In hypoxic environments, fold is inhibited in a temporary equilibrium manner by benzothiazines (0.4, 2, 10 μM). Biological cellulase 9 (CA9) and benzothiazine have corresponding Ki values of 8.0, 8.8, and 10 nM for CA9, CA2, and CA1 [2].

Benthhiazide (1, 1.5 mg/100 g BW) produces a considerable reduction in urinary calcium excretion and a dissociation of calcium and sodium excretion due to hyperprolactinemia [1].

Absorption, Distribution and Excretion
Absorbed in the digestive tract. Diuretic effect occurs within 2 hours and lasts 12-18 hours. Thiazide drugs are absorbed via the gastrointestinal tract, and their efficacy is primarily attributed to the oral route. Absorption is relatively rapid. Most drugs show significant diuretic effect within 1 hour of oral administration. /Thiazide Diuretics/ Generally, thiazide drugs with a longer duration of action have a higher binding rate to plasma proteins and are reabsorbed by the renal tubules. The drug readily crosses the placental barrier into the fetus. All thiazide drugs are likely actively secreted in the proximal tubules. Thiazide diuretics are distributed in the extracellular space, can cross the placenta, and appear in the umbilical cord blood. The diuretic effect takes effect in 2 hours, with a peak effect time of 3 to 6 hours, and the duration of action after a single dose is approximately 12 to 18 hours. Excreted via glomerular filtration and active secretion in the proximal tubules (human, oral). The antihypertensive effect takes effect in 3 to 4 days, and the effect subsides in the first week after discontinuation. It can be secreted into the breast milk of lactating women (human, orally).

Toxicity Summary
Benzothiazide, as a diuretic, increases the excretion of sodium, chloride, and water by inhibiting the early active reabsorption of chloride ions in the distal renal tubules via sodium-chloride cotransporters. Thiazides (such as benzothiazide) can also inhibit the transport of sodium ions across renal tubular epithelial cells by binding to thiazide-sensitive sodium-chloride transporters. This leads to increased potassium excretion via sodium-potassium exchange mechanisms. The hypotensive mechanism of benzothiazide is not fully understood, but it may be related to its action on carbonic anhydrase in smooth muscle or on high-conductivity calcium-activated potassium channels (KCa channels) also present in smooth muscle.

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Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation There is currently no information on the content of benzothiazide in breast milk. High-dose, potent diuresis may lead to reduced milk production. Other diuretics are superior to benzothiazide diuretics at low doses. ◉ Effects on Breastfed Infants As of the revision date, no relevant published information was found.
◉ Effects on Lactation and Breast Milk
As of the revision date, no published information was found regarding benzothiazide diuretics. The potent diuretic effects of thiazide and similar diuretics, fluid restriction, and chest binding have been used to suppress postpartum lactation. The additional effects of diuretics on these effective lactation-suppressing measures have not been studied. There are currently no data on the effects of diuretics on established lactating women.

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Protein Binding
30%

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Drug Interactions
Many diabetic patients using chlorpromazine or other sulfonylureas to control their blood sugar experience impaired glycemic control when any thiazide diuretic is added to their treatment regimen. /Thiazide Diuretics/
Concomitant use of thiazide diuretics and monoamine oxidase inhibitors may exacerbate hypotension. /Thiazide Diuretics/
…Hypokalemia may enhance the effects of neuromuscular blocking agents. Potassium-depleting diuretics are known to cause hypokalemia and may enhance this effect. /Diuretics/
...Cardioglycosides and diuretics; hypokalemia caused by diuretics can enhance the cardiotoxicity of cardioglycosides. /Diuretics/
For more complete data on interactions of benzothiazides (21 in total), please visit the HSDB record page.

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Non-human toxicity values
Oral LD50 in mice > 5000 mg/kg
Oral LD50 in rats > 10000 mg/kg
Oral LD50 in dogs > 5000 mg/kg
Intravenous injection in rabbits 410 mg/kg
For more complete data on non-human toxicity values of benzothiazides (6 in total), please visit the HSDB record page.

[1]. Hypercalciuria in hyperprolactinemic rats: effects of benzthiazide. Metabolism. 1986 Jul;35(7):668-72.

[2]. Rational drug repositioning guided by an integrated pharmacological network of protein, disease and drug. BMC Syst Biol. 2012 Jul 2;6:80.

Therapeutic Uses
Diuretics, Thiazides
Their potency, measured in milligrams, is approximately 10 times that of chlorothiazide.
Thiazides…are generally the first-line treatment for hypertension. Because thiazides cause only a limited (10%) reduction in blood pressure, they are suitable for mild cases of hypertension or as adjunctive therapy to other medications. Thiazide Diuretics
Thiazide diuretics can be used as adjunctive therapy for congestive heart failure, cirrhosis, edema caused by corticosteroids and estrogen therapy, edema caused by various renal insufficiency, and severe edema caused by pregnancy. Thiazide Diuretics
For more complete data on the therapeutic uses of benzothiazides (8 in total), please visit the HSDB record page.
Drug Warnings

Use with caution in patients with impaired hepatic function.
Thiazide Diuretics: Serum electrolytes should be measured regularly in all patients to detect electrolyte imbalances such as hyponatremia, hypochloremic alkalosis, and hypokalemia. Thiazide diuretics are contraindicated in patients with anuria, patients allergic to thiazide diuretics or other sulfonamides, and healthy pregnant women with or without mild edema. Patients with kidney disease should use thiazide diuretics with caution due to the possibility of azotemia. Thiazide diuretics: Clinical toxicity…usually caused by unexpected hypersensitivity reactions. Case reports of purpura, photosensitive dermatitis, cytopenia, and necrotizing vasculitis have been documented. Thiazide diuretics: For more complete data on drug warnings for benzothiazides (8 of 8), please visit the HSDB record page. Pharmacodynamics: Benzothiazides are used to treat hypertension and edema. Like other thiazides, benzothiazides promote the excretion of water (diuretics). Thiazides inhibit the reabsorption of sodium/chloride ions in the distal convoluted tubule of the kidney. They also lead to potassium loss and elevated serum uric acid. Thiazides are commonly used to treat hypertension, but their antihypertensive effect is not entirely attributable to their diuretic activity. Although the mechanism is not fully understood, thiazide diuretics have been shown to prevent hypertension-related morbidity and mortality. Thiazide diuretics induce vasodilation by activating calcium-activated potassium channels (large conductance channels) in vascular smooth muscle and inhibiting various carbonic anhydrases in vascular tissue.

C15H14CLN3O4S3

431.9374

430.983

91-33-8

2343

White to off-white solid powder

1.4176 (rough estimate)

680.6 °C at 760 mmHg

231-232° (U.S. patent); mp 238-239° (P'an)

365.4 °C

1.6100 (estimate)

4.869

2

7

5

26

739

0

NDTSRXAMMQDVSW-UHFFFAOYSA-N

InChI=1S/C15H14ClN3O4S3/c16-11-6-12-14(7-13(11)25(17,20)21)26(22,23)19-15(18-12)9-24-8-10-4-2-1-3-5-10/h1-7H,8-9H2,(H,18,19)(H2,17,20,21)

3-(benzylsulfanylmethyl)-6-chloro-1,1-dioxo-4H-1λ6,2,4-benzothiadiazine-7-sulfonamide

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~50 mg/mL (~115.76 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (4.82 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (4.82 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)