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P Mason

Publications and source records attributed to P Mason.

At least 55 records · Page 3Linked to original sources

Dedicated education units: 2. An evaluation.

This paper reports on an evaluation of a new concept in clinical nurse education: the Dedicated Education Unit (DEU). Developed by the School of Nursing, The Flinders University of South Australia, the DEU aims to optimise undergraduate student learning through enhancement of the clinical learning environment and collaboration between clinicians, academics and students. Three DEUs involving 91 students were evaluated, using primarily summative methods to elicit positive and negative attributes of the DEUs. Outcomes indicated that the DEU is a highly appropriate clinical placement model. (Part one of this paper explained the rationale for the DEU and its key features.)

Academic Medical Centers↗

Reduction of the viral load of HIV-1 after the intraperitoneal administration of dextrin 2-sulphate in patients with AIDS.

OBJECTIVE: To determine the safety and efficacy of the sulphated polysaccharide, dextrin 2-sulphate, when delivered to the lymphatic circulation by the peritoneal route. DESIGN: An open Phase I/II dose-escalation clinical study in which six patients with AIDS were treated with seven courses of dextrin 2-sulphate each lasting 1 month. METHODS: During each course of treatment, the drug was administered daily for 28 days using an intraperitoneal catheter. Viral load was measured at frequent intervals using a plasma tissue culture infectious dose (TCID) assay, a cellular TCID assay, p24 antigenaemia, HIV-1 RNA and HIV-1 DNA. Plasma beta-chemokine levels were also measured. RESULTS: Dose escalation was completed without toxicity. A total of 7 patient-months of treatment were completed. With increasing doses of dextrin 2-sulphate, the infectious plasma viraemia, cellular viraemia and p24 antigenaemia all fell during the period of drug administration, but with no significant change in HIV-1 RNA. This was associated with increased plasma levels of macrophage inflammatory protein (MIP)-1alpha and MIP-1beta. Dextrin 2-sulphate accumulated in peritoneal macrophages and induced the release of MIP-1alpha and MIP-1beta from these cells in vitro. These beta-chemokines could have augmented the cell surface-mediated anti-HIV-1 effect of dextrin 2-sulphate in vivo by binding to and blocking the CC-chemokine receptor-5. A second fall in infectious plasma viraemia, cellular viraemia, p24 antigenaemia and HIV-1 RNA was seen at day 100 which was then sustained for several months. A clinical improvement in Kaposi's sarcoma was also seen. CONCLUSIONS: Our results suggest that the intraperitoneal administration of dextrin 2-sulphate can reduce the replication of HIV-1 in patients with AIDS. With increasing doses of dextrin 2-sulphate, the fall in viral load was seen during the period of drug administration and again 2 months after completing treatment.

AIDS-Related Opportunistic Infections↗

Activation of serotonergic neurons in the raphe magnus is not necessary for morphine analgesia.

A wealth of pharmacological and behavioral data suggests that spinally projecting serotonergic cells mediate opioid analgesia. A population of medullary neurons, located within raphe magnus (RM) and the neighboring reticular nuclei, contains serotonin and is the source of serotonin in the spinal dorsal horn. To test whether serotonergic neurons mediate opioid analgesia, morphine was administered during recordings from medullary cells that were physiologically characterized as serotonergic (5HTp) by their slow and steady discharge pattern in the lightly anesthetized rat. Selected 5HTp cells (n = 14) were intracellularly labeled, and all contained serotonin immunoreactivity. The discharge of most 5HTp cells was not affected by an analgesic dose of systemic morphine. In a minority of cases, 5HTp cells either increased or decreased their discharge after morphine administration. However, morphine altered the discharge of some 5HTp cells in the absence of producing analgesia and conversely did not alter the discharge of most 5HTp cells in cases in which analgesia occurred. RM cells with irregular discharge patterns and excitatory or inhibitory responses to noxious tail heat were classified as ON and OFF cells, respectively. All ON and OFF cells that were intracellularly labeled (n = 9) lacked serotonin immunoreactivity. All ON cells were inhibited, and most OFF cells were excited by systemic morphine. Because 5HTp cells do not consistently change their discharge during morphine analgesia, they are unlikely to mediate the analgesic effects of morphine. Instead, nonserotonergic cells are likely to mediate morphine analgesia in the anesthetized rat. In light of the sensitivity of morphine analgesia to manipulations of serotonin, serotonin release, although neither necessary nor sufficient for opioid analgesia, is proposed to facilitate the analgesic effects of nonserotonergic RM terminals in the spinal cord.

Action Potentials↗

Autocatalytic processing of recombinant human procathepsin L. Contribution of both intermolecular and unimolecular events in the processing of procathepsin L in vitro.

The autocatalytic processing of procathepsin L was investigated in vitro using purified recombinant proenzyme expressed in Pichia pastoris. Pure intermolecular processing was studied by incubating the mutant procathepsin L (C25S), which cannot autoactivate with a small amount of mature active cathepsin L. The results clearly establish that, contrary to recent reports, intermolecular processing of procathepsin L is possible. The main cleavage sites are located at or near the N terminus of the mature enzyme, in an accessible portion of the proregion, which contains sequences corresponding to the known substrate specificity of cathepsin L. Contrary to procathepsins B, K, and S, autocatalytic processing of procathepsin L can generate the natural mature form of the enzyme. A continuous assay using the substrate benzyloxycarbonyl-Phe-Arg 4-methylcoumarinyl-7-amide hydrochloride has also been used to obtain information on the nature of the steps involved in the autocatalytic processing of wild-type procathepsin L. Processing is initiated by decreasing the pH from 8.0 to 5.3. The influence of proenzyme concentration on the rate of processing indicates the existence of both unimolecular and bimolecular steps in the mechanism of processing. The nature of the unimolecular event that triggers processing remains elusive. Circular dichroism and fluorescence measurements indicate the absence of large scale conformational change in the structure of procathepsin L on reduction of pH. However, the bimolecular reaction can be attributed to intermolecular processing of the zymogen.

Amino Acid Sequence↗

Dyskeratosis Congenita (DC) Registry: identification of new features of DC.

Dyskeratosis congenita (DC) is an inherited disorder characterized by skin pigmentation, nail dystrophy and mucosal leucoplakia. In 1995 a Dyskeratosis Congenita Registry was established at the Hammersmith Hospital. In the 46 families recruited, 76/83 patients were male, suggesting that the major form of DC is X-linked. As well as a variety of noncutaneous abnormalities, the majority (93%) of patients had bone marrow (BM) failure and this was the principal cause (71%) of early mortality. In addition to BM hypoplasia, some patients also developed myelodysplasia and acute myelod leukaemia. Pulmonary abnormalities were present in 19% of patients. In affected females the phenotype was less severe. Some female carriers of X-linked DC had clinical features. Carriers of X-linked DC showed skewed X-chromosome inactivation patterns (XCIPs), suggesting that cells expressing the normal DC allele have a growth/survival advantage over cells that express the mutant allele. Linkage analysis in multiplex families confirmed that the DKC1 gene, responsible for the X-linked form of DC, is located within Xq28 and facilitated its positional cloning. The high incidence of BM failure in association with a wide range of somatic abnormalities together with the ubiquitous expression of DKC1 suggest that, as well as having a critical role in normal haemopoiesis, this gene has a key role in normal cell biology.

Adolescent↗

Comparison of the effects of treatment with intrathecal lidocaine given before and after formalin on both nociception and Fos expression in the spinal cord dorsal horn.

BACKGROUND: It has been proposed that the measure of noxious stimulus-induced Fos (the protein product of the immediate early gene c-fos) expression in the spinal cord dorsal horn of laboratory animals may provide an estimate of the potential of specific treatments to produce preemptive analgesia. The present study examined this hypothesis by comparing the effects of intrathecal lidocaine given before and after hindpaw formalin injection on persistent nociceptive responses and Fos expression in spinal cord dorsal horn of rats. METHODS: Formalin-induced nociception and Fos expression in the spinal cord, in response to a 50-microl injection of 2.5% formalin into the hind paw, were assessed in rats given an intrathecal injection of 50 microl 2% lidocaine by lumbar puncture between the L5 and L6 vertebrae, either 3 min before (pretreatment) or 5 min after (post-treatment) formalin injection. RESULTS: Pain behaviors (hindpaw licking, elevation, and favoring) in the second phase of the formalin test were significantly reduced by pretreatment, but were unaffected by post-treatment. The number of immunocytochemically stained Fos-positive cells and the immunoprecipitation of the Fos antibodies were reduced by pretreatment, and were also reduced, to a lesser extent, by post-treatment. CONCLUSIONS: The finding that persistent nociceptive behaviors and Fos expression were suppressed by intrathecal lidocaine pretreatment suggests that nociception in the second phase of the formalin test depends on increases in central hyperexcitability generated during the first phase. On the other hand, the finding that the intrathecal injection of lidocaine after formalin treatment reduced Fos expression but not nociceptive responses indicates an uncoupling of the behavioral and Fos protein responses to formalin and suggests that changes in Fos expression may not be a good predictor of the ability of agents to produce preemptive analgesia.

Anesthetics, Local↗

Physiological survey of medullary raphe and magnocellular reticular neurons in the anesthetized rat.

The present study was designed to provide a detailed and quantitative description of the physiological characteristics of neurons in the medullary raphe magnus (RM) and adjacent nucleus reticularis magnocellularis (NRMC) under anesthetized conditions. The background discharge and noxious stimulus-evoked responses of RM and NRMC neurons were recorded in rats lightly anesthetized with isoflurane. All cells that were isolated successfully were studied. After recording background discharge, the neuronal response to repeated noxious thermal and noxious mechanical stimulation of the tail was recorded. Most cells were identified as nonserotonergic by their irregular or rapid background discharge pattern. Because the spontaneous discharge of most RM nonserotonergic cells contained pauses and bursts, a comparison between the change in rate evoked by tail heat and the range of rate changes that occur spontaneously was used to classify cells. The mean responses of ON and OFF cells were more than four times the standard deviation of the changes in rate observed spontaneously. ON cells were excited in 86% of the tail heat trials tested. Similarly, OFF cells were inhibited in 97% of the noxious tail heat trials tested. The heat-evoked changes in ON and OFF cell discharge varied over more than two orders of magnitude and were greater in cells with greater rates of background discharge. The heat-evoked responses of and cells had durations of tens of seconds to minutes and were always sustained beyond the visible motor response. Most ON and OFF cells responded to noxious tail clamp in a manner that was similar to their response to noxious heat. More than half of the NEUTRAL cells that were unresponsive to noxious heat were responsive to noxious tail clamp. A minority of ON, OFF, and NEUTRAL cells responded to innocuous brush stimulation with weak, transient responses. Although many cells discharged too infrequently to be classified, units with physiological properties that were different from those described above were rare. In conclusion, most RM and NRMC cells belong to three nonserotonergic physiological cell classes that can be distinguished from each other by the consistency, not the magnitude, of their responses to repeated noxious thermal stimulation. Because most of the heat-evoked change in and cell discharge occurs after the conclusion of the initial motor withdrawal, ON and OFF cells are likely to principally modulate the response to subsequent noxious insults.

Animals↗

Somatodendritic and axonal anatomy of intracellularly labeled serotonergic neurons in the rat medulla.

A knowledge of the anatomy of medullary serotonergic cells is critical to understanding local and brainstem circuits in which these cells participate. Serotonergic neurons (n = 16) were identified, as previously described (Mason [1997] J. Neurophysiol. 77:1087-1098) by their slow and steady background discharge in halothane anesthetized rats. Neurons were then intracellularly labeled with Neurobiotin and visualized with 3,3'diaminobenzidine. The validity of the physiological identification of serotonergic cells was confirmed by processing two neurons that were physiologically characterized as serotonergic for serotonin immunoreactivity; both tested cells contained immunoreactive serotonin. The dendrites and axon of each labeled cell were reconstructed by using a three-dimensional computerized system. Somata were small or medium in size and had fusiform, triangular, or multipolar shapes. The dendritic arbor was constricted with most dendrites extending for less than 500 microm from the soma. All labeled axons projected caudally and travelled in the ventrolateral medulla, either dorsal or ventral to the lateral reticular nucleus. Most cells had collaterals and/or dense axonal swellings in the nucleus reticularis gigantocellularis, nucleus reticularis magnocellularis, raphe magnus, and the ventrolateral medulla. Non-local collaterals and swellings were also observed in the nucleus reticularis gigantocellularis and in the ventrolateral medulla at all medullary levels. The results demonstrate that 1) the dendrites of serotonergic cells are restricted to raphe magnus and the ventral part of nucleus reticularis magnocellularis; and 2) serotonergic cells project to medullary nuclei that contain bulbospinal cells which project to dorsal, intermediate, and ventral horns. Serotonergic cell projections to brainstem sites may mediate the integration of sensory, autonomic, and motor modulation at the brainstem level.

Animals↗

Lumbar but not cervical intrathecal DAMGO suppresses extrasegmental nociception in awake rats.

he effect of intrathecally administered [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO) on withdrawal latencies evoked by noxious heat applied to either cervical or lumbar dermatomes was studied in awake rats. Administration of DAMGO to the lumbar intrathecal space produces a dose-dependent suppression of withdrawals evoked by noxious thermal stimulation in either lumbar or cervical dermatomes. Administration of the same doses of DAMGO to the cervical spinal cord produces a suppression of withdrawals evoked by stimulation in cervical but not lumbar dermatomes. Control experiments provide evidence that the drugs administered intrathecally to either enlargement do not spread to the other enlargement.

Analgesics, Opioid↗

SEROTONERGIC pontomedullary neurons are not activated by antinociceptive stimulation in the periaqueductal gray.

The antinociceptive and cardiovascular effects of midbrain periaqueductal gray (PAG) stimulation are mediated through a relay in the pontomedullary raphe magnus (RM) and adjacent nucleus reticularis magnocellularis (NRMC). To test whether the neurons important in mediating PAG-evoked effects are SEROTONERGIC, the responses of pontomedullary SEROTONERGIC-LIKE cells to PAG stimulation were tested. SEROTONERGIC-LIKE neurons (n = 21) were recorded extracellularly in halothane-anesthetized Sprague Dawley rats. Serotonergic-like neurons were distinguished by their slow and steady background discharge. Two neurons that were physiologically characterized as SEROTONERGIC-LIKE were intracellularly labeled and processed for serotonin immunoreactivity; both cells tested contained immunoreactive serotonin. Train stimulation of sites within the midbrain PAG, at intensities of </=50 microA, suppressed the tail withdrawal from noxious heat and evoked changes in blood pressure and heart rate. No SEROTONERGIC-LIKE cells were activated by single-pulse or short-train (two to five pulses) stimulation of the PAG at antinociceptive intensities. In most cases, SEROTONERGIC-LIKE cells were unaffected by long-train stimulation (5-6 sec) of the PAG, which produced antinociception and cardiovascular changes. In contrast, >50% of the cells in two nonserotonergic-like cell classes were activated at short latency by such PAG stimulation. In conclusion, monosynaptic excitation of SEROTONERGIC cells in RM/NRMC is unlikely to be necessary for the nociceptive and autonomic modulatory effects of PAG stimulation.

Animals↗

GABA-immunoreactive boutons contact identified OFF and ON cells in the nucleus raphe magnus.

The pontomedullary raphe magnus (RM) contains two physiologically defined types of neurons that participate in the opioid-induced modulation of dorsal horn nociceptive messages: OFF cells, which decrease, and ON cells, which increase their discharge rates when reflex behavior is evoked by noxious pinch or heat. Because both types of neuron have inhibitory inputs and because there is evidence that gamma-aminobutyric acid (GABA) inhibitory mechanisms within RM contribute to the antinociceptive action of opioids, we have sought anatomical evidence for a direct GABAergic input to OFF and ON cells. In this study, cells of each type located in the RM were electrophysiologically defined and intracellularly filled with horseradish peroxidase or Neurobiotin. One cell of each type was labeled in the cat, and 2-3 cells of each type were labeled in the rat. Thin sections were labeled by a postembedding immunogold procedure by using an antibody directed against glutaraldehyde-conjugated GABA. GABA-immunoreactive (GABA-ir) boutons contained small, round, clear vesicles and made symmetrical synapses with identified dendrites. GABA-ir boutons were apposed to soma and to proximal and distal dendrites of both cell types in both species. These findings demonstrate direct GABAergic input to identified OFF and ON cells in the RM. J. Comp. Neurol. 378:196-204, 1997.

Animals↗

Cytokine profiles in cerebrospinal fluid of human immunodeficiency virus-infected patients with cryptococcal meningitis: no leukocytosis despite high interleukin-8 levels. University of Zimbabwe Meningitis Group.

Cytokine levels were studied in the cerebrospinal fluid (CSF) of 16 adults with cryptococcal meningitis (CM). Low levels of tumor necrosis factor (TNF)-alpha and interferon-gamma, high levels of interleukin (IL)-1beta, IL-6, and IL-8, and the presence of IL-10 were documented. There were no significant differences in levels of TNF-alpha and interferon-gamma for CM and control patients. Mean CSF levels of IL-1beta (139.5 pg/mL), IL-6 (346 pg/mL), IL-8 (1160 pg/mL), and IL-10 (9.27 pg/mL) were significantly (P < .01) elevated in CM patients compared with levels in control patients. Despite the high CSF levels of IL-8, minimal leukocytosis was seen. Significant correlations between cryptococcal antigen titers and IL-10 levels (r = .8, P < .05), protein and cryptococcal antigen titer (r = .9, P < .05), and protein and IL-10 levels (r = .8, P < .05) were found.

AIDS-Related Opportunistic Infections↗

Physiological identification of pontomedullary serotonergic neurons in the rat.

Spinal serotonin is derived entirely from bulbar sources and plays an important role in spinal modulatory processes, including pain modulation. Establishing the electrophysiological properties of SEROTONERGIC bulbospinal neurons in the pontomedullary raphe and reticular formation is critical to understanding the physiological role of serotonin in the spinal cord. Neurons were characterized by their responses to noxious stimulation and their background discharge pattern in the lightly anesthetized rat. Characterized cells were intracellularly labeled with Neurobiotin, which was visualized with a Texas Red fluorophore. Sections containing the labeled cells were processed for serotonin immunocytochemistry with the use of a Bodipy fluorophore. Forty-seven intracellularly labeled cells were tested for serotonin immunoreactivity. The labeled neurons were located in raphe magnus, the nucleus reticularis magnocellularis, and the adjacent reticular and raphe nuclei at levels from the inferior olivary complex to the superior olivary complex. SEROTONERGIC cells were located in the raphe nuclei, in nucleus reticularis magnocellularis pars alpha, and in nucleus reticularis magnocellularis pars beta or nucleus reticularis gigantocellularis. Thirteen intracellularly labeled cells contained serotonin immunoreactivity. The background discharge rate of SEROTONERGIC cells average 1.8 Hz (range: 0.5-3.1 Hz). Discharge was steady and without sustained pauses or bursts in firing. Most serotonin-immunoreactive cells were unaffected or slightly excited by pinch and were unaffected by noxious heat. Three SEROTONERGIC cells were weakly excited by both noxious pinch and heat, whereas two SEROTONERGIC cells were briefly inhibited by these stimuli. Cells that lacked serotonin immunoreactivity were heterogeneous and included ON, OFF, and NEUTRAL cells. Nonserotonergic cells differed from SEROTONERGIC cells in having an irregular discharge pattern and/or a high mean discharge rate. A linear discriminant function, employing background discharge characteristics as independent variables, was calculated that successfully classified 13 of 13 SEROTONERGIC and 32 of 33 nonserotonergic neurons. The probability of misclassification with the use of this discriminant function was estimated to be < 10%. Employing the discriminant function on a test group of cells whose immunochemical content was unknown revealed a population of SEROTONERGIC-LIKE cells that resembled the labeled SEROTONERGIC cells in background discharge pattern, response to noxious stimulation, and nuclear location. The discharge of pontomedullary SEROTONERGIC neurons is slow and steady, suggesting that these neurons may have a role in the tonic, rather than phasic, modulation of spinal processes.

Animals↗

The predictive validity of a diagnosis of schizophrenia. A report from the International Study of Schizophrenia (ISoS) coordinated by the World Health Organization and the Department of Psychiatry, University of Nottingham.

BACKGROUND: Outcome is important in the validation of psychiatric diagnosis, as most disorders lack clinicopathological correlates. We describe the predictive validity of four definitions of schizophrenia (DSM-III-R, ICD-10, ICD-9 and CATEGO S+), in a representative cohort of patients selected during their first episode of psychosis. METHOD: Each definition of schizophrenia was applied to 99 patients. Their respective ability to predict 13-year outcome (Global Assessment of Functioning scales) was assessed. RESULTS: DSM-III-R and ICD-10 diagnoses of schizophrenia have high predictive validity for long-term outcome, and both provide relatively stable diagnoses. ICD-9 is reasonably good at predicting disability, but not symptoms, and CATEGO S+ showed no predictive validity. Adding six-month duration criteria to ICD-10, ICD-9 and CATEGO S+ improved their predictive validity, and removing the six-month duration criterion from DSM-III-R commensurately reduced predictive validity. CONCLUSIONS: Modern diagnostic systems (DSM-III-R and ICD-10) have high predictive validity, and are superior to ICD-9. The six-month duration criterion of DSM-III-R schizophrenia accounts for its predictive validity and stability over 13 years, but restricts its use in first-episode studies. The one-month duration criterion of ICD-10 is less restrictive, without major compromises in predictive validity or stability.

Adolescent↗

Cloning and expression of a single-chain antibody fragment specific for foot-and-mouth disease virus.

The gene for a single-chain antibody (VHK) to a conformational epitope on the type A12 foot-and-mouth disease virus (FMDV) particle was assembled and expressed in Escherichia coli. The VHK, purified from periplasmic extracts immunoprecipitated virus as efficiently as its parental monoclonal antibody (MAb) and exhibited the same binding specificity when tested against panel of natural and genetically engineered virus particles. The VHK neutralized type A12 virus in the presence of goat anti-mouse IgG; however, in the absence of the second antibody, only weak neutralizing activity was detected. Preliminary analysis of the mechanism of viral neutralization indicated that both the MAb and the VHK neutralize by the same mechanism. Small amounts of the VHK allowed infection of cells via Fc receptor-mediated adsorption in the presence of the second antibody. These data represent the first report of a single-chain neutralizing antibody for a picornavirus and provide insights into the mechanisms of viral neutralization and virus uptake.

Amino Acid Sequence↗

Zinc gluconate lozenges for treating the common cold. A randomized, double-blind, placebo-controlled study.

BACKGROUND: The common cold is one of the most frequent human illnesses and is responsible for substantial morbidity and economic loss. No consistently effective therapy for the common cold has been well documented, but evidence suggests that several possible mechanisms may make zinc an effective treatment. OBJECTIVE: To test the efficacy of zinc gluconate lozenges in reducing the duration of symptoms caused by the common cold. DESIGN: Randomized, double-blind, placebo-controlled study. SETTING: Outpatient department of a large tertiary care center. PATIENTS: 100 employees of the Cleveland Clinic who developed symptoms of the common cold within 24 hours before enrollment. INTERVENTION: Patients in the zinc group (n = 50) received lozenges (one lozenge every 2 hours while awake) containing 13.3 mg of zinc from zinc gluconate as long as they had cold symptoms. Patients in the placebo group (n = 50) received similarly administered lozenges that contained 5% calcium lactate pentahydrate instead of zinc gluconate. MAIN OUTCOME MEASURES: Subjective daily symptom scores for cough, headache, hoarseness, muscle ache, nasal drainage, nasal congestion, scratchy throat, sore throat, sneezing, and fever (assessed by oral temperature). RESULTS: The time to complete resolution of symptoms was significantly shorter in the zinc group than in the placebo group (median, 4.4 days compared with 7.6 days; P < 0.001). The zinc group had significantly fewer days with coughing (median, 2.0 days compared with 4.5 days; P = 0.04), headache (2.0 days and 3.0 days; P = 0.02), hoarseness (2.0 days and 3.0 days; P = 0.02), nasal congestion (4.0 days and 6.0 days; P = 0.002), nasal drainage (4.0 days and 7.0 days; P < 0.001), and sore throat (1.0 day and 3.0 days; P < 0.001). The groups did not differ significantly in the resolution of fever, muscle ache, scratchy throat, or sneezing. More patients in the zinc group than in the placebo group had side effects (90% compared with 62%; P < 0.001), nausea (20% compared with 4%; P = 0.02), and bad-taste reactions (80% compared with 30%; P < 0.001), CONCLUSION: Zinc gluconate in the form and dosage studied significantly reduced the duration of symptoms of the common cold. The mechanism of action of this substance in treating the common cold remains unknown. Individual patients must decide whether the possible beneficial effects of zinc gluconate on cold symptoms outweigh the possible adverse effects.

Administration, Oral↗