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Drug-Induced Liver Injury: Highlights from a Review of the 2015 Literature.

Numerous publications contributed to the expanding knowledge base about drug-induced liver injury (DILI) in 2015. New findings from the US D … re relatively minor and the result of cholestatic hepatotoxins. Newly described DILI agents include tolvaptan, as well as some new direct-acting antiviral protease inhibitors for chronic hepatitis C. The latter have been associated with serious acute hepatitis, hyperbilirubinemia, and decompensation. Herbal hepatotoxicity continues to be increasingly report …

Fundamental insights into autosomal dominant polycystic kidney disease from human-based cell models.

Several animal- and human-derived models are used in autosomal dominant polycystic kidney disease (ADPKD) research to gain insight in the disease mechanism. However, a consistent correlation between animal and human ADPKD models is lacking. Therefore, established human-derived models are relevant to affirm research results and translate findings into a clinical set-up. In this review, we give an extensive overview of the existing human-based cell models. We discuss their source (urine, nephrectomy and stem cell), immortalisation procedures, genetic engineering, kidney segmental origin and char

Prognostic Performance of Ellipsoid Kidney Volume Measurement in a Computed Tomography-Heavy ADPKD Cohort: A Retrospective Observational Cohort Study.

BACKGROUND: Accurate prognostic classification in autosomal dominant polycystic kidney disease is important for risk stratification and treatment decisions, including tolvaptan eligibility. Although the ellipsoid method has shown good performance for kidney volume measurement in magnetic resonance imaging cohorts, data from cohorts imaged predominantly with computed tomography remains limited. OBJECTIVE: To evaluate the agreement between the ellipsoid and manual segmentation methods for kidney volume measurement in a computed tomography-heavy cohort of patients with autosomal dominant polycys…

Unilateral adrenalectomy for a drug-resistant bilateral primary aldosteronism with heart failure: pathophysiology and surgical indication.

BACKGROUND: Patients with bilateral primary aldosteronism (PA) generally are treated with antihypertensive drugs, but optimal treatment for … of 6 antihypertensive drugs (spironolactone 25 mg/day, eplerenone 100 mg/day, azosemide 60 mg/day, tolvaptan 7.5 mg/day, enalapril 5 mg/day, and bisoprolol fumarate 10 mg/day); however, heart failure relapsed after four months of treatment. We hypothesized that hypertension caused by excess aldosterone was inducing the patient's heart failure. In order to …

Emerging therapies for autosomal dominant polycystic kidney disease with a focus on cAMP signaling.

Autosomal dominant polycystic kidney disease (ADPKD), with an estimated genetic prevalence between 1:400 and 1:1,000 individuals, is the third most common cause of end stage kidney disease after diabetes mellitus and hypertension. Over the last 3 decades there has been great progress in understanding its pathogenesis. This allows the stratification of therapeutic targets into four levels, gene mutation and polycystin disruption, proximal mechanisms directly caused by disruption of polycystin function, downstream regulatory and signaling pathways, and non-specific pathophysiologic processes sha

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… An open label extension of REPRISE showed effectiveness of tolvaptan at very advanced stages of CKD ( Torres et al., 2021 ). … Indeed the dosing of tolvaptan is limited by its powerful aquaretic effect. …

Predictors of rapid disease progression in autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common genetic diseases with a reported prevalence of 1:400 to 1:1000. Since the intact kidneys can compensate for the loss of glomerular filtration in ADPKD patients, renal insufficiency usually remains undetected until almost the fourth decade of life. Hereafter, reliable diagnostic and prognostic biomarkers to identify ADPKD progression are urgently needed. Several studies and systematic reviews tried to identify markers or predictors of rapid disease progression of ADPKD. The aim of this study is to review predictors o

[Severe hyponatremia secondary to the syndrome of inappropriate secretion of antidiuretic hormone].

The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is a common and multifactorial cause of hyponatremia that is often overlooked. The common pathophysiological mechanism is the increased production and/or action of antidiuretic hormone within the kidney, resulting in hypotonic hyponatremia. Inadequate correction of hyponatremia may have fatal neurological consequences leading to central pontine myelinolysis. We report the case of a patient with a history of recent head trauma, who came to our observation for acute-onset mental confusion secondary to severe hyponatremia due

Hyponatraemia and the syndrome of inappropriate antidiuresis (SIAD) in cancer.

Hyponatraemia is a common electrolyte abnormality seen in a wide range of oncological and haematological malignancies and confers poor performance status, prolonged hospital admission and reduced overall survival, in patients with cancer. Syndrome of inappropriate antidiuresis (SIAD) is the commonest cause of hyponatraemia in malignancy and is characterised by clinical euvolaemia, low plasma osmolality and concentrated urine, with normal renal, adrenal and thyroid function. Causes of SIAD include ectopic production of vasopressin (AVP) from an underlying tumour, cancer treatments, nausea and p

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… A reversible transaminitis has been reported with tolvaptan therapy in autosomal dominant polycystic kidney disease ( Torres et al. 2012 ) but not in hyponatraemia, where lower doses of tolvaptan are typically used ( Schrier et al. 2006 ). … Tolvaptan is a safe and effective treatment of SIAD in the oncology setting. …

Hyponatremia in Cirrhosis: An Update.

Hyponatremia is frequently seen in patients with ascites secondary to advanced cirrhosis and portal hypertension. Although not apparent in the early stages of cirrhosis, the progression of cirrhosis and portal hypertension leads to splanchnic vasodilation, and this leads to the activation of compensatory mechanisms such as renin-angiotensin-aldosterone system (RAAS), sympathetic nervous system, and antidiuretic hormone (ADH) to ameliorate low circulatory volume. The net effect is the avid retention of sodium and water to compensate for the low effective circulatory volume, resulting in the dev

Vasopressin receptor antagonists.

The first non-peptide vasopressin receptor antagonist (VRA) was recently approved by the United States Food and Drug Administration, and several others are now in late stages of clinical development. Phase 3 trials indicate that these agents predictably reduce urine osmolality, increase electrolyte-free water excretion, and raise serum sodium concentration. They are likely to become a mainstay of treatment of euvolemic and hypervolemic hyponatremia. Although tachyphylaxis to the hydro-osmotic effect of these agents does not appear to occur, their use is accompanied by an increase in thirst, an

Combination pharmacologic therapies for heart failure: what next after angiotensin-converting enzyme inhibitors and beta-blockers?

Although the introduction of angiotensin-converting enzyme (ACE) inhibitors and beta-adrenergic blockers has resulted in significant improvements in the management of heart failure (HF), morbidity and mortality remain high. Therefore, additional approaches have been sought to discover newer agents that might add incremental benefit. Although not all of these approaches have been successful, there have been some notable new approaches to therapy that have shown benefit or may be promising in terms of additional benefit. Most of these agents are targeted to achieve a more global neurohormonal bl

Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH): Optimal Management.

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

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… Tolvaptan is administered orally and has been approved in the US and Europe for the treatment of euvolaemic hyponatraemia caused by SIADH. In the SALT-1 and SALT-2 studies, patients with SIADH were randomized to receive oral tolvaptan 15 mg daily or placebo. … with tolvaptan in SIADH has not been encouraged by European guidelines. …

[Multination clinical trials: what is the relevance and what are the lessons from across-country differences?].

In the cardiovascular area, the rate of occurrence of relevant clinical events decreased over the last decades due to the large adoption of evidence-based treatments. This implies that large numbers of patients are needed to provide reliable answers to research open questions. Therefore, the conduction of multinational large-scale studies became necessary. In this setting, it is not infrequent to find relevant differences in the trial results across countries. The interpretation of these differences should be extremely cautious to avoid the well known mistakes related to subgroup analyses. To

Common drug review recommendations for orphan drugs in Canada: basis of recommendations and comparison with similar reviews in Quebec, Australia, Scotland and New Zealand.

BackgroundPublic payer reimbursement for non-oncology drugs in Canada, including orphan drugs, is based on recommendations by the Common Drug Review (CDR) (with the exception of Quebec). CDR has been criticized for negative recommendations for orphan drugs and contributing to delays in patient access to these drugs. However, it is unclear how CDR makes recommendations for orphan drugs and the role clinical and economic factors play in decision making. The objective of the present study was to analyze the basis for CDR orphan drug recommendations and to compare recommendations to those in other

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… BSC) | Noted the burden of ADPKD on patients and caregivers and stressed that only tolvaptan has been approved for treatment of ADPKD. … Patients expect tolvaptan toprolong their lives and improve QoL but also noted the challenges of using tolvaptan (large daily fluid intake, increased urination, dry mouth and thirst) | One Phase III, RCT ( n = 1445) showed that tolvaptan significantly delayed clinical progression. …

Синдром неадекватного антидиерезного вторичного воздействия на миелому: доклад о деле и обзор литературы.

Синдром неадекватного антидиеразиса (SIAD) связан с различными заболеваниями. Однако, насколько нам известно, лишь несколько исследований сообщили о том, что в качестве потенциальной причины СИАД можно использовать множественные миеломы (ММ). Мы сообщаем о случае, когда гипонатремия была основным клиническим проявлением, диагностированным SIAD и впоследствии подтвержденным как множественная миелома. После антимиеломной терапии гипонатремия была успешно исправлена после получения гематологической реакции, классифицированной как очень хорошая частичная реакция (VGPR). Это дело способствует редко

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… Fluid restriction and daily oral tolvaptan 3.75mg (Otsuka Co., Ltd, Lin-an, Zhejiang, China) corrected the sodium level. We then investigated the etiology of SIAD. The patient had no history of brain trauma, pneumonia, or drug abuse. … The diagnosis of SIADH was primarily entertained as further fluid restriction and tolvaptan administration corrected the hyponatremia ( 6 ). …

Nonmyeloablative Allogeneic Stem Cell Transplantation With Postcyclophosphamide in a Case of Acute Lymphoblastic Leukemia Complicated by Ventricular Septal Defect.

PURPOSE: We report a case of unrelated non-myeloablative allogeneic stem cell transplantation (allo-SCT) incorporating post-transplant cyclo … f right heart failure and congestive hepatopathy due to VSD enlargement. Treatment with pimobendan, tolvaptan, and spironolactone resulted in BNP reduction to <1000 pg/mL within 6 weeks, and normalization of LDH and liver function prior to the BNP peak. These medications were discontinued 4 months after the onset of right heart failure. By one year post-tra …

Metabolic Activation of Cholestatic Drug-Induced Bile Acid-Dependent Toxicity in Human Sandwich-Cultured Hepatocytes.

We previously reported a cell-based toxicity assay using sandwich-cultured hepatocytes in combination with a titrated amount of human bile acid (BA) species. In this assay, test compound-induced inhibition of BA efflux from sandwich-cultured hepatocytes leads to BA-dependent cell toxicity (BAtox, i.e., cell death due to the accumulation of BAs). Using this assay, we investigated whether 1-aminobenzotriazole (1-ABT; a nonselective cytochrome P450 inhibitor) enhanced or suppressed test compound-induced BAtox. There was a tendency that BAtox of many compounds was enhanced by 1-ABT in human hepato

The assessment and treatment of water imbalance in patients with psychosis.

Polydipsia and episodic life-threatening water intoxication remain important clinical problems for a significant portion of persons with schizophrenia. The disorders are associated with increased morbidity and mortality from a number of causes. With a basic understanding of the pathophysiology, one can easily diagnose and assess the clinical conditions. We review here the scope and pathophysiology of disordered water imbalance, including both primary and secondary polydipsia and hyponatremia. Reversible factors and possible interventions are reviewed. Treatment options for preventing water int

Heart failure medication treatment and prognosis: a retrospective cross-sectional study.

OBJECTIVE: Heart failure (HF) is a significant global public health concern and the leading cause of morbidity and mortality worldwide, impo … .681, CI 0.511-0.908), ARNIs (OR 0.191, CI 0.089-0.406), anticoagulants (OR 0.578, CI 0.403-0.829), tolvaptan (OR 0.340, CI 0.124-0.929), and SGLT-2i (OR 0.238, CI 0.058-0.969) significantly reduced the readmission rate of patients. Further subgroup analysis showed that the efficacy of the drugs varied slightly depending on the type of HF, but was consisten …

Paraneoplastic Endocrine Changes in Gastrointestinal Tumors: A Clinical and Mechanistic Review.

Paraneoplastic endocrine syndromes (PESs) are hormonal disturbances associated with malignancies that result from tumor-related production of hormone-like substances, immune-mediated mechanisms, or dysregulated signaling pathways. While they are well recognized in lung and neuroendocrine cancers, their relevance in gastrointestinal tumors remains less clearly defined. This narrative review synthesizes current knowledge on paraneoplastic endocrine manifestations in gastrointestinal malignancies, based on a structured search of the literature in major databases, including PubMed, Scopus, and Web

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… Second, the simultaneous initiation of tolvaptan and chemotherapy is mechanistically rational: tolvaptan corrects the immediate biochemical crisis while chemotherapy targets the underlying hormonal source. … In tolvaptan-naive patients with very low baseline sodium, initiating tolvaptan at the lowest available dose (7.5 mg) with daily sodium monitoring is mandatory [ 42 , 43 ]. 3.4. Non-Islet Cell Tumor Hypoglycemia 3.4.1. …