Pires, Patricia C.Fazendeiro, Ana C.Rodrigues, MarcioAlves, Gilberto...
10页
查看更多>>摘要：Phenytoin is a low aqueous solubility antiepileptic drug, but its phosphate ester prodrug fosphenytoin is soluble, although less permeable. In a previous study, the intranasal administration of aqueous-based formulations of fosphenytoin led to high but delayed phenytoin bioavailability compared to the intravenous route. In this work, we hypothesized that formulating an association of the prodrug fosphenytoin and the drug phenytoin (the active and diffusible form), could result in a faster and/or more effective brain targeting. Hence, nano or microemulsions containing both active drug and prodrug were developed and characterized regarding viscosity, osmolality, pH, mean size and in vitro drug release. Then, in vivo pharmacokinetics of a selected microemulsion containing fosphenytoin and phenytoin was evaluated in mice following intranasal administration and compared with a similar microemulsion containing fosphenytoin only. Both microemulsions led to higher brain drug levels at short time points than previously developed simpler aqueous based fosphenytoin formulations, likely due to the microemulsion's permeation enhancing effect. In addition, having a small amount of phenytoin in the formulation led to an equivalent maximum brain drug concentration and an overall higher absolute bioavailability, with a prolonged drug exposure. Hence, it can be concluded that if there is a need for a fast and prolonged therapeutic effect, a drug/phosphate ester prodrug combination in a microemulsion is ideal, but if a fast effect is all that is needed, having the prodrug alone could be enough, while considering a formulation with permeation enhancing components.
查看更多>>摘要：Breast Cancer (BC) is a highly heterogeneous malignant carcinoma that is the most frequently occurring cancer in women. The major types of BC are luminal A, basal-like, luminal B, Human Epidermal Growth Factor Receptor 2 (HER2) positive/ Estrogen Receptor (ER) negative, and Triple-Negative BC (TNBC). The conventional therapies against BC include various chemotherapeutic agents in different combinations. Along with the chemotherapeutic drugs, alternatives like hormonal therapy, radiation, and nanotechnology are emerging fields in treating breast carcinoma. Dendrimers are three-dimensional hyperbranched nanosized structures that deal with the toxicity and resistance of chemotherapeutic agents in BC. These nanocarriers can carry drugs on the surface as well as inside the cavity to the desired site. Dendrimers have high loading capacity and exhibit targeted delivery of drugs resulting in reduced side effects. The current review discusses the utilization of dendrimers for treating BC and conquering the limitations of multidrug resistance.
Kane, ZoePicetti, RobertoWilby, AlisonStanding, Joseph F....
10页
查看更多>>摘要：Background: : Tranexamic acid (TXA) is an antifibrinolytic drug that reduces surgical blood loss and death due to bleeding after trauma and post-partum haemorrhage. Treatment success is dependant on early intervention and rapid systemic exposure to TXA. The requirement for intravenous (IV) administration can in some situations limit accessibility to TXA therapy. Here we employ physiologically based pharmacokinetic modelling (PBPK) to evaluate if adequate TXA exposure maybe achieved when given via different routes of administration. Methods: : A commercially available PBPK software (GastroPlus (R)) was used to model published TXA pharmacokinetics. IV, oral and intramuscular (IM) models were developed using healthy volunteer PK data from twelve different single dose regimens (n = 48 participants). The model was verified using separate IV and oral validation datasets (n = 26 participants). Oral, IM and sub-cutaneous (SQ) dose finding simulations were performed. Results: : Across the different TXA regimens evaluated TXA plasma concentrations varied from 0.1 to 94.0 & micro;g/mL. Estimates of the total plasma clearance of TXA ranged from 0.091 to 0.104 L/h/kg, oral bioavailability from 36 to 67% and Tmax from 2.6 to 3.2 and 0.4 to 1.0 h following oral and intramuscular administration respectively. Variability in the observed TXA PK could be captured through predictable demographic effects on clearance, combined with intestinal permeability and stomach transit time following oral administration and muscle blood flow and muscle/plasma partition coefficients following intra-muscular dosing. Conclusions: : This study indicates that intramuscular administration is the non-intravenous route of administration with the most potential for achieving targeted TXA exposures. Plasma levels following an IM dose of 1000 mg TXA are predicted to exceed 15 mg/mL in < 15 min and be maintained above this level for approximately 3 h, achieving systemic exposure (AUC0-6) of 99 to 105 & micro;g*hr/mL after a single dose. Well-designed clinical trials to verify these predictions and confirm the utility of intramuscular TXA are recommended.
NSTL
Elsevier