ...Bristol-Myers Squibb have granted voluntary licences (VLs) to generic companies to mass produce the DAAs sofosbuvir and daclatasvir at low cost. However, generic manufacturers need to demonstrate bioequivalent pharmacokinetics for their DAAs, compared to the originator versions, to fulfil World Health Organization standards for prequalification. The aim of this study was to determine whether generic forms of sofosbuvir and daclatasvir had bioequivalent pharmacokinetics to the originator versions. Generic companies were contacted for results of bioequivalence studies with sofosbuvir and daclatasvir, two of the most widely used DAAs in the developing world. Data on maximum concentration (C
) and area under the curve (AUC) were compiled from five generic companies. Pre-specified limits for the 90% confidence intervals were 80-125% of the originator pharmacokinetic concentrations for AUC, and 69-145% for C
. The pharmacokinetics of generic sofosbuvir and daclatasvir were shown to be bioequivalent to the originator versions for all five generic companies. This is a crucial step towards securing prequalification of the manufacture of these drugs from these companies. WHO prequalification of bioequivalent generic DAAs could then permit their export to eligible countries for mass-treatment programmes. Mass-treatment with low-cost generic HCV DAAs is the most promising method to achieve the ambitious World Health Organization targets for HCV elimination by 2030.
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