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The purpose of replacement therapy in adrenal insufficiency (AI) is mimicking endogenous cortisol levels as closely as possible: dual release hydrocortisone (DR-HC) has been introduced to replicate the circadian cortisol rhythm. Multiple daily saliva collections could be used to assess the cortisol rhythm during real life: our aim was to study the salivary cortisol profile in AI.
Corticosteroids have been used for decades to modulate inflammation therapeutically, yet there is a paucity of data on their effects in humans. We examined the changes in cellular and molecular immune system parameters, or "immunome", in healthy humans after systemic corticosteroid administration. We used multiplexed techniques to query the immunome in 20 volunteers at baseline, and after intravenous hydrocortisone (HC) administered at moderate (250 mg) and low (50 mg) doses, to provide insight into how corticosteroids exert their effects. We performed comprehensive phenotyping of 120 lymphocyte subsets by high dimensional flow cytometry, and observed a decline in circulating specific B and T cell subsets, which reached their nadir 4-8 hours after administration of HC. However, B and T cells rebounded above baseline 24 hours after HC infusion, while NK cell numbers remained stable. Whole transcriptome profiling revealed down regulation of NF-κB signaling, apoptosis, and cell death signaling transcripts that preceded lymphocyte population changes, with activation of NK cell and glucocorticoid receptor signaling transcripts. Our study is the first to systematically characterize the effects of corticosteroids on the human immunome, and we demonstrate that HC exerts differential effects on B and T lymphocytes and natural killer cells in humans.
Low birth weight increases neonatal morbidity and mortality, and surviving infants have increased risk of metabolic and cardiovascular disturbances later in life, as well as other neurological, psychiatric, and immune complications. A gestational excess of glucocorticoids (GCs) is a well-known cause for fetal growth retardation, but the biological basis for this association remains elusive. Placental growth is closely related to fetal growth. The placenta is the main regulator of nutrient transport to the fetus, resulting from the difference between placental nutrient uptake and the placenta's own metabolism. The aim of this study was to analyze how excess hydrocortisone affects placental glucose and lipid metabolism. Human placenta explants from term physiological pregnancies were cultured for 18 hours under different hydrocortisone concentrations (2.75, 5.5, and 55 mM; 1, 2, and 20 mg/ml). Placental glucose and lipid uptake and the metabolic partitioning of fatty acids were quantified by isotopic techniques, and expression of specific glucose transporter GLUT1 was quantified by western blot. Cell viability was assessed by MTT, immunohistochemistry and caspase activity. We found that excess hydrocortisone impairs glucose uptake and lipoprotein lipase (LPL) activity, coincident with a GC-dose dependent inhibition of fatty acid oxidation and esterification. None of the experimental conditions showed an increased cell death. In conclusion, our results show that GC overexposure exerts a dysfunctional effect on lipid transport and metabolism and glucose uptake in human placental explants. These findings could well be directly related to a reduced placental growth and possibly to a reduced supply of nutrients to the fetus and the consequent fetal growth retardation and metabolic programming.
Hydrocortisone (HC) nanocrystals intended for parenteral administration of HC were produced by anti-solvent crystallisation within coaxial assemblies of pulled borosilicate glass capillaries using either co-current flow of aqueous and organic phases or counter-current flow focusing. The organic phase was composed of 7 mg/mL of HC in a 60:40 (v/v) mixture of ethanol and water and the anti-solvent was milli-Q water. The microfluidic mixers were fabricated with an orifice diameter of the inner capillary ranging from 50 µm to 400 µm and operated at the aqueous to organic phase flow rate ratio ranging from 5 to 25. The size of the nanocrystals decreased with increasing aqueous to organic flow rate ratio. The counter-current flow microfluidic mixers provided smaller nanocrystals than the co-current flow devices under the same conditions and for the same geometry, due to smaller diameter of the organic phase stream in the mixing zone. The Z-average particle size of the drug nanocrystals increased from 210⁻280 nm to 320⁻400 nm after coating the nanocrystals with 0.2 wt % aqueous solution of hydroxypropyl methylcellulose (HPMC) in a stirred vial. The differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD) analyses carried out on the dried nanocrystals stabilized with HPMC, polyvinyl pyrrolidone (PVP), and sodium lauryl sulfate (SLS) were investigated and reported. The degree of crystallinity for the processed sample was lowest for the sample stabilised with HPMC and the highest for the raw HC powder.
The benefits and risks of low-dose hydrocortisone in patients with septic shock have been investigated in numerous randomised controlled trials and trial-level meta-analyses. Yet, the routine use of this treatment remains controversial. To overcome the limitations of previous meta-analyses inherent to the use of aggregate data, we will perform an individual patient data meta-analysis (IPDMA) on the effect of hydrocortisone with or without fludrocortisone compared with placebo or usual care on 90-day mortality and other outcomes in patients with septic shock.
The present study aimed to investigate the genetic effects of hydrocortisone (HC) treatment on keloids and screen medicines to be used in a combination therapy of keloids with HC. The dataset GSE7890 was downloaded from Gene Expression Omnibus. It contained data regarding 4 fibroblast samples from normal scar tissue and 5 samples from keloid tissue with HC treatment, as well as 5 samples from normal scar and 5 samples from keloids without HC treatment. Following the identification of differentially expressed genes (DEGs), the functions of these DEGs were analyzed by Gene Ontology (GO) and pathway enrichment analyses. Furthermore, adverse effects of HC were identified using WebGestalt. Additionally, candidate small molecule drugs associated with keloids were selected from a connectivity map database. A total of 166 and 41 DEGs, with and without HC treatment respectively, were only present in dermal fibroblasts from keloids (termed genesets A and B, respectively). A set of 26 DEGs was present following both treatments (geneset C). A number of DEGs in geneset B (COL18A1 and JAG1) were associated with endothelial cell differentiation. However, in genesets A and C, certain genes (CCNB1 and CCNB2) were involved in the cell cycle and p53 signaling pathways, and a number of genes (IL1R1 and COL1A1) were associated with bone loss. Additionally, numerous small molecule drugs (including acemetacin) were associated with keloids. Thus, it has been determined that HC may treat keloids by targeting genes associated to endothelial cell differentiation (COL18A1 and JAG1). However, HC has a number of adverse effects, including bone loss. Acemetacin may be applied in a combination therapy, along with HC, to treat keloids.
Clam peptides, marine-derived biological peptides, have been broadly investigated and applied as health foods, among which immunomodulation is one of their biological activities that cannot be ignored in vivo. In this study, we concentrated on exploring the effects of Ruditapes philippinarum peptides (RPPs) on immunomodulation and the balance of intestinal microbiota in hydrocortisone (HC)-induced immunosuppressed mice. The results revealed that RPPs could increase the thymus and spleen indices and number of white blood cells, promote the secretion level of cytokines (IL-2, IL-6, TNF-α, and INF-γ), repair the morphology of the spleen and thymus, and enhance the proliferation of T-lymphocyte subsets in immunosuppressed mice. Moreover, RPPs improved the abundance of beneficial bacteria and preserved the ecological equilibrium of the gut microbiota. In conclusion, RPPs have significant immunomodulatory effects on immunosuppressed mice and may be developed as immunomodulators or immune adjuvants in functional foods and drugs; they are also beneficial to the utilization of the high value of marine shellfish.
Bariatric surgery is the effective management of obesity; however, postoperative pain is associated with a great morbidity. The management of pain is important for the enhancement of patient recovery. Local anesthetics can be injected during laparoscopic surgery into the peritoneum throughout the ports produced either before the beginning of laparoscopy or before the closure of the wound to reduce postoperative pain. Our aim is to evaluate if there is an additive analgesic effect by the administration of intraperitoneal hydrocortisone with streamed intraperitoneal bupivacaine as a method of postoperative pain relief in laparoscopic bariatric surgeries.
This study was conducted to formulate, characterize, and investigate the bioavailability of hydrocortisone (HCT) when prepared as solid dispersions. HCT was mixed in an organic solvent with polyethylene glycol 4000 (PEG 4000) and Kolliphor® P 407. Spray drying technique was employed to form a solid dispersion formulation at a specific ratio. Physical and chemical characterization of the formed particles were achieved using differential scanning calorimetry, scanning electron microscopy, Fourier transform infrared spectroscopy, and powder X-ray diffractometry. Furthermore, comparative in vitro and in vivo studies were conducted between the formulated particles against neat HCT. The formulated solid dispersion showed elongated particles with leaf-like structure. Formation of new chemical bonds in the formed particle was suggested due to the change in the vibrational wave numbers and the significant improvement in the bioavailability of the dispersed particles proved the importance of this technique.
It has been proposed that corticosteroid cross-reactions occur more frequently within structurally well-defined groups. To test this hypothesis we have compared the patch-test reactions to other corticosteroids in 96 patients allergic to hydrocortisone. We found that our data did not agree with the previously proposed classification. The presence of a substitution at the C6 or C9 position was the most important factor in determining whether a patient would be allergic to another corticosteroid. This information should facilitate the choice of an alternative corticosteroid in patients allergic to hydrocortisone, if facilities for patch testing to other corticosteroids are not available.
With the aim of identifying biomarkers of glucocorticoid action and their relationship with biomarkers of insulin action, metabolomic profiling was carried out in plasma samples from twenty healthy men who were administered either a low or medium dose insulin infusion (n = 10 each group). In addition, all subjects were given metyrapone (to inhibit adrenal cortisol secretion) + /- hydrocortisone (HC) in a randomised crossover design to produce low, medium and high glucocorticoid levels. The clearest effects of insulin were to reduce plasma levels of the branched chain amino acids (BCAs) leucine/isoleucine and their deaminated metabolites, and lowered free fatty acids and acylcarnitines. The highest dose of hydrocortisone increased plasma BCAs in both insulin groups but increased free fatty acids only in the high insulin group, however hydrocortisone did not affect the levels of acyl carnitines in either group. The clearest interaction between HC and insulin was that hydrocortisone produced an elevation in levels of BCAs and their metabolites which were lowered by insulin. The direct modulation of BCAs by glucocorticoids and insulin may provide the basis for improved in vivo monitoring of glucocorticoid and insulin action.
Alzheimer's disease (AD), an age-related degenerative disorder, is characterized by β-amyloid deposition, abnormal phosphorylation of tau proteins, synaptic dysfunction, neuroinflammation, and oxidative stress. Despite extensive research, there are no medications or therapeutic interventions to completely treat and reverse AD. Herein, we explore the potential of hydrocortisone (HC), a natural and endogenous glucocorticoid known to have potent anti-inflammatory properties, in an Aβ1-42-induced AD mouse model. Our investigation highlights the beneficial effects of HC administration on cognitive impairment, synaptic function enhancement, and neuronal protection in Aβ1-42-induced AD mice. Notably, HC treatment effectively suppresses the hyperactivation of microglia and astrocytes, leading to a reduction in proinflammatory factors and alleviation of neuroinflammation. Furthermore, HC intervention demonstrates the capacity to mitigate the generation of ROS and oxidative stress. These compelling findings underscore the potential therapeutic application of HC in AD and present promising opportunities for its utilization in AD prevention and treatment. The implications drawn from our findings indicate that hydrocortisone holds promise as a viable candidate for adjunctive use with other anti-AD drugs for the clinical management of patients presenting with moderate to severe AD.
Combined hydrocortisone and fludrocortisone therapy for septic shock has not been evaluated with an independent systematic review. We aimed to elucidate the beneficial effects of a dual corticosteroid treatment regime involving both hydrocortisone and fludrocortisone for adult patients with septic shock on mortality.
An isocratic sensitive and precise reverse phase high-performance liquid chromatography (RP-HPLC) method was developed and validated for the determination and quantification of hydrocortisone in controlled-release and conventional (tablets and injections) pharmaceutical preparations. Chromatographic separation was achieved on an ODS (C18), 5 μm, 4.6 × 150 mm, with an isocratic elution using a freshly prepared mobile phase of composition methanol : water : acetic acid (60 : 30 : 10, v/v/v) at a flow rate of 1.0 ml/min. The detection of the drug was successfully achieved at a wavelength of 254 nm. The retention time obtained for the drug was 2.26 min. The proposed method produced linear detectable responses in the concentration range of 0.02 to 0.4 mg/ml of hydrocortisone. High recoveries of 98-101% were attained at concentration levels of 80%, 100%, and 120%. The intraday and interday precision (RSD) were 0.19-0.55% and 0.33-0.71%, respectively. A comparison of hydrocortisone analyses data from the developed method and the official USP method showed no significant difference (p > 0.05) at a 95% confidence interval. The method was successfully applied to the determination and quantification of hydrocortisone in six controlled-release and fifteen conventional release pharmaceutical preparations.
Modulation of Cys-loop receptors by steroids is of physiological and therapeutical relevance. Nonetheless, its molecular mechanism has not been elucidated for serotonin (5-HT) type 3 receptors. We deciphered the mechanism of action of hydrocortisone (HC) at 5-HT type 3A receptors. Single-channel currents from the high-conductance form (∼4.7 pA, -70 mV) appear as a series of long opening events forming bursts, which group into long clusters. Although they are very infrequent, subconductance events (∼2.4 pA) are detected within clusters. HC produces a significant concentration-dependent reduction in open and burst durations, demonstrating open-channel block. In addition, it increases the appearance of subconductance levels in a concentration- and slightly voltage-dependent manner. The amplitude of the subconductance level does not change with HC concentration and its open duration is briefer than that of full amplitude events, indicating lower open-channel stability. Dual effects are distinguished from macroscopic responses: HC reduces amplitude by acting from either open or closed states, and it increases decay rates from the open state. Thus, HC acts as a negative modulator of 5-HT type 3A receptors by different mechanisms: It acts as an open-channel blocker and it favors opening to a preexisting subconductance level. The latter constitutes a novel, to our knowledge, mechanism of channel modulation, which might be applicable to other steroids and channels.
Hydrocortisone has been utilized in the management of adrenal insufficiency. For pediatric patients, the commercially available enteral form of hydrocortisone tablets (Cortoril®) is administered in powder form after being compounded by a pharmacist. However, the stability and quality of compounded hydrocortisone powder have not been verified. In this study, we formulated a 20 mg/g oral hydrocortisone powder by adding lactose monohydrate to crushed and filtered hydrocortisone tablets and assessed the stability and physical properties of this compounded product in polycarbonate amber bottles or coated paper packages laminated with cellophane and polyethylene. Stability was examined over 120 days in three storage conditions: closed bottle, in-use bottle, and laminated paper. Drug dissolution and powder X-ray diffraction analysis were conducted to assess its physicochemical stabilities. Validated liquid chromatography-diode array detection was used to detect and quantify hydrocortisone and its degradation products. Although impurity B (cortisone) and G (hydrocortisone-21-aldehyde) were found after 120 days of storage, no crystallographic and dissolution changes were noted. Hydrocortisone content was maintained between 90% and 110% of initial contents for 120 days at 25 ± 2 °C and 60 ± 5% relative humidity in all packaging conditions.
Impaired hippocampal function is believed to be important in the pathogenesis of depression. The hippocampus contains a high concentration of both mineralocorticoid (MR) and glucocorticoid receptors (GR), and the experimental administration of corticosteroids has been reported to mimic memory impairments seen in depression. Using pharmacological functional magnetic resonance imaging (phMRI) we investigated whether hippocampal function is altered after acute administration of hydrocortisone. Changes in BOLD signal following infusion of 100mg hydrocortisone given as a rapid intravenous bolus were measured in 14 healthy volunteers in a within-subject placebo-controlled crossover design. Subsequently, subjects completed an n-back task during an fMRI scan. Hydrocortisone infusion caused a significant, time-dependent increase in fMRI BOLD signal in hippocampus reaching a maximal effect at 11-19min. The n-back task increased BOLD signal in prefrontal and parietal cortical areas and decreased it in the hippocampus. After hydrocortisone the left hippocampal decrease in BOLD signal was attenuated with the magnitude of attenuation correlating with the increase seen after hydrocortisone infusion. No difference in behavioural task performance was observed. The results suggest acute hydrocortisone has rapid direct and modulatory influences on hippocampal function, probably acting through non-genomic GR or MR signalling. Hydrocortisone infusion phMRI may be a useful tool to investigate hippocampal corticosteroid receptor function in depression.
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