Ecstasy induces reactive oxygen species, kidney water absorption and rhabdomyolysis in normal rats. Effect of N-acetylcysteine and Allopurinol in oxidative stress and muscle fiber damage.
ABSTRACT: Ecstasy (Ec) use produces hyperthermia, excessive sweating, intense thirst, an inappropriate antidiuretic hormone secretion (SIADH) and a multisystemic toxicity due to oxidative stress (OS). Intense thirst induces high intake of pure water, which associated with SIADH, usually develops into acute hyponatremia (Hn). As Hn is induced rapidly, experiments to check if Ec acted directly on the Inner Medullary Collecting Ducts (IMCD) of rats were conducted. Rhabdomyolysis and OS were also studied because Ec is known to induce Reactive Oxygen Species (ROS) and tissue damage. To decrease OS, the antioxidant inhibitors N-acetylcysteine (NAC) and Allopurinol (Allo) were used.Rats were maintained on a lithium (Li) diet to block the Vasopressin action before Ec innoculation. AQP2 (Aquaporin 2), ENaC (Epitheliun Sodium Channel) and NKCC2 (Sodium, Potassium, 2 Chloride) expression were determined by Western Blot in isolated IMCDs. The TBARS (thiobarbituric acid reactive substances) and GSH (reduced form of Glutathione) were determined in the Ec group (6 rats injected with Ec-10mg/kg), in Ec+NAC groups (NAC 100mg/Kg/bw i.p.) and in Allo+Ec groups (Allo 50mg/Kg/i.p.).Enhanced AQP2 expression revealed that Ec increased water transporter expression, decreased by Li diet, but the expression of the tubular transporters did not change. The Ec, Ec+NAC and Allo+Ec results showed that Ec increased TBARS and decreased GSH, showing evidence of ROS occurrence, which was protected by NAC and Allo. Rhabdomyolysis was only protected by Allo.Results showed that Ec induced an increase in AQP2 expression, evidencing another mechanism that might contribute to cause rapid hyponatremia. In addition, they showed that NAC and Allo protected against OS, but only Allo decreased rhabdomyolysis and hyperthermia.
Project description:Introduction:Cerebral salt wasting syndrome (CSWS) is a cause of hyponatremia in the setting of intracranial pathologies such as Central Nervous System (CNS) trauma, infections, and tumors. It is important to differentiate CSWS from the syndrome of inappropriate antidiuretic hormone secretion (SIADH) as their management differs. CSWS leads to hypovolemia as opposed to euvolemia or hypervolemia in SIADH. SIADH is managed with fluid restriction and this could worsen CSWS which is managed with adminstration of intravenous crystalloids to correct hyponatremia. Case summary:A 42-year-old male was admitted after a week of low-grade fever with easy fatigability, hypersomnolence, and excessive thirst. He had polyuria which started 5 days before presentation, and unintentionally lost 3 kg of weight in the past month. He had orthostatic hypotension, and was dehydrated, but vital signs were normal with the exception of his temperature. Cerebrospinal fluid (CSF) analysis revealed a glucose of 42 mg/dl, protein 170 mg/dl, cell count 28/mm<sup>3</sup> with 65% lymphocytes which was consistant with tubercular meningitis. CSF AFB culture was positive in addition to a positive CSF PCR for <i>M. tuberculosis</i>. Discussion:Presentation of CNS infection with tuberculosis may be non-specific and its insidious onset could lead to delayed or missed diagnosis; however persistent constitutional symptoms and signs with history of weight loss and a close contact with tuberculosis may raise the possibility of tuberculosis. Early diagnosis and treatment has an excellent prognosis, but any delay contributes to death and disability despite anti-tubercular drug therapy.CSWS should be managed with salt and volume replacement, but more importantly, the causative CNS insult should also be confirmed and addressed.
Project description:Hyponatremia is a common electrolyte disorder in cancer patients and has been associated with poor prognosis. A frequent cause of cancer-related hyponatremia is the syndrome of inappropriate antidiuretic hormone (SIADH). This study was a post hoc subgroup analysis of the SALT-1 (Study of Ascending Levels of Tolvaptan in Hyponatremia) and SALT-2 clinical trials. Hyponatremic subjects with SIADH and cancer received the oral selective vasopressin V2-receptor antagonist tolvaptan (n = 12) or matching placebo (n = 16) once-daily for 30 days. The initial tolvaptan dose (15 mg) was titrated over 4 days to 30 or 60 mg per day, as needed, according to serum sodium level and tolerability. Baseline serum sodium levels in the SIADH/cancer cohort of the SALT trials was 130 and 128 mEq/L for tolvaptan and placebo, respectively. Mean change from baseline in average daily serum sodium AUC for tolvaptan relative to placebo was 5.0 versus -0.3 mEq/L (P < 0.0001) at day 4, and 6.9 versus 1.0 mEq/L (P < 0.0001) at day 30; the observed treatment effects were similar to those in the overall SIADH population (i.e., with and without cancer) at both time points. Serum sodium normalization was observed in 6/12 and 0/13 subjects at day 4 and 7/8 and 2/6 subjects at day 30 in the tolvaptan and placebo groups, respectively (P < 0.05 for both). Common treatment-emergent AEs for tolvaptan were consistent with previously reported results. In this post hoc study of the SALT trial population, oral tolvaptan was an effective and safe therapy for the treatment of hyponatremia in subjects with SIADH and cancer.
Project description:Hyponatremia, defined as serum sodium concentration <135 mEq/l, is the most common electrolyte balance disorder in clinical practice. Many causes are listed, but syndrome of inappropriate antidiuretic hormone secretion (SIADH) is certainly the most relevant, mainly in oncological and hospitalized patients. In this review, the pathophysiological and clinical aspects are described in detail. Patients' extensive medical history and structured physical and biochemical tests are considered the milestones marking the way of the SIADH management as to provide early detection and proper correction. We focused our attention on the poor prognostic role and negative effect on patient's quality of life of SIADH-induced hyponatremia in both malignant and non-malignant settings, stressing how optimal management of this electrolyte imbalance can result in improved outcomes and lower health costs.
Project description:<h4>Background</h4>Hyponatremia is a frequent and potentially life-threatening adverse side effect of thiazide diuretics. This sub-analysis of the Hyponatremia Registry database focuses on current management practices of thiazide-associated hyponatremia (TAH) and compares differences between TAH and syndrome of inappropriate antidiuretic hormone secretion (SIADH).<h4>Methods</h4>We analyzed 477 patients from 225 US and EU sites with euvolemic hyponatremia ([Na+] ?130 mEq/L) who were receiving a thiazide diuretic. Of these, 118 met criteria for true thiazide-induced hyponatremia (TIH).<h4>Results</h4>Thiazide was withdrawn immediately after hyponatremia was diagnosed only in 57% of TAH; in these patients, the median rate of [Na+] change (?daily[Na+]) was significantly higher than those with continued thiazide treatment (3.8 [interquartile range: 4.0] vs. 1.7 [3.8] mEq/L/day). The most frequently employed therapies were isotonic saline (29.6%), fluid restriction (19.9%), the combination of these two (8.2%), and hypertonic saline (5.2%). Hypertonic saline produced the greatest ?daily[Na+] (8.0[6.4] mEq/L/day) followed by a combination of fluid restriction and normal saline (4.5 [3.8] mEq/L/day) and normal saline alone (3.6 [3.5] mEq/L/day). Fluid restriction was markedly less effective (2.7 [2.7] mEq/L/day). Overly rapid correction of hyponatremia occurred in 3.1% overall, but in up to 21.4% given hypertonic saline. Although there are highly significant differences in the biochemical profiles between TIH and SIADH, no predictive diagnostic test could be derived.<h4>Conclusions</h4>Despite its high incidence and potential risks, the management of TAH is often poor. Immediate withdrawal of the thiazide is crucial for treatment success. Hypertonic saline is most effective in correcting hyponatremia but associated with a high rate of overly rapid correction. We could not establish a diagnostic laboratory-based test to differentiate TIH from SIADH.
Project description:In the syndrome of inappropriate antidiuretic hormone secretion (SIADH), hyponatremia is limited by onset of vasopressin-escape caused by loss of the water channel aquaporin-2 in the renal collecting duct despite high circulating vasopressin. Here, we use the methods of systems biology in a well-established rat model of SIADH to identify signaling pathways activated at the onset of vasopressin-escape. Using single-tubule RNA-Seq, full transcriptomes were determined in microdissected cortical collecting ducts of vasopressin-treated rats at 1, 2, and 4 days after initiation of oral water loading in comparison to time-control rats without water loading. The time-dependent mRNA abundance changes were mapped to gene sets associated with curated canonical signaling pathways and revealed evidence of perturbation of transforming growth factor ? signaling and epithelial-to-mesenchymal transition on Day 1 of water loading simultaneous with the initial fall in Aqp2 gene expression. On Day 2 of water loading, transcriptomic changes mapped to Notch signaling and the transition from G0 into the cell cycle but arrest at the G2/M stage. There was no evidence of cell proliferation or altered principal or intercalated cell numbers. Exposure of vasopressin-treated cultured mpkCCD cells to transforming growth factor ? resulted in a virtually complete loss of aquaporin-2. Thus, there is a partial epithelial-to-mesenchymal transition during vasopressin escape with a subsequent shift from quiescence into the cell cycle with eventual arrest and loss of aquaporin-2.
Project description:Context:The relevance of hyponatremia has been acknowledged by guidelines from the United States (2013) and Europe (2014). However, treatment recommendations differ due to limited evidence. Objective:In hyponatremia following pituitary surgery-caused by the syndrome of inappropriate antidiuretic hormone (SIADH) secretion-we compared fluid restriction with the pharmacological increase of water excretion by blocking the vasopressin 2 receptors with tolvaptan at a low and a moderate dose. Design:Prospective observational study. Setting:Neurosurgical Department of a University hospital with more than 200 surgical pituitary procedures per year. Patients:Patients undergoing pituitary surgery and developing serum sodium below 136 mmol/L. The diagnosis of SIADH was established by euvolemia (daily measurement of body weight and fluid balance), inappropriately concentrated urine (specific gravity), and exclusion of adrenocorticotropic and thyroid-stimulating hormone deficiency. Intervention:Patients were treated with fluid restriction (n?=?40) or tolvaptan at 3.75 (n?=?38) or 7.5 mg (n?=?48). Main Outcome Measures:Treatment efficacy was assessed by the duration of hyponatremia, sodium nadir, and length of hospitalization. Safety was established by a sodium increment below 10 mmol/L per day and exclusion of side effects. Results:Treatment with 7.5 mg of tolvaptan resulted in a significant attenuation of hyponatremia and in a significant overcorrection of serum sodium in 30% of patients. The duration of hospitalization did not differ between treatment groups. Conclusions:Tolvaptan at a moderate dose is more effective than fluid restriction in the treatment of SIADH. Overcorrection of serum sodium may be a side effect of tolvaptan even at low doses.
Project description:Rationale & Objective:Euvolemic hyponatremia often occurs due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Vasopressin 2 receptor antagonists may be used to treat SIADH. Several of the major trials used 15 mg of tolvaptan as the lowest effective dose in euvolemic and hypervolemic hyponatremia. However, a recent observational study suggested an elevated risk for serum sodium level overcorrection with 15 mg of tolvaptan in patients with SIADH. Study Design:A retrospective chart review study comparing outcomes in patients with SIADH treated with 15 versus 7.5 mg of tolvaptan. Settings & Participants:Patients with SIADH who were treated with a very low dose of tolvaptan (7.5 mg) at a single center compared with patients using a 15-mg dose from patient-level data from the observational study described previously. Predictors:Tolvaptan dose of 7.5 versus 15 mg daily. Outcomes:Appropriate response to tolvaptan, defined as an initial increase in serum sodium level > 3 mEq/L, and overcorrection of serum sodium level (>8 mEq/L per day, and >10 mEq/L per day in sensitivity analyses). Analytical Approach:Descriptive study with additional outcomes compared using t tests and F-tests (Fischer's Exact ?2 Test). Results:Among 18 patients receiving 7.5 mg of tolvaptan, the mean rate of correction was 5.6 ± 3.1 mEq/L per day and 2 (11.1%) patients corrected their serum sodium levels by >8 mEq/L per day, with 1 of these increasing by >12 mEq/L per day. Of those receiving tolvaptan 7.5 mg, 14 had efficacy, with increases ? 3 mEq/L; similar results were seen with the 15-mg dose (21 of 28). There was a statistically significant higher chance of overcorrection with the use of 15 versus 7.5 mg of tolvaptan (11 of 28 vs 2 of 18; P = 0.05; and 10 of 28 vs 1 of 18; P = 0.03, for >8 mEq/L per day and >10 mEq/L per day, respectively). Limitations:Small sample size, retrospective, and nonrandomized. Conclusions:Tolvaptan, 7.5 mg, daily corrects hyponatremia with similar efficacy and less risk for overcorrection in patients with SIADH versus 15 mg of tolvaptan.
Project description:The syndrome of inappropriate antidiuretic hormone secretion (SIADH) accounts for an important part of hyponatremia cases. The causes of SIADH can be detected almost always. As a rare disorder, Morvan Syndrome can be defined by the sum of peripheral nerve hyperexcitability, autonomic instability and neuropsychiatric features. Antibodies to voltage-gated potassium channels (Anti - VGKC-Ab) including contactin associated protein-like 2 antibodies (CASPR2-Ab) and leucine-rich glioma inactivated protein 1 antibodies (LGI1-Ab) were previously known for the potential association with this condition. We present a Morvan Syndrome in a patient who presented with various neuropsychiatric symptoms and SIADH.
Project description:Hyponatremia secondary to SIADH is frequent in cancer patients and potentially deleterious. The aim of this sub-analysis of the Hyponatremia Registry database is to analyze current diagnostic and therapeutic management practices in cancer patients with SIADH.We analyzed 358 cancer patients who had serum sodium concentration ([Na+]) ? 130 mEq/L and a clinical diagnosis of SIADH from 225 sites in the USA and EU.Precise diagnostic testing was performed in only 46%. Almost 12% of all patients did not receive any hyponatremia treatment. The most frequent therapies were fluid restriction (20%), isotonic saline (14%), fluid restriction/isotonic saline (7%), tolvaptan (8%), and salt tablets (7%). Hypertonic saline was used in less than 3%. Tolvaptan produced the greatest median rate of [Na+] change (IQR) (3.0 (4.7) mEq/L/day), followed by hypertonic saline (2.0(7.0) mEq/L/day), and fluid restriction/isotonic saline (1.9(3.2) mEq/L/day). Both fluid restriction and isotonic saline monotherapies were significantly less effective (0.8(2.0) mEq/L/day and 1.3(3.0) mEq/L/day, respectively) and were associated with clinically relevant rates of treatment failure. Only 46% of patients were discharged with [Na+] ? 130 mEq/L. Overly rapid correction of hyponatremia occurred in 11.7%.Although essential for successful hyponatremia management, appropriate diagnostic testing is not routinely performed in current practice. The most frequently employed monotherapies were often ineffective and sometimes even aggravated hyponatremia. Tolvaptan was used less often but showed significantly greater effectiveness. Despite clear evidence that hyponatremia is associated with poor outcome in oncology patients, most patients were discharged still hyponatremic. Further studies are needed to assess the beneficial impact of hyponatremia correction with effective therapies.
Project description:BACKGROUND:Tolvaptan effectively corrects hyponatremia due to the syndrome of inappropriate secretion of antidiuretic hormone (SIADH), but undesired overcorrection can occur. We hypothesized that pretherapy parameters can predict the rapidity of response to tolvaptan in SIADH. STUDY DESIGN:Multicenter historical cohort study. SETTING & PARTICIPANTS:Adults with SIADH or congestive heart failure (CHF) treated with tolvaptan for a serum sodium concentration ? 130 mEq/L at 5 US hospitals. PREDICTORS:Demographic and laboratory parameters. OUTCOMES:Rate of change in serum sodium concentration. MEASUREMENTS:Spearman correlations, analysis of variance, and multivariable linear mixed-effects models. RESULTS:28 patients with SIADH and 39 patients with CHF treated with tolvaptan (mean baseline serum sodium, 120.6 and 122.4 mEq/L, respectively) were studied. Correction of serum sodium concentration > 12 mEq/L/d occurred in 25% of patients with SIADH compared to 3% of those with CHF (P<0.001). Among patients with SIADH, the increase in serum sodium over 24 hours was correlated with baseline serum sodium concentration (r=-0.78; P<0.001), serum urea nitrogen concentration (SUN; r=-0.76; P<0.001), and estimated glomerular filtration rate (r=0.58; P=0.01). Baseline serum sodium and SUN concentrations were identified as independent predictors of change in serum sodium concentration in multivariable analyses. When patients were grouped into 4 categories according to baseline serum sodium and SUN median values, those with both low baseline serum sodium (?121 mEq/L) and low baseline SUN concentrations (?10mg/dL) exhibited a significantly greater rate of increase in serum sodium concentration (mean 24-hour increase of 15.4 mEq/L) than the other 3 categories (P<0.05). Among patients with CHF, only baseline SUN concentration was identified as an independent predictor of change in serum sodium concentration over time. LIMITATIONS:Lack of uniformity in serial serum sodium concentration determinations and documentation of water intake. CONCLUSIONS:Baseline serum sodium and SUN values are predictive of the rapidity of hyponatremia correction following tolvaptan use in SIADH. We advise caution when dosing tolvaptan in patients with both low serum sodium and SUN concentrations.