Using in vitro ADME data for lead compound selection: An emphasis on PAMPA pH 5 permeability and oral bioavailability.

Membrane permeability plays an important role in oral drug absorption. Caco-2 and Madin-Darby Canine Kidney (MDCK) cell culture systems have been widely used for assessing intestinal permeability. Since most drugs are absorbed passively, Parallel Artificial Membrane Permeability Assay (PAMPA) has gained popularity as a low-cost and high-throughput method in early drug discovery when compared to high-cost, labor intensive cell-based assays. At the National Center for Advancing Translational Sciences (NCATS), PAMPA pH 5 is employed as one of the Tier I absorption, distribution, metabolism, and elimination (ADME) assays. In this study, we have developed a quantitative structure activity relationship (QSAR) model using our ∼6500 compound PAMPA pH 5 permeability dataset. Along with ensemble decision tree-based methods such as Random Forest and eXtreme Gradient Boosting, we employed deep neural network and a graph convolutional neural network to model PAMPA pH 5 permeability. The classification models trained on a balanced training set provided accuracies ranging from 71% to 78% on the external set. Of the four classifiers, the graph convolutional neural network that directly operates on molecular graphs offered the best classification performance. Additionally, an ∼85% correlation was obtained between PAMPA pH 5 permeability and in vivo oral bioavailability in mice and rats. These results suggest that data from this assay (experimental or predicted) can be used to rank-order compounds for preclinical in vivo testing with a high degree of confidence, reducing cost and attrition as well as accelerating the drug discovery process. Additionally, experimental data for 486 compounds (PubChem AID: 1645871) and the best models have been made publicly available (https://opendata.ncats.nih.gov/adme/).

Estimating fetal exposure to the P-gp substrates, corticosteroids, by PBPK modeling to inform prevention of neonatal respiratory distress syndrome.

We have previously developed a maternal-fetal physiologically-based pharmacokinetic (m-f PBPK) model to dynamically predict (and verify) fetal-maternal exposure to drugs that passively diffuse across the placenta. Here, we extended the application of this model to dynamically predict fetal exposure to drugs which are effluxed by placental P-glycoprotein, namely the antenatal corticosteroids (ACS; dexamethasone [DEX], and betamethasone [BET]). To do so, we estimated both the placental P-gp mediated efflux clearance (CL) and the passive diffusion CL of the ACS. The efficacy and toxicity of the currently used maternal ACS dosing regimens to prevent neonatal respiratory distress syndrome could be improved by altering their dosing regimens. Therefore, to illustrate the utility of our m-f PBPK model, we used it to design alternative dosing regimens of DEX and BET that could potentially improve their efficacy and reduce their toxicity. The redesigned dosing regimens are convenient to administer, maintain maternal-fetal exposure (area under the concentration-time curve [AUC]) or maximum plasma concentration (Cmax ) or both (DEX and BET) or minimize maternal exposure while maintaining fetal drug plasma concentrations above the minimum therapeutic threshold of 1 ng/ml for 48 h (BET only; based on efficacy data in sheep). To our knowledge, this is the first study to dynamically predict fetal plasma concentrations of placental P-gp effluxed drugs. Our approach and our m-f PBPK model could be used in the future to predict maternal-fetal exposure to any drug and to design alternative dosing regimens of the drug.

Design and In Vitro Evaluation of a Slow-Release Intraocular Implant of Betamethasone.

Posterior eye diseases are a common cause of vision problems in developing countries, which have encouraged the development of new treatment models for these degenerative diseases. Intraocular implants are one of the drug delivery systems to the posterior region of the eye. Using these implants, the blood-eye barrier can be bypassed; the complications caused by repeated in vitro administrations can be eliminated, and smaller amounts of the drug would be used during the treatment process. Meanwhile, biodegradable implants have received more attention due to their biodegradable structure and the lack of need for re-surgery to remove the rest of the system from the eye. The aim of this study is to employ biodegradable implants composed of polyethylene glycol (PEG) and 3-hydroxybutyrate-co-3-hydroxyvalerat (PHBV) to deliver betamethasone to the back of the eye in the treatment of retinopathy. PHBV polymer has been selected as the main polymer with a certain ratio of drug to polymer for fabrication of enamel and different amounts of PEG with three molecular weights used as pore generators to control drug release over a period of time. Based on the analysis of the results of differential scanning calorimetry (DSC) and FTIR spectroscopy, none of the polymers were degraded in the temperature range of the manufacturing process, and among betamethasone derivatives, the best option for implant preparation is the use of its basic form. Drug release studies over a period of three months showed that implants containing PHBV HV2% and PEG 6000 had a more appropriate release profile.

Population pharmacodynamic modeling of intramuscular and oral dexamethasone and betamethasone effects on six biomarkers with circadian complexities in Indian women.

Population pharmacokinetic/pharmacodynamic (PK/PD) analysis was performed for extensive data for differing dosage forms and routes for dexamethasone (DEX) and betamethasone (BET) in 48 healthy nonpregnant Indian women in a partial and complex cross-over design. Single doses of 6 mg dexamethasone phosphate (DEX-P), betamethasone phosphate (BET-P), or 1:1 mixture of betamethasone phosphate and acetate (BET-PA) were administered orally (PO) or intramuscularly (IM) where each woman enrolled in a two-period cross-over study. Plasma concentrations collected over 96 h were described with a two-compartment model with differing PO and IM first-order absorption inputs. Overall, BET exhibited slower clearance, similar volume of distribution, faster absorption, and longer persistence than DEX with BET acetate producing extremely slow absorption but full bioavailability of BET. Six biomarkers were assessed over a 24-h baseline period with four showing circadian rhythms with complex baselines. These baselines and the strong responses seen after drug dosing were fitted with various indirect response models using the Laplace estimation methods in NONMEM 7.4. Both the PK and six biomarker responses were well-described with modest variability likely due to the homogeneous ages, weights, and ethnicities of the women. The drugs either inhibited or stimulated the influx processes with some models requiring joint inclusion of drug effects on circadian cortisol suppression. The biomarkers and order of sensitivity (lowest IC50/SC50 to highest) were: cortisol, T-helper cells, basophils, glucose, neutrophils, and T-cytotoxic cells. DEX sensitivities were generally greater than BET with corresponding mean ratios for these biomarkers of 2.86, 1.27, 1.72, 1.27, 2.69, and 1.06. Overall, the longer PK (e.g. half-life) of BET, but lesser PD activity (e.g. higher IC50), produces single-dose response profiles that appear quite similar, except for the extended effects from BET-PA. This comprehensive population modeling effort provides the first detailed comparison of the PK profiles and six biomarker responses of five commonly used dosage forms of DEX and BET in healthy women.

Population pharmacokinetic modeling of intramuscular and oral dexamethasone and betamethasone in Indian women.

Population analysis of pharmacokinetic data for five differing dosage forms and routes for dexamethasone and betamethasone in 48 healthy nonpregnant Indian women was performed that accounted for a partial and complex cross-over design. Single doses of 6 mg dexamethasone phosphate (DEX-P), betamethasone phosphate (BET-P), or 1:1 mixture of betamethasone phosphate and acetate (BET-PA) were administered orally (PO) or intramuscularly (IM). Plasma concentrations collected for two periods over 96 h were described with a two-compartment model with differing PO and IM first-order absorption inputs. Clearances and volumes were divided by the IM bioavailability [Formula: see text]. The homogeneous ages, body weights, and ethnicity of the women obviated covariate analysis. Parameter estimates were obtained by the Laplace estimation method implemented in NONMEM 7.4. Typical values for dexamethasone were clearance ([Formula: see text] of 9.29 L/h, steady-state volume ([Formula: see text] of 56.4 L, IM absorption constant [Formula: see text] of 0.460 1/h and oral absorption constant ([Formula: see text] of 0.936 1/h. Betamethasone parameters were CL/FIM of 5.95 L/h, [Formula: see text] of 72.4 L, [Formula: see text] of 0.971 1/h, and [Formula: see text] of 1.21 1/h. The PO to IM F values were close to 1.0 for both drugs. The terminal half-lives averaged about 7.5 h for DEX, 17 h for BET, and 78 h for BET from BET-PA with the latter reflecting very slow release of BET from the acetate ester. Overall, BET exhibited slower clearance, larger volume of distribution, faster absorption, and longer persistence than DEX. These data may be useful in considering exposures when substituting one form of corticosteroid for another.

Maternal Betamethasone for Prevention of Respiratory Distress Syndrome in Neonates: Population Pharmacokinetic and Pharmacodynamic Approach.

Despite antenatal corticosteroids therapy, respiratory distress syndrome (RDS) is still a leading cause of neonatal morbidity and mortality in premature newborns. To date, the relationship between in utero fetal drug exposure and occurrence of RDS remains poorly evaluated. This study aims to describe the pharmacokinetics of betamethasone in pregnant women and to evaluate the transplacental drug transfer and administration scheme for the prevention of RDS. Pregnant women > 27 weeks' gestation and who received at least a single dose of betamethasone for prevention of RDS were enrolled. Maternal, cord blood, and amniotic fluid betamethasone time-courses were analyzed using the Monolix software. A total of 220 maternal blood, 56 cord blood, and 26 amniotic fluid samples were described by a two-compartment model with two effect compartments linked by rate transfer constants. Apparent clearances and volumes of distribution parameters were allometrically scaled for a 70 kg third trimester pregnant woman. The impact of a twin pregnancy was found to increase maternal clearance by 28%. Using a fetal-to-mother exposure ratio, the median (95% confidence interval (CI)) transplacental transfer of betamethasone was estimated to 35% (95% CI 0.11-0.67). After adjustment for gestational age and twin pregnancy, RDS was found to be associated to the time spent in utero below quantifiable concentrations (i.e., < 1 ng/mL): odds ratio of 1.10 (95% CI 1.01-1.19) per day increase (P < 0.05). Trying to take into account both efficacy and safety, we simulated different dosing schemes in order to maintain a maximum of fetuses above 1 ng/mL without exceeding the total standard dose.

Flexible liposomal gel dual-loaded with all-trans retinoic acid and betamethasone for enhanced therapeutic efficiency of psoriasis.

BACKGROUND: Psoriasis is a chronic immune-mediated inflammatory skin disease without effective treatment. The utilization of all trans-retinoic acid (TRA) and betamethasone (BT) for the treatment of psoriasis is still facing difficulties, due to their relatively poor stability, limited skin permeation, and systemic side effects. Flexible liposomes are excellent in deeper skin permeation and reducing the side effects of drugs, which is promising for effective treatment of skin disorders. This work aimed to establish dual-loaded flexible liposomal gel for enhanced therapeutic efficiency of psoriasis based on TRA and BT. RESULTS: Flexible liposomes co-loaded with TRA and BT were successfully prepared in our study. The characterization examination revealed that flexible liposomes featured nano-sized particles (around 70 nm), high drug encapsulation efficiency (> 98%) and sustained drug release behaviors. Flexible liposomes remarkably increased the drug skin permeation and retention as compared with free drugs. Results on HaCaT cells suggested that flexible liposomes were nontoxic, and its cellular uptake has a time-dependent manner. In vivo studies suggested the topical application of TRA and BT dual-loaded liposomal gel had the best ability to reduce the thickness of epidermal and the level of cytokines (TNF-α and IL-6), largely alleviating the symptoms of psoriasis. CONCLUSIONS: Flexible liposomal gel dual-loaded with TRA and BT exerted a synergistic effect, which is a promising topical therapeutic for the treatment of psoriasis.

Pharmacokinetics and Pharmacodynamics of Intramuscular and Oral Betamethasone and Dexamethasone in Reproductive Age Women in India.

High-dose betamethasone and dexamethasone are standard of care treatments for women at risk of preterm delivery to improve neonatal respiratory and mortality outcomes. The dose in current use has never been evaluated to minimize exposures while assuring efficacy. We report the pharmacokinetics and pharmacodynamics (PDs) of oral and intramuscular treatments with single 6 mg doses of dexamethasone phosphate, betamethasone phosphate, or a 1:1 mixture of betamethasone phosphate and betamethasone acetate in reproductive age South Asian women. Intramuscular or oral betamethasone has a terminal half-life of 11 hours, about twice as long as the 5.5 hours for oral and intramuscular dexamethasone. The 1:1 mixture of betamethasone phosphate and betamethasone acetate shows an immediate release of betamethasone followed by a slow release where plasma betamethasone can be measured out to 14 days after the single dose administration, likely from a depo formed at the injection site by the acetate. PD responses were: increased glucose, suppressed cortisol, increased neutrophils, and suppressed basophils, CD3CD4 and CD3CD8 lymphocytes. PD responses were comparable for betamethasone and dexamethasone, but with longer times to return to baseline for betamethasone. The 1:1 mixture of betamethasone phosphate and betamethasone acetate caused much longer adrenal suppression because of the slow release. These results will guide the development of better treatment strategies to minimize fetal and maternal drug exposures for women at risk of preterm delivery.

Mucoadhesive thin films for the simultaneous delivery of microbicide and anti-inflammatory drugs in the treatment of periodontal diseases.

There is an unmet clinical need for new products to address the high percentage of the populous who present with periodontal diseases. Drug dose retention at the point of application would facilitate sustained release and more efficacious treatments. The aim of this study was to evaluate mucoadhesive polymeric thin films for simultaneous in situ delivery chlorhexidine and anti-inflammatory and analgesic drugs. Mucoadhesive thin films were prepared using a polymer mixture containing chlorhexidine (25 mg) ± diclofenac sodium (10 and 50 mg), and lidocaine hydrochloride (10 mg) or betamethasone dipropionate (10 and 50 mg). The films were assessed for in vitro drug release and localised tissue delivery, followed by determination of modulated prostaglandin E2 (PGE2) levels in ex vivo tissue and cytotoxicity using a HaCaT keratinocyte cell line. Antibacterial activity of the chlorhexidine/diclofenac film was determined against planktonic and biofilm bacteria associated with periodontal disease and dental plaque. Chlorhexidine release was consistently low (up to 10% of initial loading) from all films, whereas the release of diclofenac, betamethasone and lidocaine exceeded 50% within 30 min. The 50 mg betamethasone film released up to 4-fold more than the 10 mg film. Statistically significant reduction of PGE2 was observed in ex vivo porcine gingival tissue for films containing chlorhexidine with or without diclofenac, and betamethasone. No cytotoxicity was observed for any film, apart from 50 mg betamethasone at 24 h. Films loaded with chlorhexidine and diclofenac were inhibitory against relevant test bacteria. Between 3 and 6 log10 reductions in bacterial cell recovery was observed after biofilm exposure to the chlorhexidine films irrespective of the presence of the anti-inflammatory or anaesthetic. This work demonstrated that thin film formulations have the potential to simultaneously counter key causative factors in periodontal diseases, namely associated bacteria biofilm and chronic local inflammation.

Oral dosing for antenatal corticosteroids in the Rhesus macaque.

Antenatal corticosteroids (ACS) are standard of care for women at risk of preterm delivery, although choice of drug, dose or route have not been systematically evaluated. Further, ACS are infrequently used in low resource environments where most of the mortality from prematurity occurs. We report proof of principle experiments to test betamethasone-phosphate (Beta-P) or dexamethasone-phosphate (Dex-P) given orally in comparison to the clinical treatment with the intramuscular combination drug beta-phosphate plus beta-acetate in a Rhesus Macaque model. First, we performed pharmacokinetic studies in non-pregnant monkeys to compare blood levels of the steroids using oral dosing with Beta-P, Dex-P and an effective maternal intramuscular dose of the beta-acetate component of the clinical treatment. We then evaluated maternal and fetal blood steroid levels with limited fetal sampling under ultrasound guidance in pregnant macaques. We found that oral Beta is more slowly cleared from plasma than oral Dex. The blood levels of both drugs were lower in maternal plasma of pregnant than in non-pregnant macaques. Using the pharmacokinetic data, we treated groups of 6-8 pregnant monkeys with oral Beta-P, oral Dex-P, or the maternal intramuscular clinical treatment and saline controls and measured pressure-volume curves to assess corticosteroid effects on lung maturation at 5d. Oral Beta-P improved the pressure-volume curves similarly to the clinical treatment. Oral Dex-P gave more variable and nonsignificant responses. We then compared gene expression in the fetal lung, liver and hippocampus between oral Beta-P and the clinical treatment by RNA-sequencing. The transcriptomes were largely similar with small gene expression differences in the lung and liver, and no differences in the hippocampus between the groups. As proof of principle, ACS therapy can be effective using inexpensive and widely available oral drugs. Clinical dosing strategies must carefully consider the pharmacokinetics of oral Beta-P or Dex-P to minimize fetal exposure while achieving the desired treatment responses.

Oral antenatal corticosteroids evaluated in fetal sheep.

BACKGROUND: The use of antenatal corticosteroids (ACS) in low-resource environments is sporadic. Further, drug choice, dose, and route of ACS are not optimized. We report the pharmacokinetics and pharmacodynamics of oral dosing of ACS using a preterm sheep model. METHODS: We measured pharmacokinetics of oral betamethasone-phosphate (Beta-P) and dexamethasone-phosphate (Dex-P) using catheterized pregnant sheep. We compared fetal lung maturation responses of oral Beta-P and Dex-P to the standard treatment with 2 doses of the i.m. mixture of Beta-P and betamethasone-acetate at 2, 5, and 7 days after initiation of ACS. RESULTS: Oral Dex-P had lower bioavailability than Beta-P, giving a lower maximum maternal and fetal concentration. A single oral dose of 0.33 mg/kg of Beta-P was equivalent to the standard clinical treatment assessed at 2 days; 2 doses of 0.16 mg/kg of oral Beta-P were equivalent to the standard clinical treatment at 7 days as assessed by lung mechanics and gas exchange after preterm delivery and ventilation. In contrast, oral Dex-P was ineffective because of its decreased bioavailability. CONCLUSION: Using a sheep model, we demonstrate the use of pharmacokinetics to develop oral dosing strategies for ACS. Oral dosing is feasible and may facilitate access to ACS in low-resource environments.

Development of a simple method for simultaneous determination of tazarotene and betamethasone dipropionate and their metabolites using LC-MS method and its application to dermatopharmacokinetic study.

In our study, a method for the determination for tazarotene and betamethasone dipropionate in human tissue-engineered skin was established. Tazarotene gel, betamethasone dipropionate cream or a combination cream was administered to the skin. Then the skin was taken off at 0.25, 0.75, 1.75, 3, 5, 8, 12, 24, 36, 48 h time points after the residual drug was removed. The concentrations of tazarotene, betamethasone dipropionate and their major metabolites in skin were determined by LC-MS. Tazarotene and tazarotenic acid were detected in the concentration range of 2-200 µg/mL with an LLOQ of 2 µg/mL. Betamethasone dipropionate was detected in the concentration range 0.5-300 µg/mL with an LLOQ of 0.5 µg/mL, and betamethasone was detected at 2-200 µg/mL with an LLOQ of 2 µg/mL. The intra- and inter-day precisions of the four analytes in the skin homogenate were all <15% (RSD, %). The results showed that tazarotene could be metabolized to tazarotenic acid and betamethasone dipropionate could be metabolized to betamethasone in tissue-engineered skin. The results also revealed that this method was suitable for the simultaneous determination of tazarotene, betamethasone dipropionate and their metabolites in tissue-engineered skin.

Evaluation of Maternal Drug Exposure Following the Administration of Antenatal Corticosteroids During Late Pregnancy Using Physiologically-Based Pharmacokinetic Modeling.

Betamethasone and dexamethasone are the most widely studied antenatal corticosteroids (ACS) administered to pregnant women, just prior to the birth of a preterm neonate, to accelerate fetal lung maturation. Although betamethasone, predominantly used in developed countries, has been shown to be an effective and safe intervention for reducing neonatal mortality, the choice of ACS and optimal dosing in low and middle income countries (LMICs) remains unclear. This is primarily because the exposure-response relationships have not been established for ACS despite the long history of use. As the first step toward the optimal use of ACS in LMICs, we developed physiologically-based pharmacokinetic (PBPK) models to describe the kinetics of ACS following i.v., p.o., or i.m. dosing. In vitro data describing the cytochrome P450 3A4 enzyme contribution were incorporated and this was refined using clinical data. The models can be applied prospectively to predict kinetics of ACS in pregnant women receiving various dosing regimens.

Novel hydrogel-based ocular drug delivery system for the treatment of conjunctivitis.

PURPOSE: Conventional dosage form like eye drops showed poor therapeutic response and also require frequent dosing. Therefore, developing the dosage form to deliver the drug to the target site without much loss of drug or without causing any systemic side effects is the challenging job for the researchers in pharmaceutical industries. OBJECTIVE: The main aim of the present work was to formulate and evaluate hydrogel-based drug delivery containing combination of neomycin sulphate and betamethasone sodium phosphate in order to provide prolonged release and also better bioavailability of drugs for the treatment of eye infections. METHODS: In this study, poloxamer 407 and chitosan at different concentrations were used as the gelling agents. The prepared formulations were evaluated for clarity, pH, drug content, gelling capacity, gelling temperature and in vitro drug release study. RESULTS: From the preliminary studies, F5 formulation was selected as an optimized formulation. The optimized formulation was further evaluated for ex vivo permeation study, sterility test, HET-CAM and ocular irritation testing using rabbits. Ocular irritation by HET-CAM assay showed that the formulated gel does not cause any irritation to the blood vessels. Draize irritation test was performed using rabbits and results showed that formulation was non-irritant to the eye. CONCLUSION: The formulated hydrogel formulation can be used as an alternative to conventional ophthalmic eye drop formulation of drugs neomycin and betamethasone for the purpose of providing prolonged therapy for the treatment of conjunctivitis.

The dentin permeability of anti-inflammatory and antibacterial drugs: In vitro study.

BACKGROUND/PURPOSE: Stimuli from the oral cavity may penetrate through exposed dentinal tubules and evoke inflammatory pulp response. Anti-bacterial and anti-inflammatory drugs applied to exposed dentin may infiltrate through the dentinal tubules and cause pulp recovery. This study investigated the dentin permeability of anti-bacterial and anti-inflammation drugs via an in-vitro transwell dentin disc tube model. METHODS: Twenty-seven dentin discs prepared from extracted human molars were collected. Nine kinds of drugs were investigated with three dentin discs in each group. These nine drugs included two anti-bacterial drugs (ampicillin sodium and clindamycin phosphate), two corticosteroids (betamethasone sodium phosphate and hydrocortisone sodium succinate), three non-steroidal anti-inflammatory drugs (NSAIDs, piroxicam, lysine acetylsalicylate, and diclofenac sodium), and two natural extracts with anti-inflammatory effect (Ginsenoside Rg1 and Hinokitol). The drugs were introduced to the transwell dentin disc tube model and the 4-hour cumulative release of the drug was detected and recorded by UV-visible spectroscopy. RESULTS: We found that ampicilin sodium had better dentin permeability than clindamycin phosphate. Betamethasone sodium phosphate revealed better dentin permeability than hydrocortisone sodium succinate. Lysine acetylsalicylate showed the best dentin permeability among the three NSAIDs. Ginsenoside Rg1 had the best dentin permeability among the nine drugs tested. However, Hinokitiol could not penetrate the dentin disc after 4 h. CONCLUSION: Regarding the dentin permeability, Ginsenoside Rg1 is the best among the seven anti-inflammatory drugs tested and ampicilin sodium is the better one between the two anti-bacterial drugs tested. Therefore, these two drugs may have high potential for treating exposed dentinal tubule diseases.

Calcipotriene plus betamethasone dipropionate in aerosol foam formulation: will this effective treatment for mild-to-moderate psoriasis change clinical practice?

The fixed-combination of Cal/BD aerosol foam is now entering the Italian market. This drug was developed with a technology that allows an enhanced penetration of the active ingredients into the skin. This enhanced penetration improves local bioavailability and, consequently, Cal/BD aerosol foam therapy is associated with improved clinical outcomes if compared with other products with the same components. The efficacy and safety of Cal/BD aerosol foam were confirmed both in clinical trials and in "field-practice" studies. This short review discusses current evidence on the Cal/BD aerosol foam combination; some preliminary data collected in the Italian clinical practice will be also presented.

In vitro penetration through the skin layers of topically applied glucocorticoids.

Corticoids are actives widely used in the treatment of skin diseases. This work aims to study the penetration of 3 corticoids (betamethasone, clobetasol, and flurandrenolide), their relationship with their Log D values and the effects of the vehicles. The 3 compounds were applied on a Franz-type diffusion cell in propylene glycol solution and their respective commercial creams and ointments. The active amounts found in the stratum corneum, epidermal, and dermal layers of the skin were investigated. Their diffusions were greatly affected by the formulation; moreover higher amounts of substance in the epidermis and dermis were detected in ointments than in creams. The enhancement effect of propylene glycol was also observed. The differences between the 3 substances could be related to their lipophilicity, molecular structure, and molecular weight. The more hydrophobic compounds (clobetasol and betamethasone) are present in higher amounts in the epidermis and dermis, while the hydrophilic compound (flurandrenolide) is mostly present in the receptor fluid.

Impact of synthetic canine cerumen on in vitro penetration of auricular skin of dogs by florfenicol, terbinafine, and betamethasone acetate.

OBJECTIVE To determine the pharmacokinetics of florfenicol, terbinafine, and betamethasone acetate after topical application to canine auricular skin and the influence of synthetic canine cerumen on pharmacokinetics. SAMPLE Auricular skin from 6 euthanized shelter dogs (3 females and 3 neutered males with no visible signs of otitis externa). PROCEDURES Skin adjacent to the external opening of the ear canal was collected and prepared for use in a 2-compartment flow-through diffusion cell system to evaluate penetration of an otic gel containing florfenicol, terbinafine, and betamethasone acetate over a 24-hour period. Radiolabeled 14C-terbinafine hydrochloride and 3H-betamethasone acetate were added to the gel to determine dermal penetration and distribution. Florfenicol absorption was determined by use of high-performance liquid chromatography-UV detection. Additionally, the effect of synthetic canine cerumen on the pharmacokinetics of all compounds was evaluated. RESULTS During the 24-hour experiment, mean ± SD percentage absorption without the presence of synthetic canine cerumen was 0.28 ± 0.09% for 3H-betamethasone acetate, 0.06 ± 0.06% for florfenicol, and 0.06 ± 0.02% for 14C-terbinafine hydrochloride. Absorption profiles revealed no impact of synthetic canine cerumen on skin absorption for all 3 active compounds in the gel or on skin distribution of 3H-betamethasone acetate and 14C-terbinafine hydrochloride. CONCLUSIONS AND CLINICAL RELEVANCE 3H-betamethasone acetate, 14C-terbinafine hydrochloride, and florfenicol were all absorbed in vitro through healthy auricular skin specimens within the first 24 hours after topical application. Synthetic canine cerumen had no impact on dermal absorption in vitro, but it may serve as a temporary reservoir that prolongs the release of topical drugs.

Quantitative assessment of betamethasone dual-acting formulation in urine of patients with rheumatoid arthritis and ankylosing spondylitis after single-dose intramuscular administration and its application to long-term pharmacokinetic study.

Quantitative evaluation and assessment of pharmacokinetic parameters of Diprospan® (suspension for injection 7mg/mL (2mg+5mg/mL) of betamethasone) were performed in urine samples taken from patients with rheumatoid arthritis or ankylosing spondylitis for 28days after systemic intramuscular administration in routine clinical practice in an open-comparative prospective cohort study. The maximum betamethasone concentration was reached at day 4 of the follow-up; in some cases, ß-phase of elimination of the drug was appeared at day 14 or at day 21 of the follow-up. The deferred ß-phase elimination was likely a consequence of the physiological characteristics of the patients or of the influence of non-steroidal agents. The half-life of betamethasone was 8.5days. The elimination rate constant was 2.49h-1; the mean clearance was 4.72L/d. The recommended frequency of the drug administration to its complete elimination was estimated up to 48days. Mann-Whitney test showed no significant differences in pharmacokinetic characteristics between male and female subjects. The prolonged elimination phase was observed in patients with deviations in their body mass index, continual treatment by diclofenac and nimesulide or, possibly, after consuming an alcohol. The study was recorded in Clinical Trials open source with identifier NCT03119454.

Low-dose betamethasone-acetate for fetal lung maturation in preterm sheep.

BACKGROUND: Antenatal steroids are standard of care for women who are at risk of preterm delivery; however, antenatal steroid dosing and formulation have not been evaluated adequately. The standard clinical 2-dose treatment with betamethasone-acetate+betamethasone-phosphate is more effective than 2 doses of betamethasone-phosphate for the induction of lung maturation in preterm fetal sheep. We hypothesized that the slowly released betamethasone-acetate component induces similar lung maturation to betamethasone-phosphate+betamethasone-acetate with decreased dose and fetal exposure. OBJECTIVE: The purpose of this study was to investigate pharmacokinetics and fetal lung maturation of antenatal betamethasone-acetate in preterm fetal sheep. STUDY DESIGN: Groups of 10 singleton-pregnant ewes received 1 or 2 intramuscular doses 24 hours apart of 0.25 mg/kg/dose of betamethasone-phosphate+betamethasone-acetate (the standard of care dose) or 1 intramuscular dose of 0.5 mg/kg, 0.25 mg/kg, or 0.125 mg/kg of betamethasone-acetate. Fetuses were delivered 48 hours after the first injection at 122 days of gestation (80% of term) and ventilated for 30 minutes, with ventilator settings, compliance, vital signs, and blood gas measurements recorded every 10 minutes. After ventilation, we measured static lung pressure-volume curves and sampled the lungs for messenger RNA measurements. Other groups of pregnant ewes and fetuses were catheterized and treated with intramuscular injections of betamethasone-phosphate 0.125 mg/kg, betamethasone-acetate 0.125 mg/kg, or betamethasone-acetate 0.5 mg/kg. Maternal and fetal betamethasone concentrations in plasma were measured for 24 hours. RESULTS: All betamethasone-treated groups had increased messenger RNA expression of surfactant proteins A, B, and C, ATP-binding cassette subfamily A member 3, and aquaporin-5 compared with control animals. Treatment with 1 dose of intramuscular betamethasone-acetate 0.125mg/kg improved dynamic and static lung compliance, gas exchange, and ventilation efficiency similarly to the standard treatment of 2 doses of 0.25 m/kg of betamethasone-acetate+betamethasone-phosphate. Betamethasone-acetate 0.125 mg/kg resulted in lower maternal and fetal peak plasma concentrations and decreased fetal exposure to betamethasone compared with betamethasone-phosphate 0.125 mg/kg. CONCLUSION: A single dose of betamethasone-acetate results in similar fetal lung maturation as the 2-dose clinical formulation of betamethasone-phosphate+betamethasone-acetate with decreased fetal exposure to betamethasone. A lower dose of betamethasone-acetate may be an effective alternative to induce fetal lung maturation with less risk to the fetus.