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Treating haemangiomas with propranolol A haemangioma is a collection of small immature blood vessels. They are sometimes called ‘strawberry marks’ because the surface of some haemangiomas look a bit like a strawberry.Propanolol Haemangiomas can be superficial or deep in the skin. Some haemangiomas are a combination of the two, seen as a raised red area on the surface of the skin, and as a bluish swelling of abnormal blood vessels deeper in the skin. Very occasionally haemangiomas may occur internally. Haemangiomas are not usually obvious at birth but become apparent within a few days or weeks. They grow rapidly in the first three months, increasing in size and sometimes in redness.It is unusual for haemangiomas to grow after six to 10 months of age, when most haemangiomas tend to have a ‘rest period’ and then begin to shrink. What is propranolol? Propranolol is a beta-blocker. Some nerves release a chemical called noradrenaline when they are stimulated, which in turn stimulates ‘beta adrenergic receptors’. These can cause a variety of effects. For instance, if the beta adrenergic receptors in the heart are stimulated, the heart pumps harder and faster than before, so more blood is pumped around the body. Betablocker medicines block the beta adrenergic receptors and stop them being stimulated. How does propranolol help with haemangiomas? By blocking the beta adrenergic receptors, propranolol can make blood vessels narrower, reducing the amount of blood flowing through them. This is particularly effective in haemangiomas, by reducing the colour and making them softer. Growth of the haemangioma cells is also limited by propranolol so that the haemangioma starts to reduce in size. More research is needed to fully understand how propranolol works. The beneficial effects are usually seen very quickly. Are there side effects with propranolol treatment? Propranolol is associated with the following side effects, which happen very rarely. However, you should report any of the following to your doctor as the dose of propranolol may need to be altered or on very rare occasions, stopped. Bradycardia (slow heart rate). Hypotension (low blood pressure). Bronchspasm (temporary narrowing of the airway, leading to wheezing and coughing). Peripheral vasoconstriction (reduced blood flow to the extremities, such as fingers and toes, making them feel cold and turn a blue colour). Weakness and fatigue, showing as floppiness and disinterest in surroundings. Sleep disturbance. Hypoglycaemia (low blood sugar). Gastrointestinal disturbances such as constipation or diarrhoea. If you have any concerns about these side effects, please discuss them with your doctor, nurse or pharmacist. Are any tests needed before starting propranolol treatment? Occasionally we will suggest some tests to check that your child can safely take the medicine. These may include blood and urine tests, an electrocardiogram (ECG) and echocardiogram (echo). If your child has multiple haemangiomas visible on the skin, we may also carry out an abdominal ultrasound scan to look for any haemangiomas in the liver. What happens when my child starts treatment? Some infants will be monitored for two hours after the first dose. This monitoring allows the doctors to be absolutely sure your child can tolerate the prescribed dose. The procedure is occasionally repeated after one week when the dose is increased, although the dose is normally increased at home.

Propranolol Hydrochloride is a synthetic beta-adrenergic receptor blocking agent chemically described as 2-Propanol, 1-[(1-methylethyl)amino]-3-(1-naphthalenyloxy)-, hydrochloride,(±)-. Its molecular and structural formula:β-agonist Powder

Propranolol Hydrochloride Oral Solution is available for oral administration containing either 20 mg per 5 mL or 40 mg per 5 mL of propranolol hydrochloride USP. The oral solution contains the following inactive ingredients: citric acid anhydrous, crème de menthe flavor, disodium edetate, methyl paraben, propylene glycol, propylparaben, purified water, saccharin sodium, sorbitol solution and strawberry flavor.

Propranolol is a nonselective beta-adrenergic receptor blocking agent possessing no other autonomic nervous system activity. It specifically competes with beta-adrenergic receptor agonist agents for available receptor sites. When access to beta-receptor sites is blocked by propranolol, the chronotropic, inotropic, and vasodilator responses to beta-adrenergic stimulation are decreased proportionately. At dosages greater than required for beta-blockade, propranolol also exerts a quinidine-like or anesthetic-like membrane action, which affects the cardiac action potential. The significance of the membrane action in the treatment of arrhythmias is uncertain.

Mechanism of Action

The mechanism of the antihypertensive effect of propranolol has not been established. Factors that may contribute to the antihypertensive action include: (1) decreased cardiac output, (2) inhibition of renin release by the kidneys, and (3) diminution of tonic sympathetic nerve outflow from vasomotor centers in the brain. Although total peripheral resistance may increase initially, it readjusts to or below the pretreatment level with chronic use of propranolol. Effects of propranolol on plasma volume appear to be minor and somewhat variable.

In angina pectoris, propranolol generally reduces the oxygen requirement of the heart at any given level of effort by blocking the catecholamine-induced increases in the heart rate, systolic blood pressure, and the velocity and extent of myocardial contraction. Propranolol may increase oxygen requirements by increasing left ventricular fiber length, end diastolic pressure, and systolic ejection period. The net physiologic effect of beta-adrenergic blockade is usually advantageous and is manifested during exercise by delayed onset of pain and increased work capacity.

Propranolol exerts its antiarrhythmic effects in concentrations associated with beta-adrenergic blockade, and this appears to be its principal antiarrhythmic mechanism of action. In dosages greater than required for beta-blockade, propranolol also exerts a quinidine-like or anesthetic-like membrane action, which affects the cardiac action potential. The significance of the membrane action in the treatment of arrhythmias is uncertain.

The mechanism of the antimigraine effect of propranolol has not been established. Beta-adrenergic receptors have been demonstrated in the pial vessels of the brain.

The specific mechanism of propranolol’s antitremor effects has not been established, but beta-2 (noncardiac) receptors may be involved. A central effect is also possible. Clinical studies have demonstrated that propranolol is of benefit in exaggerated physiological and essential (familial) tremor
Propranolol is highly lipophilic and almost completely absorbed after oral administration. However, it undergoes high first-pass metabolism by the liver and on average, only about 25% of propranolol reaches the systemic circulation. Peak plasma concentrations occur about 1 to 4 hours after an oral dose.

Administration of protein-rich foods increase the bioavailability of propranolol by about 50% with no change in time to peak concentration, plasma binding, half-life, or the amount of unchanged drug in the urine.

Distribution

Approximately 90% of circulating propranolol is bound to plasma proteins (albumin and alpha1 acid glycoprotein). The binding is enantiomer-selective. The S(-)-enantiomer is preferentially bound to alpha1 glycoprotein and the R(+)- enantiomer preferentially bound to albumin. The volume of distribution of propranolol is approximately 4 liters/kg.

High Quality Indapamide 99% CAS: 26807-65-8 Product Name: Indapamide CAS: 26807-65-8 Standard: Corporate Standard Natural/Synthetic: Synthetic Source of extraction: for export only Level: Pharmaceutical grade Content: 99% Appearance: white powder Packing: 25 / cardboard drum can be split Field: Diuretic antihypertensive drugs Deferred Products: Indapamide Tablets, Indapamide Capsules, Indapamide Sustained Release Tablets Use: For the treatment of mild to moderate essential hypertension Dosage: Adults: conventional oral dose 1. Hypertension: 2.5mg each time, once daily. It can be increased to 5 mg once daily after 4 weeks. The maintenance dose is 2.5mg each time, every other day. 2. Water and sodium retention: Each 2.5mg, once daily. It can be increased to 5 mg once daily after 1 week. Elderly dose: dosage. High Quality Indapamide 99% CAS: 26807-65-8 Brief Introduction of Active Pharmaceutical Ingredients Indapamide: 1. Indapamide is a thiazide-like diuretic drug marketed by Servier, generally used in the treatment of hypertension, as well as decompensated heart failure. Combination preparations with perindopril (an ACE inhibitor antihypertensive) are also available. 2. White needle crystal or crystalline powder, odorless, tasteless. It is almost insoluble in water or dilute hydrochloric acid, while it can be dissolved in ethanol or ethyl acetate, and it is soluble in acetone, acetic acid, slightly soluble in chloroform or ether. 3. Indapamide is currently the most popular non-prescription diuretic antihypertensive drug with good efficacy, stable blood pressure, fewer side effects, etc. Medical Application of Active Pharmaceutical Ingredients Indapamide: 1. This medication is used to treat high blood pressure. Indapamide is also used to reduce extra salt and fluid in the body (edema) caused by a certain heart problem (congestive heart failure). Lowering high blood pressure helps prevent strokes, heart attacks, and kidney problems. Decreasing extra salt and fluid in the body helps to decrease swelling and breathing problems from congestive heart failure and increases your ability to exercise. 2. Indapamide is a "water pill" (diuretic) that increases the amount of urine you make. Getting rid of extra water and salt may help to relax the blood vessels so that bloodcan flow more easily. These effects help to lower blood pressure and decrease the amount of work the heart must do to pump blood. Function of Active Pharmaceutical Ingredients Indapamide: 1. Indapamide have diuretic and calcium antagonist dual effect by inhibiting the proximal end of the distal convoluted tubule Na+ reabsorption, resulting in diuresis, while by blocking Ca2+ influx especially a higher selectivity for vascular smooth muscle to dilate the small blood vessels of the outer periphery, resulting in antihypertensive effect. But the effect to vascular smooth muscle is stronger than the diuretic effect. 2. It can lower blood pressure with lower dose compared to diuretic effect. Higher dose will display diuretic effect. But there is no disadvantage compared to thiazide diuretics, that it does not cause orthostatic hypotension, flushing and reflex tachycardia, nor blood lipids, glucose metabolism and renal function.

Factory Supply Pharmaceutical Raw Material High Quality Indapamide 99%

1. Indapamide is a thiazide-like diuretic drug marketed by Servier, generally used in the treatment of hypertension, as well as decompensated heart failure. Combination preparations with perindopril (an ACE inhibitor antihypertensive) are also available.Indapamide powder

2. White needle crystal or crystalline powder, odorless, tasteless. It is almost insoluble in water or dilute hydrochloric acid, while it can be dissolved in ethanol or ethyl acetate, and it is soluble in acetone, acetic acid, slightly soluble in chloroform or ether.

3. Indapamide is currently the most popular non-prescription diuretic antihypertensive drug with good efficacy, stable blood pressure, fewer side effects, etc.
1. Indapamide have diuretic and calcium antagonist dual effect by inhibiting the proximal end of the distal convoluted tubule Na+ reabsorption, resulting in diuresis, while by blocking Ca2+ influx especially a higher selectivity for vascular smooth muscle to dilate the small blood vessels of the outer periphery, resulting in antihypertensive effect. But the effect to vascular smooth muscle is stronger than the diuretic effect.

2. It can lower blood pressure with lower dose compared to diuretic effect. Higher dose will display diuretic effect. But there is no disadvantage compared to thiazide diuretics, that it does not cause orthostatic hypotension, flushing and reflex tachycardia, nor blood lipids, glucose metabolism and renal function.

Indapamide Application
1. This medication is used to tr

White needle crystal or crystalline powder, odorless and tasteless. Almost insoluble in water or dilute hydrochloric acid, soluble in ethanol or ethyl acetate, soluble in acetone, acetic acid, slightly soluble in chloroform or ether.β-agonist Powder

Indapamide is an over-the-counter diuretic antihypertensive drug commonly used in China, which has the advantages of good efficacy, stable antihypertensive and less side effects.

Indapamide has dual effects of diuresis and calcium antagonism. By inhibiting Na+ reabsorption at the proximal end of the distal convoluted tubule, it can produce diuretic effect and block Ca2+ internal flow. It is highly selective to vascular smooth muscle, so as to dilate peripheral small blood vessels and generate antihypertensive effect. But the effect on vascular smooth muscle stronger diuretic effect, below the diuretic doses can step-down, higher doses showed diuretic effect, but no thiazide diuretic shortcomings, namely not cause orthostatic hypotension, flush and reflective tachycardia, on blood picture, metabolism of blood fat, sugar and renal function also had no obvious effect, therapeutic doses of heart rate, cardiac output, no significant changes in electrocardiogram (ecg) were on the central nervous system and plant nerve has no obvious effect. The antihypertensive effect was produced by oral administration for 2 ~ 3h and maintained for 24h. The diuretic effect appeared for 3h and reached the maximum effect for 4 ~ 6h. Different from other diuretics, this product has high lipid solubility. After oral absorption, the plasma concentration of liver and kidney is the highest, while the concentration of heart, lung, muscle and fat is lower. This product is mainly excreted from the kidney by metabolites and 5% prototype. Indapamide is suitable for mild and moderate primary hypertension, can also be used for congestive heart failure caused by water sodium retention, with renal failure are also applicable to the patients with high blood pressure, diabetes, hyperlipidemia, use antihypertensive effect is remarkable, and beta blockers used curative effect is better, because this drug has diuretic effect, can cause hypokalemia, can complement potassium at the same time.

Galanthamine is natural extracted from Lycoris radiate, is a tertiary alkaloid derived from snowdrop and closely related species.galantamine powder
Galanthamine acts as a reversible competitive acetylcholinesterase (AChE) inhibitor, while acts weaker on butyrylcholinesterase (BuChE).
Galanthamine is used in the treatment of disorders of the central nervous system and may be used as an antidote to nonpolarizing muscle relaxants.Galantamine hydrobromide is a white to almost white powder; sparingly soluble in water; insoluble chloroform, ether and alcohol..

Application of Galantamine
Galantamine is the anti-cholinesterase, weak effect. Galantamine has strong effect to the central nervous system through the blood brain barrier. Galantamine mainly cures the infantile paralysis sequelae, sweeny and myasthenia gravis pseudoparalytica, etc. Galantamine also can be applied to puerilism, posttraumatic apoplexy, polyneuritis and radiculitis.
Function of Galantamine
Galanthamine is the anti-cholinesterase, weak effect.
Galantamine has strong effect to the central nervous system through the blood brain barrier.
Galantamine mainly cures the infantile paralysis sequelae, sweeny and myasthenia gravis
pseudoparalytica, etc.
Galantamine also can be applied to puerilism, posttraumatic apoplexy, polyneuritis and radiculitis.

Clinic function: mainly used in myasthenia gravis, poliovirus quiescent stage and sequela, also in polyneuritis, funiculitis and sensorimotor barrier caused by nervous system disease or traumatism. Galantamine major used in Alzheimer’s disease, has the principal function for dement and dysmnesia caused by organic brain damage.

Calculate the quantity of each ingredient for the amount to be prepared. Accurately weigh or measure each ingredient. Mix the furosemide powder with a small quantity of SyrSpend SF Alka or simple syrup to form a smooth paste. Geometrically, add the SyrSpend SF Alka or simple syrup to final volume, mixing well after each addition. Package and label.Furosemide powder

Use: Furosemide is used to treat edema associated with a number of disorders, including congestive heart failure, nephrotic syndrome, and hepatic cirrhosis; it also has been used as an adjunct in the treatment of acute pulmonary edema.

Packaging: Package in tight, light-resistant containers.1

Labeling: Keep out of reach of children. Shake well. Store in a refrigerator. Discard after ____ [time period].Stability: A beyond-use date of 14 days when stored in a refrigerator may be used for this preparation made with SyrSpend SF Alka or syrup NF.1,2

Quality Control: Quality-control assessment can include weight/volume, pH, specific gravity, active drug assay, color, rheologic properties/pourability, physical observation, and physical stability (discoloration, foreign materials, gas formation, mold growth).3

Discussion: Furosemide (Lasix, Frusemide, C12H11ClN2O5S, MW 330.74) is a sulfonamide-derivative loop diuretic that inhibits the Na-K-2Cl cotransporter in the thick ascending limb of the loop of Henle. Furosemide is a fine, white to slightly yellow, odorless, practically tasteless, crystalline powder with a pKa of 3.9, and it melts at about 203°C-205°C with decomposition. Chemically, furosemide is 4-chloro-N-furfuryl-5-sulfamoylanthranilic acid. Furosemide is practically insoluble in water or dilute acids. It is freely soluble in solutions of alkali hydroxides and sparingly soluble in alcohol. Furosemide is subject to photodegradation by several mechanisms; consequently, it should be preserved in light-resistant containers. This photodegradation is minimized at pH 7, and the degradation rate increases as the pH becomes more acidic or basic. Furosemide should be packaged in well-closed containers and stored at room temperature, with excursions permitted between 15°C and 30°C, and it should be protected from light. The injection has a pH in the range of 8.0 to 9.3 and contains not more than 3.6 USP EU per mg of furosemide.1

If the source of the active drug is tablets, Lasix tablets for oral administration also contain lactose monohydrate NF, magnesium stearate NF, starch NF, talc USP, and colloidal silicon dioxide NF. The white Lasix tablets for oral administration are available in dosage strengths of 20, 40, and 80 mg. Tablets, if used, must be thoroughly pulverized before incorporation into the vehicle. To obtain 1 gram of the drug from tablets, from 12.5 to 50 tablets may be required depending on which strength is used. The 80-mg strength is preferred; obviously, the use of fifty 20-mg tablets would yield a large quantity of powder, resulting in some thickening of the preparation.

SyrSpend SF Alka is a dry powder for reconstitution. SyrSpend SF Alka provides a reasonable solution for preparing oral liquid dosage forms with acid-labile active pharmaceutical ingredients, including furosemide. It is preservative-free and alcohol-free and is suitable for problematic patients, such as neonates. SyrSpend SF Alka also allows for direct compounding in the dispensing container for maximum efficiency if the prescription or order requires 100 mL. Smaller or larger volumes may be feasible with some manipulation. SyrSpend SF Alka is buffered to pH levels 7 for acid-labile active pharmaceutical ingredients. It is preservative-free and unflavored, and it is available in a dispensing container with preweighed powder to make 100 mL (contains 6.3 g powder) or 200 mL (contains 12.6 g powder).4

Syrup (simple syrup) is a clear, sweet vehicle used as a sweetening agent and as the base for many flavored and medicated syrups. It contains 85% w/v sucrose in water and has a specific gravity of not less than 1.30. Syrup is generally self-preserving as long as the sucrose concentration is maintained sufficiently high. However, syrup NF contains a preservative unless it is used when freshly prepared. It is preferable to prepare syrup NF without the use of heat, but it may be prepared with boiling water. It should be stored in tight containers, preferably in a cool place. The pH is in the range of 6.5 to 7.5

How does formoterol for COPD work?

Formoterol is a long-acting beta2-adrenergic receptor agonist (beta2-agonist) that works in the lungs as a bronchodilator. Its action has a rapid onset and its effects are maintained for at least 12 hours.

It becomes effective after binding to correspondent receptors, called beta-adrenoceptors, and activating them by stimulating the adenyl cyclase, an enzyme found inside the cells of the lung muscles and is involved in the synthesis of cyclic adenosine monophosphate (cAMP). When cAMP levels are elevated, the muscle cells of the airways become relaxed, leading to bronchodilation.

There are three types of beta-adrenoceptors in three different types of cells: the muscle cells of the airways, the heart, and the adipose (fat) tissue cells. This means that formoterol may have functions in other cells, but its precise function is not known.
Studies of formoterol

The effectiveness of formoterol in the treatment of COPD has been shown in various clinical studies, whether as a pressurized metered dose inhaler or a dry powder inhaleMost studies show that formoterol has proven efficacy, safety, and tolerability profiles in people with COPD.

The National Heart, Lung and Blood Institute and the World Health Organization collaborated on the Global Initiative for COPD – GOLD, and according to this initiative, long-acting bronchodilators are of primary importance to manage COPD symptoms, are used on an as-need or regular basis to reduce or prevent symptoms, and are convenient and effective.Most studies evaluating formoterol for the treatment of COPD attribute its success to its rapid action and selective activity toward the beta2-adrenergic receptors. Formoterol can work as rapidly as five minutes, and its effects are maintained for up to 12 hours.

Studies have also shown that formoterol controls symptoms better than ipratropium and is more effective than theophylline in reducing exacerbations and increasing the number of days without rescue medication, and with a better tolerance.
Indications and side effects

Formoterol is not intended to be used to treat asthma. People with asthma who take LABA medicines such as formoterol have an increased risk of death due to severe asthma problems.Formoterol won’t cure COPD but it will help relieve symptoms of the condition. It also doesn’t relieve sudden breathing difficulties. For an attack that has already started, short-acting bronchodilators such as albuterol, levalbuterol, ipratroprium or the combination albuterol/ipratropium can be used if prescribed by your doctor.

Formoterol side effects can include flu-like symptoms, headache, sore throat, dry throat, cough, runny nose, chills, fever, loss of voice, muscle cramps, or swollen glands in the neck. See your doctor if these occur.

Foradil is a bronchodilator that belongs to the long-acting beta2-adrenergic receptor agonist class of compounds. Novartis' Foradil Aerolizer was approved in February 2001 for the maintenance treatment of asthma and the prevention of bronchospasm in reversible obstructive airways disease. Foradil is also indicated for the acute prevention of exercise-induced bronchospasm (EIB), when administered on an occasional, as needed basis.Formoterol powder

In September 2001, a second FDA approval was obtained - the Foradil Aerolizer can now be used for long term administration in the maintenance treatment of bronchoconstriction in patients with COPD, including chronic bronchitis and emphysema.

Foradil is administered via a dry powder inhaler called the Aerolizer, which unlike traditional metered-dose inhalers, provides patients with the reassurance that they are in control of dosing. The Aerolizer offers patients little resistance to inhalation, and produces a whirring noise which signals that the drug is being inhaled. Patients can taste the powder and then open the device to check that they have inhaled all of the dose.

Asthma is a chronic inflammatory lung disease that affects 15 million Americans. According to the World Health Organization, each year 180,000 people die from asthma worldwide. The disease is characterized by shortness of breath, wheezing, tightness in the chest, and a cough that lasts more than a week.

COPD is a common chronic lung disease and a leading cause of mortality worldwide, with 2.25 million deaths a year. By 2025, the World Health Organization estimates that COPD will be the third leading cause of death globally. Since both asthma and COPD are chronic conditions, the goal of treatment is management and improvement of quality of life, rather than cure.

Clinical Results
The effectiveness of Foradil as a treatment for asthma was evaluated in five key trials involving more than 7,000 subjects, including over 1,600 mild to moderate asthmatics. In these placebo-controlled trials, Foradil was administered in 12 and 24 mcg twice daily doses.

Overall, these studies demonstrated both dosages of Foradil to be significantly better than placebo at improving lung function and quality of life in asthmatic subjects. Foradil provided subjects with clinically significant bronchodilation for a 12 hour period.

Clinical trials were also conducted to compare Foradil to the compound ipratropium bromide in subjects with COPD. Results showed that Foradil was significantly superior at reducing clinical symptoms and improving quality of life scores.
Formoterol fumarate is a long-acting selective beta2-adrenergic receptor agonist (beta2-agonist). Inhaled formoterol fumarate acts locally in the lung as a bronchodilator.

The pharmacologic effects of beta2 adrenoceptor agonist drugs, including formoterol, are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3', 5'-adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells. (from Foradil Prescribing Information)

What is ethacrynic acid?

Ethacrynic acid is a loop diuretic (water pill) that prevents your body from absorbing too much salt, allowing the salt to instead be passed in your urine.

Ethacrynic acid is used to treat fluid retention (edema) in people with congestive heart failure, liver disease, or a kidney disorder such as nephrotic syndrome.Ethacrynic acid may also be used for purposes not listed in this medication guide.

Important Information
You should not use ethacrynic acid if you are unable to urinate, or if you have recently had severe watery diarrhea.

Before taking this medicine
You should not use ethacrynic acid if you are allergic to it, or if:you are unable to urinate; oryou have recently had severe watery diarrhea.To make sure ethacrynic acid is safe for you, tell your doctor if you have:

cirrhosis or other liver disease;
heart disease;an electrolyte imbalance (such as low levels of potassium or magnesium in your blood);kidney disease;gout; orif you are on a low-salt diet.
Ethacrynic acid is not expected to be harmful to an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using ethacrynic acid.It is not known whether ethacrynic acid passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine.Ethacrynic acid is not approved for use by anyone younger than 18 years old.

How should I take ethacrynic acid?
Follow all directions on your prescription label. Your doctor may occasionally change your dose to make sure you get the best results. Do not use this medicine in larger or smaller amounts or for longer than recommended.

Take this medicine after a meal, unless your doctor tells you otherwise.Ethacrynic acid will make you urinate more often and you may get dehydrated easily. Follow your doctor's instructions about using potassium supplements or getting enough salt and potassium in your diet.While using ethacrynic acid, you may need frequent blood tests and weight checks.Store at room temperature away from moisture and heat. Keep the bottle tightly closed when not in use.