Dispersible hydrolytically sensitive nanoparticles for nasal delivery of thyrotropin releasing hormone (TRH).

Nose-to-brain delivery of drugs is affected by nanoparticles (NPs) deposited on the olfactory surface and absorbed directly into the brain. Thyrotropin releasing hormone (TRH), a water soluble drug used for treating suicidal patients, was incorporated into a fast degrading poly(sebacic anhydride) (PSA) NPs. NPs were prepared by a solvent-antisolvent process under strict anhydrous environment to obtain high TRH loading and to avoid premature PSA degradation and TRH release. PSA and TRH were dissolved in a mixture of dichloromethane and ethanol and added dropwise to a dispersion of mannitol particles in heptane as an antisolvent. Mannitol powder was included in the antisolvent, so that formed NPs adhered to the mannitol microparticles for easy isolation and immediate dispersion in water prior to use. The size, surface charge, and morphology of the TRH-PSA NPs were determined using dynamic light scattering (DLS), zeta-potential, and Scanning Electron Microscopy (SEM), respectively. The NPs prepared were uniform and spherical of ~250 nm. Further, the in vitro release profile of TRH from NPs lasted for 12 h with most TRH released within the first hour in water. Concentration dependent cell toxicity studies revealed low toxicity level at low concentrations of the NPs. Surface adsorption of the NPs was also uniform on the cell surface as examined through the odyssey near infrared fluorescence (NIR) images using Indocyanine green (ICG). The NPs are designed to enable direct delivery to the olfactory epithelium using a refillable nasal atomizer that deposits mist onto the olfactory neuro-epithelium.

Dual-hormone artificial pancreas: benefits and limitations compared with single-hormone systems.

Technological advances have made the artificial pancreas a reality. This has the potential to improve the lives of individuals with Type 1 diabetes by reducing the risk of hypoglycaemia, achieving better overall glucose control, and enhancing quality of life. Both single-hormone (insulin-only) and dual-hormone (insulin and glucagon) systems have been developed; however, a focused review of the relative benefits of each artificial pancreas system is needed. We reviewed studies that directly compared single- and dual-hormone systems to evaluate the efficacy of each system for preventing hypoglycaemia and maintaining glycaemic control, as well as their utility in specific situations including during exercise, overnight and during the prandial period. We observed additional benefits with the dual-hormone artificial pancreas for reducing the risk of hypoglycaemic events overall and during exercise over the study duration. The single-hormone artificial pancreas was sufficient for maintenance of euglycaemia in the overnight period and for preventing late-onset post-exercise hypoglycaemia. Future comparative studies of longer duration are required to determine whether one system is superior for improving mean glucose control, eliminating severe hypoglycaemia, or improving quality of life.

Population Pharmacokinetics of Subcutaneous Pasireotide in Healthy Volunteers and Cushing's Disease Patients.

BACKGROUND AND OBJECTIVE: Pasireotide (SOM230, Signifor®) is a somatostatin analog approved in a subcutaneous formulation for the treatment of Cushing's disease. This analysis characterizes the population pharmacokinetics (PopPK) of subcutaneous pasireotide jointly in healthy volunteers (HVs) and Cushing's disease patients (CDPs), evaluating the effects of age, body size, and population on pasireotide pharmacokinetics. METHODS: The analysis dataset included five phase I studies and one each from phase II and phase III. A three-compartment, linear structural pharmacokinetic model was used. Models were specified a priori that varied in the relationship between HVs and CDPs, and the model with the lowest value of the Bayes Information Criterion (BIC) was selected. It was then used to illustrate various features of pasireotide pharmacokinetics. RESULTS AND CONCLUSIONS: In the final model, the estimated values of apparent clearance (CL/F), central volume of distribution, and deep peripheral volume of distribution of pasireotide in CDP were 59, 43, and 225% those of HVs at the same age and body size. Clearance increased with body size and decreased with age similarly for CDPs and HVs. The estimated CL/F for a typical CDP (40 years old, lean body weight [LBW] 49 kg) was 3.72 L/h, and for a typical HV (29 years old, LBW 61 kg) was 7.96 L/h. The model was judged adequate by visual predictive checks and diagnostic plots separately for HVs and CDPs and can be used for simulations for deriving exposure-response metrics for pharmacokinetic/pharmacodynamic analyses.

Rational Design of Dual Agonist-Antibody Fusions as Long-acting Therapeutic Hormones.

Recent studies have suggested that modulation of two or more signaling pathways can achieve substantial weight loss and glycemic stability. We have developed an approach to the generation of bifunctional antibody agonists that activate leptin receptor and GLP-1 receptor. Leptin was fused into the complementarity determining region 3 loop of the light chain alone, or in combination with exendin-4 (EX4) fused at the N-terminus of the heavy chain of Herceptin. The antibody fusions exhibit similar or increased in vitro activities on their cognate receptors, but 50-100-fold longer circulating half-lives in rodents compared to the corresponding native peptides/proteins. The efficacy of the leptin/EX4 dual antibody fusion on weight loss, especially fat mass loss, was enhanced in ob/ob mice and DIO mice compared to the antibody fusion of either EX4 or leptin alone. This work demonstrates the versatility of this combinatorial fusion strategy for generating dual antibody agonists with long half-lives.

Population pharmacokinetics of unbound hydrocortisone in critically ill neonates and infants with vasopressor-resistant hypotension.

OBJECTIVES: To determine the population pharmacokinetics of unbound hydrocortisone in critically ill neonates and infants receiving IV hydrocortisone for treatment of vasopressor-resistant hypotension and to identify patient-specific sources of pharmacokinetic variability. DESIGN: Prospective observational cohort study. SETTING: Level 3 neonatal ICU. PATIENTS: Sixty-two critically ill neonates and infants receiving IV hydrocortisone as part of standard of care for the treatment of vasopressor-resistant hypotension: median gestational age 28 weeks (range, 23-41), median weight 1.2 kg (range, 0.5-4.4), and 29 females. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Unbound baseline cortisol and postdose hydrocortisone concentrations measured from blood samples being drawn for routine laboratory tests. A one-compartment model best described the data. Allometric weight and postmenstrual age were significant covariates on unbound hydrocortisone clearance and volume of distribution. Final population estimates for clearance, volume of distribution, and baseline cortisol concentration were 20.2 L/hr, 244 L, and 1.37 ng/mL, respectively. Using the median weight and postmenstrual age of our subjects (i.e., 1.2 kg and 28 wk) in the final model, the typical unbound hydrocortisone clearance and volume of distribution were 1.0 L/hr and 4.2 L, respectively. The typical half-life for unbound hydrocortisone was 2.9 hours. A sharp and continuous increase in unbound hydrocortisone clearance was observed at 35 weeks postmenstrual age. CONCLUSIONS: We report the first pharmacokinetic data for unbound hydrocortisone, the pharmacologically active moiety, in critically ill neonates and infants with vasopressor-resistant hypotension. Unbound hydrocortisone clearance increased with body weight and was faster in children with an older postmenstrual age. Unbound hydrocortisone clearance increased sharply at 35 weeks postmenstrual age and continued to mature thereafter. This study lays the groundwork for evaluating unbound hydrocortisone exposure-response relationships and drawing definitive conclusions about the dosing of IV hydrocortisone in critically ill neonates and infants with vasopressor-resistant hypotension.

Hormone-related pharmacokinetic variations associated with anti-breast cancer drugs.

INTRODUCTION: Breast cancer is the most common female cancer, with more than one million new patients diagnosed annually worldwide. Generally speaking, there are three types of drugs used in management of breast cancer namely: hormonal treatment, chemotherapeutic agents and target-based agents. There is increasing evidence that hormones play an important role in development of both hormone-dependent and hormone-independent breast cancers. AREAS COVERED: This review summarizes the pharmacokinetics of various types of drugs used to treat breast cancer. Furthermore, the authors discuss hormone-related variations including: the menstrual status, gender and exogenous hormones influencing drug absorption, distribution, metabolism or excretion (ADME). The authors also describe the physiological factors such as body weight and age that affect the pharmacokinetics of several drugs. EXPERT OPINION: The factors affecting the pharmacokinetics of anti-breast cancer drugs are multifaceted. Hormones appear to be a key factor determining the pharmacokinetics (and efficacy) of hormonal therapy due to their role in cancer progression. In chemotherapy, the effects of hormones on the drug pharmacokinetics are possibly mediated through P-glycoprotein (P-gp) efflux and/or cytochrome P450 metabolism. In many cases, dosing regimen should be adjusted for drugs used in treatment of breast cancers based on the hormone levels in the body.

[Erythrocytes - the new application in medicine]. / Erytrocyty - nowe zastosowanie w medycynie.

The new forms of drugs with better proprieties from traditional ones were sought for a long time. Erythrocytes applied as carriers of therapeutic substances are among promising. They are characterized by slower release of active substances, less toxicity, as well as better biocompatibility and biodegradation in the organism. It is especially important in administration of drugs with numerous side effects in therapy of chronic diseases e.g. malignancies. Investigations conducted from over twenty years showed, that erythrocytes are universal carriers in which different therapeutic substances were successfully closed, e.g. cytostatics, antibiotics, hormones and vitamins, as well as enzymes and vaccines. Some of the erythrocyte drug delivery systems are now studied at the clinical level, e.g. dexamthasone 21-phosphate in treatment of inflammatory bowel disease and chronic obstructive pulmonary disease. This substance encapsulated in human erythrocytes was also officially registered by European Medicines Agency, as the orphan drug in treatment of cystic fibrosis: Reports on application of carrier erythrocytes in patients with rare genetic diseases have also appeared.

Uptake of pharmaceuticals, hormones and parabens into vegetables grown in soil fertilized with municipal biosolids.

Several recent greenhouse studies have established the potential for uptake of human pharmaceuticals from soil fertilized with municipal biosolids into a variety of crops. In the present study, a field experiment was undertaken to evaluate the uptake of organic micropollutants from soil fertilized with municipal biosolids at a regulated application rate into tomatoes, carrots, potatoes and sweet corn produced under normal farming conditions. The vegetables were grown according to farming practices mandated by the province of Ontario Canada, the key feature being a one-year offset between biosolid application and the harvest of crops for human consumption. Biosolids at application, and crop samples following harvest were analyzed for 118 pharmaceuticals and transformation products, 17 hormones or hormone transformation products, and 6 parabens. Analyte concentrations in the biosolids were consistent with those detected in other surveys. Eight of the 141 analytes were detected in one or two crop replicates at concentrations ranging from 0.33 to 6.25 ng/g dry weight, but no analytes were consistently detected above the detection limit in all triplicate treated plots. Overall, this study suggests that the potential for micropollutant uptake into crops under normal farming conditions is low.

Combination therapy of Western drugs and herbal medicines: recent advances in understanding interactions involving metabolism and efflux.

INTRODUCTION: While complementary and alternative medicine markets prosper with an increasing number of consumers of herbal medicines, there is an associated likelihood for herb-drug interactions to occur. Modulation of the activity of metabolic enzymes and/or active transporters by chemical constituents of herbal medicines may influence the therapeutic outcomes of coadministered allopathic medicines due to changes in their pharmacokinetic profiles. Although valuable information on herb-drug interactions is obtained by in vitro studies, such as the mechanisms of interaction, clinical significance of interactions is ultimately demonstrated by in vivo data. AREAS COVERED: The authors outline the mechanisms of herb-drug pharmacokinetic interactions briefly and discuss pharmacokinetic interactions between different therapeutic classes of Western drugs and herbal medicines. Furthermore, the authors also discuss herb-drug interactions from both in vitro and in vivo studies with specific focus on recent findings. EXPERT OPINION: Basic and clinical researches have contributed to the comprehension of the underlying mechanisms involved as well as the practical implications of herb-drug interactions. This provides a foundation for development of guidelines to inform patients about herb-drug interactions that can affect their health.

Thiolated glycol chitosan bearing α-cyclodextrin for sustained delivery of PEGylated human growth hormone.

The extensive use of human growth hormone (hGH), emerging as protein therapeutics, has been limited by its instability in biological fluids and short biological half-life. In this study, thiolated glycol chitosan bearing α-cyclodextrin (TGC-CD), in situ cross-linked by poly(ethylene glycol)-diacrylate (PEG-DA), was synthesized to develop a sustained release system for PEGylated hGH (PEG-hGH). TGC-CD could form a stable inclusion complex with PEG-hGH by the physical interaction between the inner cavity of CD and PEG. Such a complex was readily cross-linked in the presence of PEG-DA via a Michael-type addition reaction. From the in vitro release experiments of PEG-hGH, it was confirmed that PEG-hGH was completely released from the complex for 12 h in PBS (pH 7.4), whereas the release rate of PEG-hGH was significantly reduced by the chemical cross-linking of the complex. PEG-hGH, released from the cross-linked complexes, maintained its structural integrity, which was demonstrated using circular dichroism spectroscopy. Overall, TGC-CD might be useful for sustained delivery of PEG-hGH.

Lipid effects of endocrine medications.

Various alterations of lipid homeostasis have a significant role in the pathophysiology of the artherosclerotic process. The effects of usual lipid-lowering agents such as statins, fibrates, or niacin are well known, but other endocrine therapeutic agents could also affect the blood levels of various lipoproteins and, in turn, influence atheroma formation. In this review, we attempt to summarize the effect of several hormonal and non-hormonal endocrine agents on lipid metabolism, including insulin, thyroid hormone, sex hormones, glucocorticoids, growth hormone, and several anti-diabetic agents.

In vivo absorption of steroidal hormones from smart polymer based delivery systems.

The purpose of this study was to develop smart polymer based controlled delivery systems to deliver steroidal hormones after single subcutaneous (s.c.) injection at predetermined rates over extended period of time. In vivo absorption and pharmacokinetics of levonorgestrel (LNG) and testosterone (TSN) were investigated from the thermosensitive and phase sensitive polymeric controlled delivery systems. A selective, reliable, and rapid method for determination of serum LNG concentration was developed using high-performance liquid chromatography-tandom mass spectrometry with atmospheric pressure chemical ionization interface (HPLC-MS-MS with APCI), while TSN in serum samples was detected and quantified by a competitive immunoassay. The delivery systems controlled the absorption of LNG in rabbits up to 6 weeks from thermosensitive and approximately 4 weeks from phase sensitive polymeric delivery systems. In vivo study of TSN delivery systems in castrated rabbits controlled the release of TSN for at least 2 months from both thermosensitive and phase sensitive polymers. Thermosensitive and phase sensitive polymer formulations significantly (p < 0.05) increased relative bioavailability of steroidal hormones compared to control. In conclusion, thermosensitive and phase sensitive polymer based delivery systems controlled the release in vivo in rabbits for longer duration after single s.c. injection.

New in vitro dermal absorption database and the prediction of dermal absorption under finite conditions for risk assessment purposes.

Most QSARs for dermal absorption predict the permeability coefficient, K(p), of a molecule, which is valid for infinite dose conditions. In practice, dermal exposure mostly occurs under finite dose conditions. Therefore, a simple model to predict finite dose dermal absorption from infinite dose data (K(p) and lag time) and the stratum corneum/water partition coefficient (K(SC,W)) was developed. To test the model, a series of in vitro dermal absorption experiments was performed under both infinite and finite dose conditions using acetic acid, benzoic acid, bis(2-ethylhexyl)phthalate, butoxyethanol, cortisone, decanol, diazinone, 2,4-dichlorophenol, ethacrynic acid, linolenic acid, octylparaben, oleic acid, propylparaben, salicylic acid and testosterone. For six substances, the predicted relative dermal absorption was not statistically different from the measured value. For all other substances, measured absorption was overpredicted by the model, but most of the overpredictions were still below the European default absorption value. In conclusion, our finite dose prediction model provides a useful and cost-effective estimate of dermal absorption, to be used in risk assessment for non-volatile substances dissolved in water at non-irritating concentrations.

Is the vagina an adequate route for the administration of hormonal contraceptives?

The vaginal route of drug administration provides women with a valid alternative to more conventional methods of contraception. Drugs absorbed in the upper part of the vagina can bypass the liver and, if metabolized, are subject to a reduced hepatic first-pass effect. Current vaginally-administered contraceptive formulations deliver similar doses of gestagens to those provided by oral methods but release lower amounts of oestrogens. This results in a systemic exposure to gestagens similar to that achieved via other routes, thereby maintaining contraceptive efficacy while limiting systemic, but not uterine, exposure to oestrogen. In this way, the probability of systemic oestrogen-related adverse effects are theoretically reduced without compromising cycle control. In addition, the fact that the effects of a contraceptive ring last a complete cycle makes it more user-friendly than other methods and results in better patient compliance. The present review will explain in detail the specificities of this route of delivery of hormonal contraception and will compare it to more classic forms of contraception received via the oral (pill), intramuscular (injected), transdermic (patch) and subcutaneous (implants) routes of administration.

Determination of human absorbed dose of 67GA-DTPA-ACTH based on distribution data in rats.

The absorbed radiation dose to human organs has been estimated, following intravenous administration of (67)Ga-labelled adrenocorticotrophic hormone (ACTH) using distribution data from injected normal rats. Four rats were sacrificed at exact time intervals and the percentage of injected dose per gram of each organ was measured by direct counting from rat data. The Medical Internal Radiation Dose formulation was applied to extrapolate from rat to human and to project the absorbed radiation dose for various organs in a human. From rat data, it is estimated that a 185-MBq injection of (67)Ga-diethylenetriaminepentaacetic acid-ACTH into a human might result in an estimated absorbed dose of 2.22 mGy to the whole body; the highest absorbed dose was in the bladder wall with 82.1 mGy and the organs that received the next highest doses were the lungs 31.8, liver 22.6 and spleen 8.72 mGy. These results suggest that it should be possible to perform early imaging of the lung anomalies.

Addition of somatostatin-14 to a standard total parenteral nutrition-mixture in the treatment of fistulae: a clinical, double-blind, randomised, cross-over study.

UNLABELLED: BACKGROUND/STUDY AIMS: Somatostatin and total parenteral nutrition (TPN) are routinely used in the treatment of pancreatic and enterocutaneous fistulae. The objective of this clinical randomised cross-over study was to investigate the serum levels of somatostatin infused alongside TPN by a separate intravenous line, and when it had been added to the TPN mixture. PATIENTS/METHODS: The subjects were recruited by the treating physicians and the nutrition nurses. From the patients who started the study, no one dropped out. Ten patients were treated with a standard TPN mixture and somatostatin 6 mg/day. Patients were randomised to two possible regimens: 'somatostatin plus TPN--somatostatin separately--somatostatin plus TPN' or 'somatostatin separately--somatostatin plus TPN--somatostatin separately'. Each regimen consisted of 3 x 3 days of therapy, during which, serum levels of somatostatin were measured daily. Pre- and posttreatment samples were also analysed. RESULTS: When somatostatin was infused separately, the mean serum level was 884.8 pg/ml (SD: 557.3; range: 54-1900). When added to TPN, the mean serum level was 807.5 pg/ml (SD: 505.8; range 162-2279) (p value of difference = 0,473). The mean pretreatment level was 17.1 pg/ml (SD: 7.5; range: 8-33), and posttreatment was 32.8 pg/ml (SD: 26.5; range: 16-97). CONCLUSIONS: These results demonstrate that serum levels of somatostatin are similar in both treatment regimens and therefore may be added to a TPN mixture.

[Pharmacodynamic properties of a combination of met-enkephalin and alpha 1-13 adrenocorticotropic hormone]. / Farmakodinamske karakteristike kombinacije met-enkephalin-a i alpha 1-13 adrenokortikotropnog hormona.

ENKORTEN is newly registered drug in Bosnia and Herzegovina. It consists of two peptide components: met-enkephalin and alpha 1-13-corticotropine (alpha-ACTH 1-13), previously called alpha-melanocyte-stimulating hormone-like (alpha-MSH-like) Met-enkephalin and alpha-MSH exhibited cytoprotective effects individually and statistically significant additive effect was registered when both peptides were applied in combination on the model of ethanol induced gastric lesions in rats. Combination has immunomodulatory effects. Method of selective immunomodulation with antigens and peptides in immunological mediated diseases and malignant tumors is directed towards long-term remission without so many adverse effects characteristic for immunosuppressive drugs. Adverse reactions registered for so long with ENKORTEN were mild, reversible and usually developed during and immediately after drug application.

Regulación del proceso de reparación ósea por hormonas / Regulation of the bone healing process by hormones

The skeleton has several important functions, such as structural functions that provide mobility, support, and protection for the body. It also has an important function as a reservoir for calcium and phosphorus. The aim of this article is to show the principal hormones that are involved with the bone healing process. In this article, it will be pointed the mineral homeostatic mechanisms in the skeleton, controlled by the calcium-regulating hormones: parathyroid hormone (PTH) that maintains the normal extracellular calcium levels by enhancing osteoclastic bone resorption and liberating calcium from the adult skeleton; estrogen, considering that both osteoblasts and osteoclasts express estrogen receptors, it is reasonable to assume that the effects of estrogen on skeletal remodeling could be caused, at least partly, by a direct effect on bone cells; androgen with important functions on the adult male phenotype, anabolic actions on skeleton, muscle and bone, including the effects of their metabolism in diverse tissues; and steroids that inhibit the synthesis of proteins, collagen, and proteoglycans in articular cartilage, and inactivate vitamin D, limiting calcium absorption by the gastrointestinal tract, and increasing the urinary excretion of calcium, they also inhibit the release of growth hormone, which further decreases soft tissue and bone repair and lead to a decrease in bone, ligament, and tendon strength.

El esqueleto humano tiene varias importantes funciones, tales como las estructurales que proporcionan la movilidad, soporte y protección del cuerpo. Además, tiene función de reserva de calcio y fósforo. El objetivo de este artículo es mostrar las principales hormonas envueltas en los procesos de reparación ósea. Se muestran los mecanismos de homeostasis mineral en el esqueleto, controlados por las hormonas reguladoras del calcio: hormona de la paratiroide, que mantiene normales los niveles de calcio extracelular aumentando la reabsorción ósea por osteoclastos y liberando el calcio del esqueleto humano; estrógeno, considerando que tanto los oesteoblastos como los osteoclastos presentan receptores para estrógeno, es razonable presumir que los efectos del estrógeno en la remodelación ósea puedan ser causados, por lo menos parcialmente, por un diferente efecto en las células óseas; andrógeno con importantes funciones en el fenotipo masculino, acciones anabólicas en el esqueleto, músculos y huesos, incluyendo los efectos de su metabolismo en diversos tejidos; y esferoides que inhiben la síntesis de proteínas, colágeno y proteoglicanos en el cartílago articular e inactivan la vitamina D, limitando la absorción de calcio por el tracto gastrointestinal y aumentando la excreción urinaria de calcio, ellos también inhiben la liberación de hormona del crecimiento, lo que llevará a una disminución de tejido blando y de la reparación ósea y en consecuencia a una disminución en la fuerza de los huesos, ligamentos y tendones.

ACTH stimulation test in the captive cheetah (Acinonyx jubatus).

Serum cortisol response was assessed in 8 captive cheetahs, of varying ages, after the intravenous administration of 500 microg of tetracosactide (Synacthen Depot, Novartis, Kempton Park) while maintained under general anaesthesia. In addition, 8 cheetahs were anaesthetised and given an equal volume of saline in order to establish baseline cortisol concentrations at similar stages of anaesthesia. A significant difference in the median cortisol concentration measured over time was found following ACTH administration in the ACTH group (P < 0.001). There was no difference between the median cortisol concentrations in the ACTH group at time-points 120, 150 and 180 min after ACTH stimulation (P = 0.867). Thus it appears appropriate to collect serum 120 to 180 min after tetracosactide administration to assess maximal stimulation of the adrenal in the cheetah. No statistically significant rise was seen in the anaesthetised control group following the injection of saline (P = 0.238).

Generation of biochemical response patterns of different substances using a whole cell assay with multiple signaling pathways.

Distinctive generation of biochemical response patterns of eight different substances, using an assay based on pigment containing cells, was demonstrated. Xenopus laevis melanophores, transfected with human beta(2)-adrenergic receptor, were seeded in a 96 well microplate and used to generate individual biochemical images through a two transient measuring protocol that contributes to highlight the response signatures of the agents. Adequate signal processing creates distinctive patterns in a time-concentration response space suitable for substance classification. The concept of biochemical images is introduced here. The assays were evaluated both with a standard microplate reader and with a computer screen photo-assisted technique (CSPT) yielding similar results. Since CSPT platforms only demand standard computer sets and web cameras as measuring setup, applications for these kind of assays outside main-laboratories were discussed.