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Clinical Pharmacology and Therapeutics Mar 2024The lethality of torsades de pointes (TdP) by drugs is one of main reasons that some drugs were withdrawn from the market. In order to assess drug-induced TdP risks, a...
The lethality of torsades de pointes (TdP) by drugs is one of main reasons that some drugs were withdrawn from the market. In order to assess drug-induced TdP risks, a model of cardiac ionic current suppression in human ventricular myocytes (ToR-ORd model), combined with the maximum effective free therapeutic plasma concentration or the maximum effective free therapeutic myocyte concentration was often used, with the latter proved to be more relevant and more accurate. We aimed to develop a whole-body physiologically-based pharmacokinetic (PBPK) model, incorporated with a human cardiomyocyte pharmacodynamic (PD) model, to provide a comprehensive assessment of drug-induced TdP risks in normal and specific scenarios. Quinidine served as an example to validate the PBPK-PD model via predicting plasma quinidine concentrations and quinidine-induced changes in QT interval (ΔQTc). The predicted plasma quinidine concentrations and ΔQTc values following oral administration or intravenous administration of quinidine were comparable to clinic observations. Visual predictive checks showed that most of the observed plasma concentrations and ΔQTc values fell within the 5th and 95th percentiles of simulations. The validated PBPK-PD model was further applied to assess the TdP risks using frequencies of early afterdepolarization and long-QT syndrome occurrence in 4 scenarios, such as therapeutic dose, supra-therapeutic dose, alkalosis, and hyperkalemia in 200 human subjects. In conclusion, the developed PBPK-PD model may be applied to predict the quinidine pharmacokinetics and quinidine-induced TdP risks in healthy subjects, but also simulate quinidine-induced TdP risks under disease conditions, such as hypokalemia and alkalosis.
Topics: Humans; Quinidine; Torsades de Pointes; Electrocardiography; Long QT Syndrome; Alkalosis; DNA-Binding Proteins
PubMed: 38117225
DOI: 10.1002/cpt.3156 -
Medicine Dec 2023Gitelman syndrome (GS) is an uncommon autosomal recessive tubulopathy resulting from a functional deletion mutation in the SLC12A3 gene. Its onset is typically insidious... (Review)
Review
RATIONALE
Gitelman syndrome (GS) is an uncommon autosomal recessive tubulopathy resulting from a functional deletion mutation in the SLC12A3 gene. Its onset is typically insidious and challenging to discern, and it is characterized by hypokalemia, metabolic alkalosis, and reduced urinary calcium excretion. There is limited literature on the diagnosis and management of GS in individuals with concomitant diabetes.
PATIENT CONCERNS
A 36-year-old male patient with a longstanding history of diabetes exhibited suboptimal glycemic control. Additionally, he presented with concurrent findings of hypokalemia, hypomagnesemia, hypocalciuria, and metabolic alkalosis.
DIAGNOSIS
Building upon the patient's clinical manifestations and extensive laboratory evaluations, we conducted thorough genetic testing, leading to the identification of a compound heterozygous mutation within the SLC12A3 gene. This definitive finding confirmed the diagnosis of GS.
INTERVENTIONS
We have formulated a detailed medication regimen for patients, encompassing personalized selection of hypoglycemic medications and targeted electrolyte supplementation.
OUTCOMES
Following 1 week of comprehensive therapeutic intervention, the patient's serum potassium level effectively normalized to 3.79 mmol/L, blood glucose parameters stabilized, and there was significant alleviation of clinical symptoms.
LESSONS
GS has a hidden onset and requires early diagnosis and intervention based on patient related symptoms and laboratory indicators in clinical practice, and personalized medication plans need to be provided according to the specific situation of the patient.
Topics: Male; Humans; Adult; Gitelman Syndrome; Hypokalemia; Solute Carrier Family 12, Member 3; Diabetes Mellitus; Alkalosis
PubMed: 38115360
DOI: 10.1097/MD.0000000000036663 -
The American Journal of Emergency... Feb 2024Consumption of alkaline electrolyzed water (AEW) has become increasingly popular for consumer use. Although these alkaline water products are now commonly used, they are...
Consumption of alkaline electrolyzed water (AEW) has become increasingly popular for consumer use. Although these alkaline water products are now commonly used, they are of questionable health benefit. Some individuals believe that it may help their dyspepsia. Furthermore, there is a paucity of evidence on its toxicologic profile and adverse effects. This is a single case report of a 42-year-old female with a past medical history of gestational diabetes, necrotizing pancreatitis, presented to the Emergency Department for 3 weeks of lethargy, weakness, difficulty walking, and vomiting. She endorsed consuming 5 liters (L) of alkaline water daily for the past month. Initial labs showed pH 7.69, potassium 1.6meQ/L, sodium 133 meQ/L, chloride 65 mmol/L, magnesium 0.9 meQ/L, and bicarbonate 46 mmol/L, and lactate of 13.2 mmol/L. EKG showed sinus tachycardia with QTc of 630 milliseconds. Patient was treated supportively with intravenous fluids and electrolyte replacement. The potassium rose to 6.6 meQ/L, which then the patient was treated for hyperkalemia. After four days of intravenous fluid and electrolyte replacement, the patient's electrolytes and acid-base status normalized, and she was transferred to the medical floors for further management. This case report illustrates severe metabolic alkalosis and hypokalemia in the setting of chronic alkaline water exposure. It also is an example of alkalemia with hyperlactatemia, or "lactic alkalosis". To our knowledge, there is no previous literature reporting serious adverse effects of alkaline bottled water products.
Topics: Female; Humans; Adult; Hypokalemia; Alkalosis; Electrolytes; Potassium; Water
PubMed: 38097490
DOI: 10.1016/j.ajem.2023.11.039 -
Frontiers in Pharmacology 2023Licorice, one of the most commonly used herbs, can cause hypokalemia, metabolic alkalosis, and apparent mineralocorticoid excess, also known as pseudoaldosteronism....
Licorice, one of the most commonly used herbs, can cause hypokalemia, metabolic alkalosis, and apparent mineralocorticoid excess, also known as pseudoaldosteronism. Herein, we present a case of diaphragmatic dysfunction caused by licorice administration. An 80-year-old woman who had been taking dietary supplements and following a restricted diet for approximately 6 months was brought to the emergency department with impaired consciousness. Chronic respiratory acidosis was observed, and hypertension and hypokalemia became more prominent during hospitalization. History revealed that she was taking herbal medicines containing licorice. Based on the results of hormone tests, the patient was diagnosed with pseudoaldosteronism. Chest radiography and pulmonary function tests confirmed the clinical diagnosis of diaphragmatic dysfunction. The metabolic alkalosis resulting from licorice administration may have contributed to the impairment of the respiratory muscles. This case suggests that caution should be exercised when using licorice in patients with preexisting health or medical issues such as advanced age, malnutrition, and electrolyte imbalance.
PubMed: 38074128
DOI: 10.3389/fphar.2023.1289755 -
The American Journal of Case Reports Dec 2023BACKGROUND Gitelman syndrome (GS) is a rare inherited autosomal recessive salt-losing renal tubulopathy. Early-onset GS is difficult to differentiate from Bartter... (Review)
Review
BACKGROUND Gitelman syndrome (GS) is a rare inherited autosomal recessive salt-losing renal tubulopathy. Early-onset GS is difficult to differentiate from Bartter syndrome (BS). It has been reported in some cases that cyclooxygenase (COX) inhibitors, which pharmacologically reduce prostaglandin E2(PGE2) synthesis, are helpful for GS patients, especially in children, but the long-term therapeutic effect has not yet been revealed. CASE REPORT A 4-year-old boy was first brought to our hospital for the chief concern of short stature and growth retardation. Biochemical tests demonstrated severe hypokalemia, hyponatremia, and hypochloremic metabolic alkalosis. The patient's serum magnesium was normal. He was diagnosed with BS and treated with potassium supplementation and indomethacin and achieved stable serum potassium levels and slow catch-up growth. At 11.8 years of age, the patient showed hypomagnesemia and a genetic test confirmed that he had GS with compound heterozygous mutations in the SLC12A3 gene. At the age of 14.8 years, when indomethacin had been taken for nearly 10 years, the boy reported having chronic stomachache, while his renal function remained normal. After proton pump inhibitor and acid inhibitor therapy, the patient's symptoms were ameliorated, and he continued to take a low dose of indomethacin (37.5 mg/d divided tid) with good tolerance. CONCLUSIONS Early-onset GS in childhood can be initially misdiagnosed as BS, and gene detection can confirm the final diagnosis. COX inhibitors, such as indomethacin, might be tolerated by pediatric patients, and long-term therapy can improve the hypokalemia and growth retardation without significant adverse effects.
Topics: Adolescent; Child; Child, Preschool; Humans; Male; Bartter Syndrome; China; Gitelman Syndrome; Growth Disorders; Hypokalemia; Indomethacin; Potassium; Solute Carrier Family 12, Member 3
PubMed: 38069462
DOI: 10.12659/AJCR.941627 -
International Journal of Molecular... Dec 2023The ClC-K channels and are crucial for the transepithelial transport processes required for sufficient urinary concentrations and sensory mechanoelectrical...
The ClC-K channels and are crucial for the transepithelial transport processes required for sufficient urinary concentrations and sensory mechanoelectrical transduction in the cochlea. Loss-of-function alleles in these channels are associated with various clinical phenotypes, ranging from hypokalemic alkalosis to sensorineural hearing loss (SNHL) accompanied by severe renal conditions, i.e., Bartter's syndrome. Using a stepwise genetic approach encompassing whole-genome sequencing (WGS), we identified one family with compound heterozygous variants in the ClC-K channels, specifically a truncating variant in in trans with a contiguous deletion of and . Breakpoint PCR and Sanger sequencing elucidated the breakpoint junctions derived from WGS, and allele-specific droplet digital PCR confirmed one copy loss of the _ contiguous deletion. The proband that harbors the variants is characterized by SNHL without hypokalemic alkalosis and renal anomalies, suggesting a distinct phenotype in the ClC-K channels in whom SNHL predominantly occurs. These results expanded genotypes and phenotypes associated with ClC-K channels, including the disease entities associated with non-syndromic hearing loss. Repeated identification of deletions across various extents of suggests a mutational hotspot allele, highlighting the need for an in-depth analysis of the intergenic region, especially in undiagnosed SNHL patients with a single hit in .
Topics: Humans; Alkalosis; Bartter Syndrome; Chloride Channels; Deafness; Genetic Association Studies; Genotype; Hearing Loss, Sensorineural; Mutation
PubMed: 38069401
DOI: 10.3390/ijms242317077 -
Nephrology (Carlton, Vic.) Mar 2024Type 1 Bartter syndrome causes hypokalaemia and metabolic alkalosis owing to mutation in the SLC12A1 gene. Meanwhile, hypocalcaemia is rare in Bartter syndrome, except...
Type 1 Bartter syndrome causes hypokalaemia and metabolic alkalosis owing to mutation in the SLC12A1 gene. Meanwhile, hypocalcaemia is rare in Bartter syndrome, except in type 5 Bartter syndrome. Herein, we describe two siblings with type 1 Bartter syndrome with recurrent transient severe hypocalcaemia. They each visited our hospital several times with chief complaints of numbness in the limbs, shortness of breath and tetany after stresses such as exercise or fever. Severe hypocalcaemia was also observed with a serum calcium level of approximately 6.0 mg/dL at each visit. The clinical symptoms and abnormalities in laboratory findings quickly improved with rest and intravenous treatment. In a steady state, no severe hypocalcaemia was evident, but serum intact parathyroid hormone (PTH) levels were high. In recent years, a large-scale study has revealed that type 1 and type 2 Bartter syndrome have high PTH values. In addition, there are reports that these patients develop hypocalcaemia due to PTH resistance. Therefore, our patient was also in a PTH-resistant state, and hypocalcaemia was thought to be exacerbated by physical stress. It is not well known that Bartter syndrome patients other than those with type 5 suffer from hypocalcaemia. And hypocalcaemia was not detected in normal examinations under steady-state conditions. Therefore, in patients with type 1 and type 2 Bartter syndrome, severe hypocalcaemia may occur, but may go unnoticed. When following up these patients, the attending physician must keep in mind that such patients are in a PTH-resistant state and that physical stress can cause severe hypocalcaemia.
Topics: Humans; Hypocalcemia; Bartter Syndrome; Siblings; Parathyroid Hormone; Solute Carrier Family 12, Member 1
PubMed: 38062639
DOI: 10.1111/nep.14261 -
Hormone Research in Paediatrics Dec 2023A reninoma (juxtaglomerular cell tumour) is a rare cause of secondary hypertension that can present with headaches alongside the triad of severe hypertension,...
INTRODUCTION
A reninoma (juxtaglomerular cell tumour) is a rare cause of secondary hypertension that can present with headaches alongside the triad of severe hypertension, hypokalemia, and metabolic alkalosis.
CASE PRESENTATION
We describe a case of a 15-year-old previously healthy girl who presented with headaches and hypertensive urgency who had severe hypokalemia, moderate hyponatremia and elevated aldosterone and renin levels. Abdominal ultrasound and MRI with contrast revealed a unilateral mass localized to the right kidney. Despite treatment of her hypertension, she had persistent hyponatremia with clinical euvolemia which was consistent with the paraneoplastic syndrome of inappropriate antidiuretic hormone secretion (SIADH). She underwent radical nephrectomy which normalized her blood pressure and aldosterone and renin values. The pathology findings were consistent with a reninoma with a mitotic rate of 1-2 mitoses per 10 high power fields.
DISCUSSION/CONCLUSION
Hypertension in the pediatric age group requires work-up to rule out secondary causes. The classic triad of hypertension, hypokalemia, and metabolic alkalosis warrants assessment for aldosterone-mediated hypertension which can be a result of a renin-producing tumour. Curative approach requires surgical resection of the tumour. Reninomas may rarely manifest with a paraneoplastic phenomenon including SIADH, as seen in our case. Although reninomas are benign tumours, there are also a few reports of malignant transformation and metastases. Features uncommon in reninomas such as mitotic activity warrant long-term surveillance.
PubMed: 38052189
DOI: 10.1159/000533521 -
Journal of the ASEAN Federation of... 2023The majority of patients with congenital adrenal hyperplasia (CAH) present with a deficiency of 21-hydroxylase or 11-beta-hydroxylase, which account for 90% and 7% of...
The majority of patients with congenital adrenal hyperplasia (CAH) present with a deficiency of 21-hydroxylase or 11-beta-hydroxylase, which account for 90% and 7% of cases, respectively. However, CAH due to 17α-hydroxylase deficiency (17OHD) is an extremely rare form of CAH (<1% of all CAH cases) that leads to a deficiency of cortisol and sex steroids, along with features of aldosterone excess. This is a case of a 51-year-old single female who was referred to us for the evaluation of new-onset hypertension and hypokalaemia of one-year duration. She was born out of a second-degree consanguineous marriage and reared as a female. She was diagnosed to have testicular feminization syndrome when she presented with a history of primary amenorrhea, absence of secondary sexual characteristics, and bilateral labial swellings at pubertal age. Subsequently, she underwent gonadectomy at the age of 16. Due to the presence of hypertension, metabolic alkalosis and bilaterally enlarged adrenals on CT scan, 46, XY disorders of sexual development (DSD) was considered. A karyotype confirmed the presence of 46, XY chromosomal sex, and genetic analysis revealed a mutation in the gene, thus confirming the diagnosis of 17α-hydroxylase deficiency.
Topics: Male; Humans; Female; Adolescent; Middle Aged; Adrenal Hyperplasia, Congenital; Steroid 17-alpha-Hydroxylase; Hydrocortisone; Steroid 11-beta-Hydroxylase; Hypertension
PubMed: 38045661
DOI: 10.15605/jafes.038.02.08 -
BMC Nephrology Nov 2023Prolonged hemodialysis (HD) is performed from 6 to 12 h and can last up to 24 h. To prevent system clotting some studies suggest that Regional Citrate Anticoagulation...
Quality indicators in prolonged hemodialysis with regional citrate anticoagulation with the genius system: retrospective cohort of critical patients with acute kidney injury.
BACKGROUND
Prolonged hemodialysis (HD) is performed from 6 to 12 h and can last up to 24 h. To prevent system clotting some studies suggest that Regional Citrate Anticoagulation (RCA) use reduces bleeding rates relative to systemic heparin. However, there may be difficulties in the patient's clinical management and completing the prescribed HD with Genius system using RCA.
OBJECTIVE
To analyze safety Quality Indicators (IQs) and follow up on prolonged HD with 4% sodium citrate solution in a Genius® hybrid system.
METHODS
This is a retrospective cohort conducted in an intensive care unit.
RESULTS
53 random sessions of prolonged HD with 4% sodium citrate solution of critically ill patients with AKI assessed. Evaluated safety indicators were dysnatremia and metabolic alkalosis, observed in 15% and 9.4% of the sessions, respectively. Indicators of effectiveness were system clotting which occurred in 17.3%, and the minimum completion of the prescribed HD time, which was 75.5%.
CONCLUSION
The assessment of the indicators showed that the use of RCA with a 4% sodium citrate solution in prolonged HD with the Genius system in critically ill patients with AKI can be performed in a simple, safe, and effective way.
Topics: Humans; Acute Kidney Injury; Anticoagulants; Citrates; Citric Acid; Critical Illness; Heparin; Quality Indicators, Health Care; Renal Dialysis; Retrospective Studies; Sodium Citrate
PubMed: 38036951
DOI: 10.1186/s12882-023-03342-8