Morphine Concentrations Research Articles

Safe implementation of standard concentration infusions in paediatric intensive care.

To evaluate safety, following introduction of standard concentrations of morphine infusions in paediatric critical care. Implementation: A multidisciplinary team was convened, and several workstreams designated, including derivation of concentrations, manufacturing, supply, prescribing, administration using smart pump technology, training and evaluation. Safety Evaluation: Retrieval of all existing data on medication errors linked to morphine use using our hospital incident reporting system and risk assessment of errors in relation to standard concentration implementation. The pilot identified several areas for improvement, stock control, reasons for reverting from standard to variable concentrations and sources of error. Improvements included the following: refining morphine concentrations and weight limits for bands, pump reprogramming and education. Long-term Safety: Over an 8-year period, 126 morphine-related incidents occurred (two-thirds in the 3years around introduction). Of note, 67% (85/126) resulted in no patient harm; the remainder 33% resulted in low harm. Analysis of administration errors revealed that up to 70% could be eliminated by refining technology to include bar coding. These included the following: wrong syringe selection (24%), wrong pump mode (28%) and wrong patient weight inputted (18%). Introduction of standard infusions is safe and effective. We are exploring ways to further refine safety and extending to other drugs.

Competitive voltammetric morphine immunosensor using a gold nanoparticle decorated graphene electrode

The authors describe a voltammetric immunosensor for morphine (MOR) that is based on a graphene screen printed electrode (GSPE) modified with gold nanoparticles (AuNP) which were electrodeposited on its surface. The gold nanoparticles were characterized by scanning electron microscopy, X-ray photoelectron spectroscopy and cyclic voltammetry. Cysteamine was then self-assembled on the gold-modified electrodes via thiol interaction in order to introduce terminal amino groups to the electrode surface. The electrodes were then used to fabricate the immunosensor by covalent immobilization of antibodies against MOR. The sensor works on the basis of a competition between MOR and the morphine-bovine serum albumin (MOR-BSA) conjugate for the immobilized antibodies on the sensor surface and the resulting change in the square wave voltammetry reduction current using the hexacyanoferrate system as an electrochemical probe. The competitive immunoassay enables sensitive and selective detection of MOR in the 0.1 to 100 ng·mL−1 MOR concentration range, with a 90 pg·mL−1 detection limit. The method was applied to the determination of MOR in spiked saliva samples and showed high recoveries. We believe that this immunosensor offers a simple, rapid, sensitive and accurate MOR test.

Doping relevant substances in horse feed

Horse feed material of Swiss and foreign production available on the Swiss market was tested with regard to possible contamination with 7 different alkaloids, atropine and colchicine. Twenty-eight feed samples as well as 2 poppy seed samples were analyzed. Out of 28 feed samples 18 were positive for prohibited substances in Equestrian sports. The concentration of prohibited substances was in none of the samples high enough to cause an effect on the body of the horse. The poppy seed sample, which was obtained by conventional harvesting and cleaning methods, contained a very high Morphine concentration compared to the sample which was harvested by hand. Despite high quality standards a contamination with prohibited substances in horse feed cannot be excluded.

Opioids Inhibit Angiogenesis in a Chorioallantoic Membrane Model

Background: Angiogenesis is an important characteristic of cancer. Switching from the avascular phase to the vascular phase is a necessary process for tumor growth. Therefore, research in cancer treatment has focused on angiogenesis as a drug target. Despite the widespread use of opioids to treat pain in patients with cancer, little is known about the effect of these drugs on vascular endothelium and angiogenesis. Objectives: We aimed to investigate the efficacies of morphine, codeine, and tramadol in 3 different concentrations on angiogenesis in hens’ eggs. Study Design: This is a prospective, observational, controlled, in-vivo animal study. Setting: Single academic medical center. Methods: This study was conducted on the chorioallantoic membrane (CAM) of fertilized hens’ eggs. The efficacies of morphine, codeine, and tramadol in 3 different concentrations were evaluated on angiogenesis in a total of 165 hens’ eggs. Results: Statistically significant differences were found between drug-free agarose used as a negative control and concentrations of morphine of 10 µM and 1 µM, a concentration of tramadol of 10 µM, and concentrations of codeine of 10 µM and 1 µM. Concentrations of morphine of 10 µM and 1 µM showed strong antiangiogenic effects. While codeine had strong antiangiogenic effects at high concentrations, at 0.1 µM it was shown to have weak antiangiogenic effects. However, tramadol at a concentration of 10 µM had only weak antiangiogenic effects. Limitations: This is just a CAM model study. Conclusion: In this study, we tested the effects of 3 different opioid drugs on angiogenesis in 3 different concentrations, and we observed that morphine was a good anti-angiogenic agent, but tramadol and codeine only had anti-angiogenic effects at high doses. Key Words: Morphine, codeine, tramadol, opioid, bevacizumab, chorioallantoic membrane (CAM), angiogenesis

Morphine Pharmacodynamics in Mechanically Ventilated Preterm Neonates Undergoing Endotracheal Suctioning

To date, morphine pharmacokinetics (PKs) are well quantified in neonates, but results about its efficacy are ambiguous. This work presents an analysis of a previously published study on pain measurements in mechanically ventilated preterm neonates who received either morphine or placebo to improve comfort during invasive ventilation. The research question was whether morphine reduces the pain associated with endotracheal or nasal suctioning before, during, and after suctioning. Because these neonates cannot verbalize their pain levels, pain was assessed on the basis of several validated pain measurement instruments (i.e., COMFORT‐B, preterm infant pain profile [PIPP], Neonatal Infant Pain Scale (NIPS), and visual analogue scale (VAS)). The item response theory (IRT) was used to analyze the data in order for us to handle the data from multiple‐item pain scores. The analysis showed an intra‐individual relationship between morphine concentrations and pain reduction, as measured by COMFORT‐B and VAS. However, the small magnitude of the morphine effect was not considered clinically relevant for this intervention in preterm neonates.

Efficacy of subcutaneous morphine patient controlled analgesia compared to intravenous morphine patient controlled analgesia in cesarean section

Background: Cesarean section causes moderate to severe pain in the first 48 hours postoperatively, thus requiring an adequate perioperative pain management, as of the mother can be quickly discharged and immediately can perform daily activities after surgery such as breastfeeding and nurse the baby. Objective: To determine the efficacy of subcutaneous morphine patient controlled analgesia (SC-PCA) in lowering VAS (visual analogue score), total morphine consumption and postoperative side effect of cesarean section compared with intravenous morphine patient controlled analgesia (IV- PCA). Methods: This study is an experimental clinical trial using consecutive sampling technique. Sixty-four subjects were allocated into two groups of PCA morphine subcutaneously (SC-PCA) and the group PCA morphine intravenously (IV-PCA), each consisting of 32 subjects using permuted block randomization. Morphine concentration was 5 mg/ml (group SC-PCA) or the concentration of 1mg/ml (group IV-PCA). Both groups were then analyzed for VAS ratings, total morphine consumption, and adverse effects, postoperatively at 4th, 8th, and 24th hour. Statistic analysis using repeated ANOVA test and t-test with p <0.05 considered significant. Result: Morphine consumption in IV-PCA group showed lower than SC-PCA (9.41 mg vs 4,9mg) p <0.001 24 at 24 hours postoperatively. The resting VAS at 4th hours significantly lower in IV-PCA group (1.06 ± 0.71 vs 0.81 ± 1.40, p=0.029) and at 8th hours (1.03 ± 0.59 vs 0.94 ± 0,9, p=0.048). The moving VAS at 4th hours significant lower in IV-PCA group (2.31 ± 0.47 vs 1.45 ± 2.06, p=0.019) but the resting or moving VAS are not different clinically. Side effects of nausea and vomiting are more common in IV-PCA group. We conclude that SC-PCA provides analgesia more effective and decreases side effects in patients undergo cesarean section with spinal anesthesia.

Morphine Can Inhibit the Growth of Breast Cancer MCF-7 Cells by Arresting the Cell Cycle and Inducing Apoptosis

Morphine is widely used for relieving cancer pain in patients with advanced cancer. However, whether morphine can suppress or promote the progression of cancer in breast cancer patients receiving morphine analgesia remains unclear. Therefore, we used an in vitro model treated with morphine and naloxone to investigate the effects of morphine on breast cancer cell line MCF-7. MCF-7 cells were cultured with different concentrations (0.01 to 10 µM) of morphine at 12th, 24th, 36th, 48th, 60th and 72nd hours. Then, cell viability was measured through the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and cell cycle and apoptosis assays were detected by flow cytometry (FCM). In addition, cell proliferation was conducted by colony formation assay. In this study, we have found that morphine (0.01 to 10 µM) could significantly reduce the cell vitality, growth and colony formation rate of MCF-7 cells, which has a certain relationship with cell cycle progression arrested at the G0/G1 and G2/M phase and MCF-7 cells apoptosis. Moreover, naloxone along with morphine could not reverse these effects, which indicates that the inhibition of MCF-7 breast cancer cell growth and proliferation by morphine could be its independent effect, not associated with opioid receptors. Morphine can inhibit cell growth by blocking the cell cycle and promote apoptosis in MCF-7 cells. Hence, morphine may be unable to promote the progression of cancer in breast cancer patients receiving morphine analgesia.

Dose-dependent effects of morphine on lipopolysaccharide (LPS)-induced inflammation, and involvement of multixenobiotic resistance (MXR) transporters in LPS efflux in teleost fish

Opioid drugs, such as morphine (MO), detected in aquatic environments worldwide, may harm fish due to their semi-persistence and ability to potently interact with molecular targets conserved across vertebrates. Here, we established a waterborne bacterial lipopolysaccharide (LPS) challenge assay with zebrafish embryos as a model to investigate chemically-induced disruption of the innate immune system, and used it to study the effects of MO exposure. Exposure to 1 mg/L MO resulted in pronounced immunosuppression, reflected in downregulation of several inflammation-related genes, including myd88, trif, traf6, p38, nfκb2, il-1β, il-8 and ccl34a. Fish exposed to 1 mg/L MO accumulated 11.7 ng/g (wet weight) of MO, a concentration comparable to that reported in blood of chronic drug abusers subject to higher infection rates. Surprisingly, exposure to lower MO concentrations (100 ng/L–100 μg/L) led to exacerbation of LPS-induced inflammation. Two ATP-binding cassette (ABC) transporters known to be involved in the xenobiotic efflux - abcb4 and abcc2, also known as multixenobiotic resistance (MXR) transporters - were downregulated at 100 ng/L MO. We hypothesized that ABC/MXR transporters could modulate the severity of inflammation by being involved in efflux of LPS, thus regulating its accumulation in the organism. Indeed, we could demonstrate that blocking of ABC/MXR transporters by an inhibitor, cyclosporine A, results in stronger inflammation, coinciding with higher LPS accumulation, as visualized with fluorescently labeled LPS. Our work demonstrates that MO can disrupt fish innate immune responses at environmentally relevant concentrations. We also provide evidence for a role of ABC/MXR transporters in LPS efflux in fish. These finding may be applicable across other taxa, as ABC transporters are evolutionary conserved. Since diverse environmentally present chemicals are known to interfere with ABC/MXR transporters' expression or activity, our discovery raises concerns about potential adverse effects of such compounds on the immune system responses in aquatic organisms.

Time-dependent postmortem redistribution of morphine and its metabolites in blood and alternative matrices-application of CT-guided biopsy sampling.

Interpretation of postmortem morphine concentrations in forensic toxicology provides several pitfalls such as missing information on tolerance, analyte stability, or postmortem redistribution (PMR). Recently, it had been shown that computed tomography (CT)-guided collection of biopsies using a robotic arm (virtobot) provides a valuable strategy for systematic studies on time-dependent PMR. Using this technique, time-dependent PMR of morphine and its metabolites was investigated in 12 cases. At admission to the institute (t1), femoral and heart blood (right ventricle) as well as biopsies from the right lung, the right kidney, liver, spleen, and muscle tissue were collected. At autopsy approximately 24h later (t2), samples from the same body regions were collected again. Additionally, gastric contents, urine, brain tissue, and heart blood from the left ventricle was collected. Morphine, normorphine, hydromorphone, morphine-3-glucuronide, morphine-6-glucuronide, and morphine-sulfate were quantified with LC-MS/MS. In femoral blood, significant increase of morphine concentrations was observed, although ultimately not relevant for forensic interpretation. In the alternative matrices, increases as well as decreases were observed without a clear trend. The morphine metabolites did not exhibit relevant concentration changes. Investigation of underlying redistribution mechanisms indicated that concentration change (i.e., increase) of morphine in femoral blood rather resulted from diffusion processes than from release of morphine from its conjugates. Concentration changes in heart blood might have been caused by redistribution from lung tissue or gastric content. This study also proved that CT-guided collection of biopsies using a virtobot arm is an invaluable tool for future studies on PMR redistribution of other substance groups.

Clinical concentrations of morphine are cytotoxic on proliferating human fibroblasts in vitro.

Morphine and other opioids are routinely used systemically and as wound infusions in the postoperative period. Their effect on wound and fracture healing remains unclear. The primary outcome was to assess the potential cytotoxicity of clinically relevant concentrations of morphine on human fibroblasts. Laboratory in-vitro study. Institute of Physiology, Zurich Center for Integrative Human Physiology, University of Zurich. Monolayers of human fibroblasts. Exposure of human fibroblast monolayers to several concentrations of morphine, for different periods of time, with and without an artificially induced inflammatory process. Cell count, cell viability, cell proliferation and apoptosis. A concentration, time and exposure-dependent cytotoxic effect of morphine-mediated apoptosis was observed. Simulated inflammatory conditions seemed to lessen toxic effects. Cytotoxic effects of morphine are exposure, time and concentration dependent. Simulating aspects of inflammatory conditions seems to increase resistance to morphine cytotoxicity especially in the presence of higher concentration and longer exposure times.

Postmortem Concentration and Redistribution of Diazepam, Methadone, and Morphine with Subclavian and Femoral Vein Dissection/Clamping.

Postmortem redistribution (PMR) concerns blood drug concentration variations after death, depending on many factors such as sampling site and technique. In our study, we focused on sampling method. 30 cases were sampled, each at cardiac, subclavian, femoral, and popliteal sites. Targeted substances were diazepam, methadone, and morphine. Blind stick and dissection/clamping techniques were concomitantly performed at subclavian and femoral sites. Subclavian and femoral concentrations were compared according to technique used. To assess the influence of sampling technique on PMR, central/peripheral ratios were calculated depending on sampling method. Results show that drug concentrations tend to be lower when drawn from a clamped subclavian or femoral vein whereas ratios including subclavian and/or femoral blood concentration are influenced according to the technique used. In conclusion, clamping a subclavian or femoral vessel before sampling tends to result in lower drug concentrations and may influence ratios, suggesting the importance of isolating vessels from thoraco-abdominal viscera.

Accuracy in Obtaining 100 μg from 10 mg of Morphine for Spinal Anesthesia

(J Clin Anesth. 2015;27:638–645) A 100 μg is the recommended dose of morphine for patients following a cesarean section. In France there is a variety of morphine concentrations available, including 1 mg/1 mL and 10 mg/1 mL, and 100 μg/1 mL. These different concentrations may increase the likelihood of an erroneous dosage being administered. There are also many different dilution methods that are used to prepare a dose of morphine, which can further complicate attempts to arrive at the standard postcesarean dose of 100 μg. The authors of this study attempted to evaluate the effectiveness of common dilution procedures by measuring the concentration of morphine obtained when the dilution techniques were used to obtain a dose from a 10-mg/1-mL ampule of morphine.

CHANGING PRESCRIBING CULTURE – A FOCUS ON CODEINE POSTPARTUM

AimTo eliminate the prescribing of codeine and codeine combination products postpartum to improve safety in breast fed infants.Concerns have been raised over the use of codeine and codeine combination products...

EVALUATION OF THE CURRENT PRACTICE OF DELIVERING INTRAVENOUS OPIOIDS INFUSIONS IN A UK PAEDIATRIC HOSPITAL

IntroductionOpiate intravenous infusions are the therapy of choice in severe pain. However, administering infusions to children requires complex dosage calculations, rate adjustments and often multiple manipulations of injectable medicines to...

Heroin overdose.

This narrative review aims to provide a brief history of the development of the heroin overdose field by discussing a selection of major 'classics' from the latter part of the 20th century. Papers considered landmarks were selected from 1972, 1977, 1983, 1984 and 1999. Findings of earlier works suggest much of what later research was to demonstrate. These include arguing that overdoses occurred primarily among tolerant older users, that most 'overdose' deaths involved low morphine concentrations, that most overdoses involve polypharmacy, that drug purity has only a moderate influence on overdose rates and that instant death following heroin administration is rare. Landmark studies of heroin overdose from the 1970s, 1980s and 1990s laid the foundations for subsequent overdose research, mainly by identifying the major demographic characteristics of overdose cases, risk factors, survival times and behaviours at overdose events.

Sources and magnitude of error in preparing morphine infusions for nurse-patient controlled analgesia in a UK paediatric hospital.

Background Administering nurse/patient controlled analgesia (N/PCA) to children requires complex dose calculations and multiple manipulations to prepare morphine solutions in 50mL syringes for administration by continuous infusion with additional boluses. Objective To investigate current practice and accuracy during preparation of morphine N/PCA infusions in hospital theatres and wards at a UK children's hospital. Methods Direct observation of infusion preparation methods and morphine concentration quantification using UV-Vis spectrophotometry. The British Pharmacopoeia specification for morphine sulphate injection drug content (±7.5%) was used as a reference limit. Results Preparation of 153 morphine infusions for 128 paediatric patients was observed. Differences in preparation method were identified, with selection of inappropriate syringe size noted. Lack of appreciation of the existence of a volume overage (i.e. volume in excess of the nominal volume) in morphine ampoules was identified. Final volume of the infusion was greater than the target (50mL) in 33.3% of preparations. Of 78 infusions analysed, 61.5% had a morphine concentration outside 92.5-107.5% of label strength. Ten infusions deviated by more than 20%, with one by 100%. Conclusions Variation in morphine infusion preparation method was identified. Lack of appreciation of the volume overage in ampoules, volumetric accuracy of different syringe sizes and ability to perform large dilutions of small volumes were sources of inaccuracy in infusion concentration, resulting in patients receiving morphine doses higher or lower than prescribed.

Effects of thienorphine on the contraction of isolated ureter and bladder of guinea pigs

Opioid analgesics are widely used in moderate to severe pain including renal colic. Morphine is believed to cause spasm of ureter and affect the bladder contractions. Thienorphine is a partial opioid agonist that is a good candidate for the treatment of opioid dependence and pain. This study examined the effects of thienorphine on the guinea pig isolated ureter and bladder. The contractile amplitude of isolated ureter induced by KCl (40mM) was not influenced by thienorphine or buprenorphine, whereas morphine increased the amplitude of the isolated ureter. Thienorphine, buprenorphine or naloxone concentration-dependently antagonized the isolated ureter contraction induced by morphine. Thienorphine (1.0–32.0μM) or buprenorphine (1.0–32.0μM) had no effects on the spontaneous or acetylcholine (Ach) induced contractions of isolated bladder, but decreased the amplitude of the contractions of isolated bladder at 100μM concentration. Morphine (0.1–3.2mM) concentration dependently increased the spontaneous movement and Ach (1μM) induced contractions of isolated bladder. The mRNA levels of μ receptor in the ureter and bladder was as the same as that in the frontal cortex. In comparison, the mRNA levels of κ receptor, δ receptor and N/OFQ receptor was fewer than that in the frontal cortex. In summary, thienorphine has little influence on the guinea pig isolated ureter and bladder compared with morphine, which may result in a lack of adverse renal colic effects.

Pharmacokinetic models of morphine and its metabolites in neonates:: Systematic comparisons of models from the literature, and development of a new meta-model

Morphine is commonly used for pain management in preterm neonates. The aims of this study were to compare published models of neonatal pharmacokinetics of morphine and its metabolites with a new dataset, and to combine the characteristics of the best predictive models to design a meta-model for morphine and its metabolites in preterm neonates. Moreover, the concentration-analgesia relationship for morphine in this clinical setting was also investigated.A population of 30 preterm neonates (gestational age: 23–32weeks) received a loading dose of morphine (50–100μg/kg), followed by a continuous infusion (5–10μg/kg/h) until analgesia was no longer required. Pain was assessed using the Premature Infant Pain Profile. Five published population models were compared using numerical and graphical tests of goodness-of-fit and predictive performance. Population modelling was conducted using NONMEM® and the $PRIOR subroutine to describe the time-course of plasma concentrations of morphine, morphine-3-glucuronide, and morphine-6-glucuronide, and the concentration-analgesia relationship for morphine.No published model adequately described morphine concentrations in this new dataset. Previously published population pharmacokinetic models of morphine, morphine-3-glucuronide, and morphine-6-glucuronide were combined into a meta-model. The meta-model provided an adequate description of the time-course of morphine and the concentrations of its metabolites in preterm neonates. Allometric weight scaling was applied to all clearance and volume terms. Maturation of morphine clearance was described as a function of postmenstrual age, while maturation of metabolite elimination was described as a function of postnatal age. A clear relationship between morphine concentrations and pain score was not established.

Detection of Methamphetamine and Morphine in Urine and Saliva Using Excitation–Emission Matrix Fluorescence and a Second-Order Calibration Algorithm

A new method was developed to determine the methamphetamine and morphine concentrations in urine and saliva based on excitation–emission matrix fluorescence coupled to a second-order calibration algorithm. In the case of single-drug abuse, the results showed that the average recoveries of methamphetamine and morphine were 95.3 and 96.7% in urine samples, respectively, and 98.1 and 106.2% in saliva samples, respectively. The relative errors were all below 5%. The simultaneous determination of methamphetamine and morphine in urine using two second-order algorithms was also investigated. Satisfactory results were obtained with a self-weighted alternating trilinear decomposition algorithm. The root-mean-square errors of the predictions were 0.540 and 0.0382 μg/mL for methamphetamine and morphine, respectively. The limits of detection of the proposed methods were very low and sufficient for studying methamphetamine and morphine in urine.

Development of a Whole-Body Physiologically Based Pharmacokinetic Approach to Assess the Pharmacokinetics of Drugs in Elderly Individuals.

BackgroundBecause of the vulnerability and frailty of elderly adults, clinical drug development has traditionally been biased towards young and middle-aged adults. Recent efforts have begun to incorporate data from paediatric investigations. Nevertheless, the elderly often remain underrepresented in clinical trials, even though persons aged 65 years and older receive the majority of drug prescriptions. Consequently, a knowledge gap exists with regard to pharmacokinetic (PK) and pharmacodynamic (PD) responses in elderly subjects, leaving the safety and efficacy of medicines for this population unclear.ObjectivesThe goal of this study was to extend a physiologically based pharmacokinetic (PBPK) model for adults to encompass the full course of healthy aging through to the age of 100 years, to support dose selection and improve pharmacotherapy for the elderly age group.MethodsFor parameterization of the PBPK model for healthy aging individuals, the literature was scanned for anthropometric and physiological data, which were consolidated and incorporated into the PBPK software PK-Sim®. Age-related changes that occur from 65 to 100 years of age were the main focus of this work. For a sound and continuous description of an aging human, data on anatomical and physiological changes ranging from early adulthood to old age were included. The capability of the PBPK approach to predict distribution and elimination of drugs was verified using the test compounds morphine and furosemide, administered intravenously. Both are cleared by a single elimination pathway. PK parameters for the two compounds in younger adults and elderly individuals were obtained from the literature. Matching virtual populations—with regard to age, sex, anthropometric measures and dosage—were generated. Profiles of plasma drug concentrations over time, volume of distribution at steady state (V ss) values and elimination half-life (t ½) values from the literature were compared with those predicted by PBPK simulations for both younger adults and the elderly.ResultsFor most organs, the age-dependent information gathered in the extensive literature analysis was dense. In contrast, with respect to blood flow, the literature study produced only sparse data for several tissues, and in these cases, linear regression was required to capture the entire elderly age range. On the basis of age-informed physiology, the predicted PK profiles described age-associated trends well. The root mean squared prediction error for the prediction of plasma concentrations of furosemide and morphine in the elderly were improved by 32 and 49 %, respectively, by use of age-informed physiology. The majority of the individual V ss and t ½ values for the two model compounds, furosemide and morphine, were well predicted in the elderly population, except for long furosemide half-lifes.ConclusionThe results of this study support the feasibility of using a knowledge-driven PBPK aging model that includes the elderly to predict PK alterations throughout the entire course of aging, and thus to optimize drug therapy in elderly individuals. These results indicate that pharmacotherapy and safety-related control of geriatric drug therapy regimens may be greatly facilitated by the information gained from PBPK predictions.Electronic supplementary materialThe online version of this article (doi:10.1007/s40262-016-0422-3) contains supplementary material, which is available to authorized users.