Preparation and Application of Decanoic Acid/Arginine Hydrogels to a Transdermal Formulation.

We prepared a supramolecular hydrogel composed of decanoic acid and arginine (C10/Arg gel) and evaluated its application to a transdermal formulation. C10/Arg gel adjusted to pH 7 with 1 M NaOH aq or 1 M HCl aq provided a translucent hydrogel with a lamellar liquid crystal structure in the concentration region of decanoic acid ≥12% and arginine ≤9%. Rheological measurements showed that C10/Arg gel is a viscoelastic material with both solid and liquid properties, with elasticity being dominant over viscosity in the low shear stress region. The skin permeability of hydrocortisone (HC) and indomethacin (IM) from C10/Arg gels was investigated in vitro using hairless mouse skin and compared to control formulation drug suspensions (IM or HC) in water. The cumulative permeation amount of HC and IM from the C10/Arg gel at 10 h after application was approximately 16 and 11 times higher than that of the control, respectively. On the other hand, the flux of IM decreased with increasing arginine concentration, likely due to the acid-base interaction between Arg and IM in C10/Arg gel. Adequate drug skin permeation enhancement by C10/Arg gel requires optimizing the gel composition for each specific drug.

Plasma Cortisol, Aldosterone, and Ascorbic Acid Concentrations in Patients with Septic Shock Do Not Predict Treatment Effect of Hydrocortisone on Mortality. A Nested Cohort Study.

Rationale: Whether biomarkers can identify subgroups of patients with septic shock with differential treatment responses to hydrocortisone is unknown.Objectives: To determine if there is heterogeneity in effect for hydrocortisone on mortality, shock resolution, and other clinical outcomes based on baseline cortisol, aldosterone, and ascorbic acid concentrations.Methods: From May 2014 to April 2017, we obtained serum samples from 529 patients with septic shock from 22 ICUs in Australia and New Zealand.Measurements and Main Results: There were no significant interactions between the association with 90-day mortality and treatment with either hydrocortisone or placebo for total cortisol (odds ratio [OR], 1.09; 95% confidence interval [CI], 1.02-1.16 vs. OR, 1.07; 95% CI, 1.00-1.13; P = 0.70), free cortisol (OR, 1.20; 95% CI, 1.04-1.38 vs. OR, 1.16; 95% CI, 1.02-1.32; P = 0.75), aldosterone (OR, 1.01; 95% CI, 0.97-1.05 vs. OR, 1.01; 95% CI, 0.98-1.04; P = 0.99), or ascorbic acid (OR, 1.11; 95% CI, 0.89-1.39 vs. OR, 1.05; 95% CI, 0.91-1.22; P = 0.70), respectively. Similar results were observed for the association with shock resolution. Elevated free cortisol was significantly associated with 90-day mortality (OR, 1.13; 95% CI, 1.00-1.27; P = 0.04), but total cortisol, aldosterone, and ascorbic acid were not.Conclusions: In patients with septic shock, there was no heterogeneity in effect of adjunctive hydrocortisone on mortality, shock resolution, or other clinical outcomes based on cortisol, aldosterone, and ascorbic acid concentrations. Plasma aldosterone and ascorbic acid concentrations are not associated with outcome.

Stress hormones kinetics in ventricular fibrillation cardiac arrest and resuscitation: Translational and therapeutic implications.

BACKGROUND: Knowing the kinetics of endogenous stress hormones during cardiac arrest and cardiopulmonary resuscitation (CRP) will help to optimize personalized physiology-guided treatment. The aim of this study was to examine the dynamic changes in stress hormones in a swine model of ventricular fibrillation (VF) cardiac arrest. METHODS: Ventricular fibrillation was induced in 10 healthy Landrace/Large White piglets, which were subsequently left untreated for 8 min. All animals were resuscitated according to the 2015 European Resuscitation Council guidelines. The concentration of adrenalin, noradrenalin, and cortisol was measured at baseline and at the 4th and 8th minute of VF-cardiac arrest, as well as at 30-min, 60-min, 24 h and 48 h post-ROSC. RESULTS: By the end of the 4th min of VF, the animals of the ROSC group exhibited significantly higher adrenaline levels compared to those of the no-ROSC group (7264 pg/ml vs. 1648 pg/ml, p = 0.03). Noradrenaline was higher in the ROSC group at the 4th min of VF (3021 pg/ml vs. 1626 pg/ml, p = 0.02). Cortisol levels in the ROSC group were significantly lower by the end of the 8th min of VF [16.25 ng/ml vs. 92.82 ng/ml, p = 0.03]. With a cut-off point of 5970 pg/ml, adrenaline at the 4th min of VF exhibited 100% sensitivity and 80% specificity for predicting ROSC. CONCLUSION: Higher endogenous adrenaline and lower endogenous cortisol levels were associated with ROSC.

Ultradian rhythmicity of plasma cortisol is necessary for normal emotional and cognitive responses in man.

Glucocorticoids (GCs) are secreted in an ultradian, pulsatile pattern that emerges from delays in the feedforward-feedback interaction between the anterior pituitary and adrenal glands. Dynamic oscillations of GCs are critical for normal cognitive and metabolic function in the rat and have been shown to modulate the pattern of GC-sensitive gene expression, modify synaptic activity, and maintain stress responsiveness. In man, current cortisol replacement therapy does not reproduce physiological hormone pulses and is associated with psychopathological symptoms, especially apathy and attenuated motivation in engaging with daily activities. In this work, we tested the hypothesis that the pattern of GC dynamics in the brain is of crucial importance for regulating cognitive and behavioral processes. We provide evidence that exactly the same dose of cortisol administered in different patterns alters the neural processing underlying the response to emotional stimulation, the accuracy in recognition and attentional bias toward/away from emotional faces, the quality of sleep, and the working memory performance of healthy male volunteers. These data indicate that the pattern of the GC rhythm differentially impacts human cognition and behavior under physiological, nonstressful conditions and has major implications for the improvement of cortisol replacement therapy.

The circadian rhythm of corticosteroid-binding globulin has little impact on cortisol exposure after hydrocortisone dosing.

CONTEXT: Optimization of hydrocortisone replacement therapy is important to prevent under- and over dosing. Hydrocortisone pharmacokinetics is complex as circulating cortisol is protein bound mainly to corticosteroid-binding globulin (CBG) that has a circadian rhythm. OBJECTIVE: A detailed analysis of the CBG circadian rhythm and its impact on cortisol exposure after hydrocortisone administration. DESIGN AND METHODS: CBG was measured over 24 hours in 14 healthy individuals and, employing a modelling and simulation approach using a semi-mechanistic hydrocortisone pharmacokinetic model, we evaluated the impact on cortisol exposure (area under concentration-time curve and maximum concentration of total cortisol) of hydrocortisone administration at different clock times and of the changing CBG concentrations. RESULTS: The circadian rhythm of CBG was well described with two cosine terms added to the baseline of CBG: baseline CBG was 21.8 µg/mL and interindividual variability 11.9%; the amplitude for the 24 and 12 hours cosine functions were relatively small (24 hours: 5.53%, 12 hours: 2.87%) and highest and lowest CBG were measured at 18:00 and 02:00, respectively. In simulations, the lowest cortisol exposure was observed after administration of hydrocortisone at 23:00-02:00, whereas the highest was observed at 15:00-18:00. The differences between the highest and lowest exposure were minor (≤12.2%), also regarding the free cortisol concentration and free fraction (≤11.7%). CONCLUSIONS: Corticosteroid-binding globulin has a circadian rhythm but the difference in cortisol exposure is ≤12.2% between times of highest and lowest CBG concentrations; therefore, hydrocortisone dose adjustment based on time of dosing to adjust for the CBG concentrations is unlikely to be of clinical benefit.

Residual endogenous corticosteroid production in patients with adrenal insufficiency.

OBJECTIVE: This study aimed at comparing precursors of endogenous corticosteroid production in patients with primary adrenal insufficiency and in secondary adrenal insufficiency. DESIGN: Twenty patients with primary adrenal insufficiency and matched controls and 19 patients with secondary adrenal insufficiency participated in this ancillary analysis of two different studies. PATIENTS AND MEASUREMENTS: Patients with primary adrenal insufficiency were on stable hydrocortisone and fludrocortisone therapy. Patients with secondary adrenal insufficiency received two different doses of hydrocortisone in a randomized crossover study. Main outcome measures were concentrations of precursors of cortisol and aldosterone measured by LC-MS/MS RESULTS: Compared to controls, progressively lower concentrations of the glucocorticoid precursors 11-deoxycortisol, 11-deoxycorticosterone and corticosterone concentrations were found in patients with secondary adrenal insufficiency on lower hydrocortisone dose, secondary adrenal insufficiency on higher hydrocortisone dose and primary adrenal insufficiency, respectively. Half of the primary adrenal insufficient patients showed evidence of residual endogenous cortisol or aldosterone synthesis, as determined by quantifiable 11-deoxycortisol, 11-deoxycorticosterone and corticosterone conce ntrations. In secondary adrenal insufficient patients with higher endogenous cortisol production, as indicated by 11-deoxycortisol concentrations above the median, no increased cortisol exposure was observed both by plasma pharmacokinetic parameters and 24-hour free cortisol excretion in urine. CONCLUSIONS: Adrenal corticosteroid production is likely to continue during treatment in a considerable percentage of patients with both primary and secondary adrenal insufficiency. In patients with secondary adrenal insufficiency, this synthesis appears to be sensitive to the dose of hydrocortisone. However, the residual corticosteroid concentrations were quantitatively low and its clinical significance remains therefore to be determined.

Blood lead levels and hypothalamic-pituitary-adrenal function in middle-aged individuals.

Experimental and epidemiological studies suggested that exposure to lead (Pb) may influence the hypothalamic-pituitary-adrenal (HPA) axis. However, previous studies have yielded mixed results. We evaluated changes in basal salivary cortisol levels and acute cortisol responsivity to psychological stress in relation with blood Pb levels (BPb), in Caucasian individuals 50-67 years of age. Data were collected through the Study of Genetics, Stress and Cognitive Development (2004-2006). Diurnal basal and stress-reactive salivary cortisol levels were collected and BPb levels were determined using inductively coupled plasma mass spectroscopy. A total of 65 participants were included in the current study. General linear mixed models were used to assess the association between BPb level and change in cortisol secretion over time, for diurnal basal pattern and stress-reactive pattern, respectively. The geometric mean BPb was 2.70µg/dL (± 1.44) and two exposure groups were created based on the median value of 2.48µg/dL. No difference in geometric mean of salivary cortisol (µg/dL) at awakening was observed between High and Low BPb groups (0.23 (± 0.11) vs 0.20 (± 0.11), p = 0.36). The overall pattern of change in both diurnal basal (from the awakening to bedtime) and reactive salivary cortisol (during the stress induction protocol) did not differ between groups. In these middle-aged and older adults, we concluded that Pb exposure, within the range observed in the current study, was associated with neither diurnal nor stress-reactive cortisol secretion. Further investigation with larger datasets are needed to confirm our observations.

A hydrocortisone derivative binds to GAPDH and reduces the toxicity of extracellular polyglutamine-containing aggregates.

Huntington's disease (HD) has been recently shown to have a horizontally transmitted, prion-like pathology. Thus, the migration of polyglutamine-containing aggregates to acceptor cells is important for the progression of HD. These aggregates contain glyceraldehyde-3-phosphate dehydrogenase (GAPDH), which increases their intracellular transport and their toxicity. Here, we show that RX624, a derivative of hydrocortisone that binds to GAPDH, prevents the formation of aggregates of GAPDH-polyglutamine excreted into the culture medium by PC-12 rat cells expressing mutant huntingtin. RX624 was previously shown to be unable to penetrate cells and, thus, its principal therapeutic action might be the inhibition of polyglutamine-GAPDH complex aggregation in the extracellular matrix. The administration of RX624 to SH-SY5Y acceptor cells that incubated in conditioned medium from PC-12 cells expressing mutant huntingtin caused an approximately 20% increase in survival. This suggests that RX624 might be useful as a drug against polyglutamine pathologies, and that is could be administered exogenously without affecting target cell physiology. This protective effect was validated by the similar effect of an anti-GAPDH specific antibody.

Immediate versus modified release hydrocortisone in mitotane-treated patients with adrenocortical cancer.

OBJECTIVE: Mitotane induces hepatic CYP3A4 activity, resulting in accelerated cortisol inactivation, and also increases cortisol binding globulin (CBG). Therefore, higher hydrocortisone doses are required in patients with adrenocortical cancer (ACC) on mitotane treatment. Modified release hydrocortisone has not been used in mitotane-treated ACC patients yet. AIM: Case series to compare serum cortisol, calculated free serum cortisol and ACTH levels in ACC patients on mitotane treatment with immediate and modified release hydrocortisone. DESIGN: Pharmacokinetics of immediate and modified release hydrocortisone, each administered at a dose of 40-20-0 mg, in nine patients with ACC and adjuvant mitotane treatment. For comparison, ten patients with secondary adrenal insufficiency (SAI) on three different hydrocortisone regimens and ten healthy males were included. METHODS: Serum cortisol and plasma ACTH were measured by chemiluminescent enzyme immunoassay, and CBG by RIA, followed by calculation of free cortisol. RESULTS: Calculated free serum cortisol levels after 40 mg immediate release hydrocortisone in ACC patients (46 ± 14 nmol/l) were similar to those after 10 mg immediate release hydrocortisone intake in men with SAI (64 ± 16 nmol/l) or to the physiological morning free cortisol levels in healthy subjects (31 ± 5 nmol/l). Compared to immediate release hydrocortisone, free cortisol levels after 40 mg modified release hydrocortisone in ACC patients were significantly lower (12 ± 3 nmol/l; P = 0·03) resulting in a generally lower AUC (98 ± 21 vs 149 ± 37 nmol h/l; P = 0·02). CONCLUSIONS: 40-20-0 mg immediate release, but not modified release hydrocortisone, resulted in sufficient glucocorticoid coverage in patients with ACC receiving mitotane treatment. The use of equivalent doses of modified release hydrocortisone preparation should be avoided in patients on mitotane treatment.

Clinical significance of serum cortisol levels following surgery for congenital heart disease.

OBJECTIVE: Use of hydrocortisone to treat refractory haemodynamic instability in patients recovering from surgery for congenital heart disease is common practice at many centres. We aimed to determine whether there is a relationship between total serum cortisol concentrations and haemodynamic response to this therapy. Material and methods We retrospectively reviewed patients <21 years who underwent cardiac surgery from 2011 to 2013, received hydrocortisone within 72 hours postoperatively, and had total serum cortisol measurements contemporaneous with its administration. Favourable responders were defined as patients in whom, at 24 hours after hydrocortisone initiation, either (1) systolic blood pressure was increased or unchanged and vasoactive-inotrope score was decreased or (2) systolic blood pressure increased by ⩾10% of baseline and vasoactive-inotrope score was unchanged. Variables were compared using t-tests or Mann-Whitney U tests as appropriate. RESULTS: In total, 24 patients were reviewed, with a median age of 1.4 months and range of 0.1-232 months. Among them, 14 (58%) patients responded favourably to hydrocortisone. At 24 hours, the median change in vasoactive-inotrope score was -18% in favourable responders and +31% in those who did not respond favourably, p=0.001. The mean pre-hydrocortisone total serum cortisol in favourable responders was 17.4±10.9 µg/dl compared with 46.1±44.7 µg/dl in those who did not respond favourably, p=0.03. CONCLUSION: Total serum cortisol obtained before initiation of hydrocortisone was significantly lower in patients who responded favourably to this therapy. Total serum cortisol may therefore be helpful in identifying children recovering from cardiac surgery who may or may not haemodynamically improve with hydrocortisone.

Improvement of side-effects and treatment on the experimental colitis in mice of a resin microcapsule-loading hydrocortisone sodium succinate.

CONTEXT: Extensive or long-time use of corticosteroids often causes many toxic side-effects. The ion exchange resins and the coating material, Eudragit, can be used in combination to form a new oral delivery system to deliver corticosteroids. OBJECTIVES: The resin microcapsule (DRM) composed by Amberlite 717 and Eudragit S100 was used to target hydrocortisone (HC) to the colon in order to improve its treatment effect on ulcerative colitis (UC) and reduce its toxic side-effects. METHODS: Hydrocortisone sodium succinate (HSS) was sequentially encapsulated in Amberlite 717 and Eudragit S100 to prepare the HSS-loaded resin microcapsule (HSS-DRM). The scanning electron microscopy (SEM) was employed to investigate the morphology and structure of HSS-DRM. The in vitro release and in vivo studies of pharmacokinetics and intestinal drug residues in rat were used to study the colon-targeting of HSS-DRM. The mouse induced by 2,4,6-trinitrobenzenesulfonic acid was used to study the treatment of HSS-DRM on experimental colitis. RESULTS: SEM study showed good morphology and structure of HSS-DRM. In the in vitro release study, > 80% of HSS was released in the colon environment (pH 7.4). The in vivo studies showed good colon-targeting of HSS-DRM (Tmax = 0.97 h, Cmax = 118.28 µg/mL of HSS; Tmax = 2.16 h, Cmax = 64.47 µg/mL of HSS-DRM). Moreover, the HSS-DRM could reduce adverse reactions induced by HSS and had good therapeutic effects on the experimental colitis. CONCLUSIONS: The resin microcapsule system has good colon-targeting and can be used in the development of colon-targeting preparations.

Evaluation of γ-cyclodextrin effect on permeation of lipophilic drugs: application of cellophane/fused octanol membrane.

According to the Biopharmaceutics Classification System, oral bioavailability of drugs is determined by their aqueous solubility and the ability of the dissolved drug molecules to permeate lipophilic biological membranes. Similarly topical bioavailability of ophthalmic drugs is determined by their solubility in the aqueous tear fluid and their ability to permeate the lipophilic cornea. Enabling pharmaceutical excipients such as cyclodextrins can have profound effect on the drug bioavailability. However, to fully appreciate such enabling excipients, the relationship between their effects and the physicochemical properties of the permeating drug needs to be known. In this study, the permeation enhancing effect of γ-cyclodextrin (γCD) on saturated drug solutions containing hydrocortisone (HC), irbesartan (IBS), or telmisartan (TEL) was evaluated using cellophane and fused cellulose-octanol membranes in a conventional Franz diffusion cell system. The flux (J), the flux ratio (JR) and the apparent permeability coefficients (Papp) demonstrate that γCD increases drug permeability. However, its efficacy depends on the drug properties. Addition of γCD increased Papp of HC (unionized) and IBS (partially ionized) through the dual membrane but decreased the Papp of TEL (fully ionized) that displays low complexation efficacy. The dual cellophane-octanol membrane system was simple to use and gave reproducible results.

[Spacer, Aerosol Therapy through Space and Time]. / Spacer, Aerosoltherapie durch Raum und Zeit.

Aim of the literature review Within this review, results of a literature analysis on the application of spacers with pressurized metered dose inhalers (pMDI) are described and evaluated. Methods Next to an extensive revision on effects of spacers, the impacts of current guidelines and the conditions for product authorisations on the use of spacers are described which result from the interplay of characteristics from dose inhalers with a spacer. Results Spacers are generally useful to avoid coordination problems concerning the actuation of a pMDI at the beginning of an inhalation. Furthermore, in comparison to the pMDI application without a spacer a reduced mouth-throat deposition is applicable to all pMDI spacer combinations. However, some new pMDI release the aerosol in a quality that may not necessarily require a spacer to avoid a high drug deposition in the mouth-throat area as the aerosol quality will not be greatly improved with a spacer. The delivered mass of the active ingredient as well as the aerosol quality released from a spacer vary substantially with the use of different spacers. A change of spacer while using the same dose inhaler can maximally result in a doubling or halving of the quantity of the active ingredient applied. These facts are nowadays considered by the European regulatory agency. Conclusion If a spacer application is intended for pMDIs that were developed and approved after 2009, the correspondent SMP (Summary of Product Characteristics) should at least make one specific recommendation for a spacer that should be based upon relevant in vitro data or additional in vivo data. If a different spacer than the recommended one is used, the effectively applied dose cannot be correctly anticipated. This should be considered when choosing a spacer.

A stable hydrocortisone nanosuspension for improved dissolution: Preparation, characterization and in vitro evaluation.

Drug nanosuspensions have gained tremendous attraction as a platform in drug delivery. In the present work, a nanosuspension was prepared by a wet milling approach in order to increase saturation solubility and dissolution of the water insoluble drug, hydrocortisone. Size of the generated particeles was 290 nm ± 9 nm having a zeta potential of -1.9 mV ± 0.6 mV. Nanosized particles were found to have a rod shape with a narrow particle size distribution (PDI =0.17). Results of differential scanning calorimetry and X-ray diffraction analyses revealed minor modifications of crystallinity of hydrocortisone following the milling process. Solubility of hydrocortisone was enhanced by nanonization to 875µg/ml ±2.5, an almost 2.9-fold compared to the raw hydrocortisone. Moreover, the nanosuspension formulation substabtially enhanced the dissolution rate of hydrocortisone where >97% of the hydrocortisone was dissolved within 10 minutes opposed to 22.3% for the raw 50% for the raw hydrocortisone and the commercial tablet, respectively. The bioavailability study resulted in AUC 0-9h for HC nanosuspensions (31.50±2.50), which is significantly (p<0.05) higher compared to the AUC 0-9h (14.85±3.25) resulted for HC solution. The nanosuspension was physically stable at room temperature for 24 months.

Pharmacokinetics of intra-articular betamethasone sodium phosphate and betamethasone acetate and endogenous hydrocortisone suppression in exercising horses.

To the date, no reports exist of the pharmacokinetics (PK) of betamethasone (BTM) sodium phosphate and betamethasone acetate administered intra-articular (IA) into multiple joints in exercising horses. The purpose of the study was to determine the PK of BTM and HYD concentrations in plasma and urine after IA administration of a total of 30 mg BTM. Eight 4 years old Thoroughbred mares were exercised on a treadmill and BTM was administered IA. Plasma and urine BTM and HYD were determined via high performance liquid chromatography spectrometry for 6 weeks. Concentration-time profiles of BTM and HYD in plasma and urine were used to generate PK estimates for non-compartmental analyses and comparisons among times and HYD concentrations. BTM in plasma had greater Tmax (Tmax 0.8 h) vs. urine (Tmax 7.1 h). Urine BTM concentration (ng/mL) and amount (AUClast ; h × ng/mL) were greater than plasma. HYD was suppressed for at least 3 days (<1 ng/mL) for all horses. The time of last quantifiable concentration of BTM (Tlast ; hour) was not significantly different in plasma than urine. Use of highly sensitive HPLC-MS/MS assays enabled early detection and prolonged and consistent determination of BTM in plasma and urine.

The role of ceramide chain length distribution on the barrier properties of the skin lipid membranes.

The skin barrier function is provided by the stratum corneum (SC). The lipids in the SC are composed of three lipid classes: ceramides (CERs), cholesterol (CHOL) and free fatty acids (FFAs) which form two crystalline lamellar structures. In the present study, we investigate the effect of CER chain length distribution on the barrier properties of model lipid membranes mimicking the lipid composition and organization of SC. The membranes were prepared with either isolated pig CERs (PCERs) or synthetic CERs. While PCERs have a wide chain length distribution, the synthetic CERs are quite uniform in chain length. The barrier properties were examined by means of permeation studies using hydrocortisone as a model drug. Our studies revealed a reduced barrier in lipid membranes prepared with PCERs compared to synthetic CERs. Additional studies revealed that a wider chain length distribution of PCERs results in an enhanced hexagonal packing and increased conformational disordering of the lipid tails compared to synthetic CERs, while the lamellar phases did not change. This demonstrates that the chain length distribution affects the lipid barrier by reducing the lipid ordering and density within the lipid lamellae. In subsequent studies, the effect of increased levels of FFAs or CERs with a long acyl chain in the PCERs membranes was also studied. These changes in lipid composition enhanced the level of orthorhombic packing, reduced the conformational disordering and increased the barrier of the lipid membranes. In conclusion, the CER chain length distribution is an important key factor for maintaining a proper barrier.

Variation in absorption and half-life of hydrocortisone influence plasma cortisol concentrations.

BACKGROUND: Hydrocortisone therapy should be individualized in congenital adrenal hyperplasia (CAH) patients to avoid over and under replacement. We have assessed how differences in absorption and half-life of cortisol influence glucocorticoid exposure. PATIENTS AND METHODS: Forty-eight patients (21 M) aged between 6·1 and 20·3 years with CAH due to CYP21A2 deficiency were studied. Each patient underwent a 24-h plasma cortisol profile with the morning dose used to calculate absorption parameters along with an intravenous (IV) hydrocortisone (15 mg/m(2) body surface area) bolus assessment of half-life. Parameters derived were maximum plasma concentration (Cmax ), time of maximum plasma concentration (tmax ), time to attaining plasma cortisol concentration <100 nmol/l and half-life of cortisol. RESULTS: Mean half-life was 76·5 ± 5·2 (range 40-225·3) min, Cmax 780·7 ± 61·6 nmol/l and tmax 66·7 (range 20-118) min. Time taken to a plasma cortisol concentration less than 100 nmol/l was 289 (range 140-540) min. Those with a fast half-life and slow tmax took longest to reach a plasma cortisol concentration less than 100 nmol/l (380 ± 34·6 min), compared to those with a slow half-life and fast tmax (298 ± 34·8 min) and those with a fast half-life and fast tmax (249·5 ± 14·4 min) (One-way anovaF = 4·52; P = 0·009). CONCLUSIONS: Both rate of absorption and half-life of cortisol in the circulation play important roles in determining overall exposure to oral glucocorticoid. Dose regimens need to incorporate estimates of these parameters into determining the optimum dosing schedule for individuals.

Metabolite profiling and pharmacokinetic evaluation of hydrocortisone in a perfused three-dimensional human liver bioreactor.

Endotoxin lipopolysaccharide (LPS) is known to cause liver injury primarily involving inflammatory cells such as Kupffer cells, but few in vitro culture models are applicable for investigation of inflammatory effects on drug metabolism. We have developed a three-dimensional human microphysiological hepatocyte-Kupffer cell coculture system and evaluated the anti-inflammatory effect of glucocorticoids on liver cultures. LPS was introduced to the cultures to elicit an inflammatory response and was assessed by the release of proinflammatory cytokines, interleukin 6 and tumor necrosis factor α. A sensitive and specific reversed-phase-ultra high-performance liquid chromatography-quadrupole time of flight-mass spectrometry method was used to evaluate hydrocortisone disappearance and metabolism at near physiologic levels. For this, the systems were dosed with 100 nM hydrocortisone and circulated for 2 days; hydrocortisone was depleted to approximately 30 nM, with first-order kinetics. Phase I metabolites, including tetrahydrocortisone and dihydrocortisol, accounted for 8-10% of the loss, and 45-52% consisted of phase II metabolites, including glucuronides of tetrahydrocortisol and tetrahydrocortisone. Pharmacokinetic parameters, i.e., half-life, rate of elimination, clearance, and area under the curve, were 23.03 hours, 0.03 hour(-1), 6.6 × 10(-5) l⋅hour(-1), and 1.03 (mg/l)*h, respectively. The ability of the bioreactor to predict the in vivo clearance of hydrocortisone was characterized, and the obtained intrinsic clearance values correlated with human data. This system offers a physiologically relevant tool for investigating hepatic function in an inflamed liver.

Increased bioavailability of hydrocortisone dissolved in a cream base.

BACKGROUND/OBJECTIVES: The aim of this study was to compare vasoconstrictor activity and, by inference, the clinical anti-inflammatory effectiveness of hydrocortisone in two different formulations: 1% dissolved hydrocortisone cream and 1% dispersed hydrocortisone cream. Moisturising capacity and safety were also determined. METHODS: Both topical preparations were applied without occlusion on forearms twice daily for 5 days. An assessment of vasoconstriction was performed in a double-blinded manner pretreatment and then thrice daily for 6 days and once 7 days post-application, using an objective rating scale. For the dissolved preparation only, moisturising capacity was determined by measurement of transepidermal water loss (TEWL) at 0, 2, 4, 6 and 24 h, and also by the measurement of water content at 0 and 24 h. Safety was assessed by repeat insult patch tests (RIPT). RESULTS: In all, 10 volunteers completed the vasoconstrictor and moisturising studies, while 52 completed the RIPT. For 1% dissolved hydrocortisone cream and 1% dispersed hydrocortisone cream, respectively, areas under the blanching curves were 1240 and 295; total scores were 129.0 and 31.5; summed % total possible scores were 161.3 and 39.4; Tm/10 mean values were 3.47 and 1.64. The 1% dissolved hydrocortisone cream was found to be statistically more potent than the 1% dispersed hydrocortisone cream. Furthermore, the 1% dissolved hydrocortisone cream was found to be moisturising compared to no treatment. No adverse events were observed. CONCLUSIONS: A cream containing 1% dissolved hydrocortisone exhibits greater vasoconstrictor activity than a cream containing 1% dispersed hydrocortisone.

An oral multiparticulate, modified-release, hydrocortisone replacement therapy that provides physiological cortisol exposure.

OBJECTIVE: It is not possible with current hydrocortisone replacement to mimic the diurnal cortisol profile in patients with adrenal insufficiency. Previous attempts with modified-release technology were unsuccessful. Our objective was to develop hydrocortisone formulations that recreate the diurnal cortisol profile using multiparticulate technology. DESIGN AND MEASUREMENTS: Screening by in vitro dissolution profiles, pharmacokinetic (PK) testing in dexamethasone-suppressed dogs and humans, and comparison with a reference population. SETTING: Field laboratories and clinical research facility. RESULTS: Formulations were generated using an enteric (delayed release) design configuration with an extended (sustained release) dissolution profile. In vitro dissolution confirmed delayed and sustained hydrocortisone release. However, in dogs and humans, sustained release resulted in reduced bioavailability. A formulation, DIURF-006, was developed that maintained delayed release but omitted the sustained-release functionality. PK characterization of DIURF-006 showed that, despite absence of a sustained-release component, absorption was sufficiently sustained to deliver extended hydrocortisone absorption. In dexamethasone-suppressed volunteers (n = 16) receiving a twice-daily 'toothbrush' regimen (20 mg at 23:00 h and 10 mg at 07:00 h), DIURF-006 gave a similar cortisol profile to physiological cortisol levels: DIURF-006 vs physiological, Geomean AUC 5610 vs 4706 h * nmol/l, Geomean Cmax 665 vs 594 nmol/l and Median Tmax 8·5 h vs clock time 08:12 h for peak cortisol. The relative bioavailability of DIURF-006 vs hydrocortisone was 89%, and cortisol levels increased linearly with doses between 5 and 30 mg. CONCLUSION: A multiparticulate oral hydrocortisone formulation with only an enteric coat provides delayed and sustained absorption and when given in a 'toothbrush' regimen provides physiological cortisol exposure.