What Is Penicillamine?

Penicillamine is a metabolite of penicillin, a white fine-crystalline powder. 198.5 ° C. Soluble in water, slightly soluble in ethanol, insoluble in ether or chloroform. Has a special odor and bitter taste. It can be prepared by hydrolyzing penicillin. In clinical treatment of rheumatoid arthritis, chronic active hepatitis, scleroderma, dry mouth and eyes, arthritis syndrome and other autoimmune diseases, there are obvious curative effects.

Chinese name: Penicillamine
Foreign name: penicillamine

CAS number: 52-67-5
Molecular formula: C5H11NO2S
Molecular weight: 149.21100

Introduction to penicillamine compounds

Penicillamine Basic Information

Chinese name: penicillamine

Chinese alias: 3,3-dimethyl-D (-)-cysteine; Nimesin; D-(-)-penicillamine; -mercaptovaline; D-penicillamine; dimethyl Cysteine

English name: D-penicillamine

English alias: Cuprimin; emtexate; 3,3-Dimethyl-D-cysteine, 3-Mercapto-D-valine, D-()-2-Amino-3-mercapto-3-methylbutanoic acid; HD-Pen-OH; Perdolat; (2S) -2-amino-3-methyl-3-sulfanylbutanoic acid; penicillamine; D-, -Dimethylcysteine; Depamine; Penicillamine; 3,3-Dimethyl-D (-)-cysteine; D-Penicillamine; D-Valine, 3-mercapto-; Sufirtan; 3-mercapto-D-valine; D (-)-Penicillamine; Depen; d-valin; D--Mercaptovaline; Cuprenil; usan; D-PenicillaMine; Artamine;

CAS number: 52-67-5

MDL number: MFCD00064302

EINECS number: 200-148-8

RTECS number: YV9425000

BRN number: 1722375

PubChem number: 24898564

Molecular formula: C ₅ H ₁₁ NO ₂ S

Structural formula:

Molecular weight: 149.21100

Exact mass: 149.05100

PSA: 102.12000

LogP: 0.80700

Penicillamine physical and chemical properties

Appearance and properties: white powder

Density: 1.204g / cm ³

Melting point: 210 ° C (dec.) (Lit.)

Boiling point: 251.8ºC at 760mmHg

Flash point: 106.1ºC

Refractive index: -63 ° (C = 1, 1mol / L NaOH)

Water solubility: 11.1 g / 100 mL (20 ºC)

Stability: Stable. Incompatible with strong oxidizing agents.

Storage conditions: 2-8ºC

Penicillamine Safety Information

Symbol: GHS07

Signal Word: Warning

Hazard statement: H315; H319; H335

Cautionary statement: P261; P305 + P351 + P338

Customs code: 2930909090

WGK Germany: 2

Danger category code: R36 / 37/38

Safety instructions: S26-S36-S24 / 25

RTECS number: YV9425000

Dangerous goods mark: Xi; T; Xn ^[1]

Penicillamine Toxicology Data

The median lethal dose (rat, oral) is> 10000 mg / kg. Intravenous LD50 in mice was 2289 mg, kg.

Penicillamine molecular structure data

1. Molar refractive index: 38.13

2. Molar volume (cm / mol): 123.8

3. Isotonic specific volume (90.2K): 326.2

4. Surface tension (dyne / cm): 48.1

5. Polarizability (10-24cm3): 15.11

Penicillamine calculated chemical data

1. Hydrophobic parameter calculation reference value (XlogP): None

2.Number of hydrogen-bonded donors: 3

3.Number of hydrogen bond acceptors: 4

4.Number of rotatable chemical bonds: 2

5.Number of tautomers: none

6. Topological molecular polar surface area 64.3

7.Number of heavy atoms: 9

8.Surface charge: 0

9.Complexity: 124

10.Number of isotope atoms: 0

11. Determine the number of atomic stereocenters: 1

12. Uncertain number of atomic stereocenters: 0

13. Determine the number of chemical bond stereocenters: 0

14. Uncertain number of chemical bond stereocenters: 0

15.Number of covalent bond units: 1

Penicillamine synthesis method

Degraded or synthesized by penicillin. Derived from penicillin G potassium salt solution.

Penicillamine uses

It is an antidote for heavy metals such as copper, mercury, and copper. It is also used to treat autoimmune diseases such as hepatolenticular degeneration (Wilson's disease) and rheumatoid arthritis caused by copper deposition in tissues. Patients who are allergic to penicillin, hematopoietic dysfunction, and impaired renal function are disabled. ^[2]

Penicillamine Pharmacopoeia Standard

Penicillamine source (name), content (potency)

This product is D-3-mercapto valine. Calculated as dry product, containing C5H11NO2S shall not be less than 95.0%.

Penicillamine traits

This product is white or off-white crystalline powder.

This product is soluble in water, slightly soluble in ethanol, and insoluble in chloroform or ether.

Specific rotation

Take this product, accurately weigh it, add 1mol / L sodium hydroxide solution to dissolve and quantitatively dilute it to make a solution containing about 50mg per 1ml, and measure it according to the law (Appendix VIE of the second edition of the Pharmacopoeia, 2010 edition). To -65.0 °.

Penicillamine identification

(1) Take about 40mg of this product, add 4ml of water to dissolve it, add 2ml of phosphotungstic acid solution (1 10), shake well, and after standing for a few minutes, the solution is dark blue.

(2) Take this product and the penicillamine reference substance, dissolve and dilute each with water to make a solution containing 2.5 mg per 1 ml, and perform the test according to thin layer chromatography (Appendix VB of Part Two of the Pharmacopoeia, 2010 Edition), and draw the two solutions Each 2l was spotted on the same silica gel G thin layer plate, using n-butanol-glacial acetic acid-water (72:18:18) as a developing agent, developed, dried at 105 ° C for 10 minutes, and placed in an iodine vapor cylinder for 5 For 10 minutes, the position and color of the main spots displayed by the test solution should be the same as the position and color of the main spots displayed by the reference solution.

(3) Take about 0.5mg of this product, add 0.5ml of hydrochloric acid and 4ml of acetone to dissolve it warmly, cool in an ice bath, rub the tube wall with a glass rod to precipitate a white precipitate, filter, and wash the precipitate with acetone , Dry in air, take this precipitate to make up a 1% aqueous solution, it should be dextro-rotatory.

Penicillamine check

acidity

Take this product, add water to make a solution containing 10mg per 1ml, and determine it according to law (Appendix VI H of the Pharmacopoeia Part II of the 2010 edition). The pH value should be 4.0 6.0.

Penicillamine disulfide

Take about 0.125g of this product, accurately weigh it, place it in a 100ml measuring bottle, add diluent (take 1.0g of ethylenediamine tetraacetic acid disodium, dissolve and dilute with water to make 1000ml, shake well) dissolve and dilute to the mark, shake It is used as a test solution; another appropriate amount of a penicillamine disulfide reference substance dried to constant weight at 105 ° C is accurately weighed, dissolved in a diluent and diluted quantitatively to make a solution containing approximately 12.5 g per 1 ml. , As a reference solution; take an appropriate amount of penicillamine reference substance and penicillamine disulfide reference substance, add diluent to dissolve and dilute to make a solution containing 1 mg of penicillamine and 0.1 mg of penicillamine per 1 ml As a system suitability test solution. Measured according to high performance liquid chromatography (Appendix V D of Part Two of the Pharmacopoeia, 2010 edition), using octadecylsilane bonded silica as a filler; sodium phosphate sodium hexanesulfonate solution [take 6.9 g of sodium dihydrogen phosphate and hexane 0.2g of sodium sulfonate, add 900ml of water to dissolve, adjust the pH to 3.0 ± 0.1 with phosphoric acid solution (1 10), and then dilute to 1000ml with water, mix]] as the mobile phase; the detection wavelength is 210nm. Take 20l of the system suitability test solution and inject it into the liquid chromatograph. Record the chromatogram. The resolution of the penicillamine peak and the penicillamine disulfide peak should be greater than 3.0. Take 20l of the reference solution into the liquid chromatograph, adjust the detection sensitivity so that the peak height of the main component chromatographic peak is about 25% of the full range, and then accurately measure each 20l of the test solution and the reference solution and inject them into the liquid phase. Chromatograph, record chromatogram. Calculated by the peak area based on the external standard method, penicillamine-containing disulfide must not exceed 1.0%.

penicillin

Measured according to the antibiotic microbiological test method (Appendix A of Part Two of the 2010 Pharmacopoeia).

Media preparation

6.0g, trypsin digested casein 4.0g, yeast extract 3.0g, beef extract 1.5g, glucose 1.0g, agar 15.0g, water 1000ml, adjust the pH to 6.5 6.7 after sterilization, and destroy at 115 ° C Bacteria for 30 minutes.

Test bacteria

Micrococcus luteus was prepared according to Micrococcus luteus [CMCC (B) 28001].

Preparation of reference solution

Accurately weigh the appropriate amount of penicillin reference substance, add sterilized phosphate buffer (pH 6.0) to dissolve and quantitatively dilute to make a solution containing 0.02 units per 1ml.

Preparation of test solution

Take 1g of this product and weigh it accurately. Place in a separating funnel, add 9ml of water to dissolve, add 10ml of ether and 1ml of phosphate buffer solution (pH 2.5), shake and extract for 1 minute, and separate the aqueous layer into another separating funnel. Extract twice with 10 ml of ether, combine the ether layers, add 9 ml of water and 1 ml of phosphate buffer (pH 2.5), shake for 30 seconds, and discard the aqueous layer (the above operation should be completed within 6-7 minutes). The ether layer was extracted with 10 ml of sterilized phosphate buffer solution (pH 6.0) for 3 minutes, 5 ml of the aqueous layer was taken as the test solution (1), and 0.1 ml of penicillinase was added to the remaining water layer (each 1 ml of penicillinase should be greater than 3 million units) Leave it at 36 to 37 ° C for 1 hour as the test solution (2).

Assay

Take no less than 4 double dishes, add 10ml of medium to the bottom layer of each pair, add 5ml of medium to the bacteria layer, and place 6 stainless steel tubes in each pair of dishes. Add the reference solution to The test solution (1) and the test solution (2) were cultured at 29 to 30 ° C for 24 hours, and the diameters of each zone of inhibition were measured. The average diameter of the zone of inhibition caused by the test solution (1) must not be larger than the reference substance. The average diameter of the bacteriostatic zone caused by the solution. The test solution (2) must not produce bacteriostatic zones (0.2 units / g).

Loss on drying

Take this product, use phosphorus pentoxide as a desiccant, and dry under reduced pressure at 60 ° C to constant weight, and the weight loss should not exceed 0.5% (Appendix L of the second edition of the Pharmacopoeia of the 2010 edition).

Determination of penicillamine

Take about 0.15g of this product, accurately weigh, add acetate buffer solution (take 5.4g of sodium acetate, put in a 100ml measuring bottle, add 50ml of water to dissolve, adjust the pH to 4.6 with glacial acetic acid, dilute to the mark with water, shake 100ml dissolved and diluted to the mark, according to the potentiometric titration method (Appendix A of the second edition of the Pharmacopoeia, 2010 edition), with a platinum electrode as the indicator electrode, a mercury-mercury sulfate electrode as the reference electrode, and a mercury nitrate titration solution (0.05mol / L) Slowly titrate to the end. Each 1ml of mercury nitrate titration solution (0.05mol / L) is equivalent to 7.461mg of C5H11NO2S. ^[3]

Description of penicillamine compounds

Pharmacological effects of penicillamine

1 Networking. Heavy metal poisoning, this product can complex copper, iron, mercury, lead, arsenic and other heavy metals to form a stable and soluble complex and excreted from the urine. Its lead-dispelling effect is inferior to calcium sodium edetate, and its mercury-dispelling effect is not as good as that of dimercaptopropanol. However, this product can be taken orally with slightly less adverse reactions. It can be used when mild heavy metal poisoning or other complexing agents are contraindicated. Wilson's disease is a common chromosomal recessive genetic disease. A large amount of copper is mainly deposited in liver and brain tissues, which causes degeneration of lenticular nucleus and cirrhosis. This product can combine with copper deposited in tissues to form soluble complexes and excreted in urine. . cystine urine and stones, this product can react with cystine to form a cysteine-penicillamine disulfide mixture, thereby reducing the concentration of cystine in urine; the solubility of this mixture is better than cystine It is 50 times larger, so it can prevent the formation of cystine stones; long-term use for 6 to 12 months may gradually dissolve the formed cystine stones.

2 Anti-rheumatoid arthritis: The mechanism of action for treating rheumatoid arthritis is unknown. After treatment, it was found that lymphocyte function was improved, and the levels of IgM rheumatoid factor and immune complexes in serum and joint capsule fluid were significantly reduced, but the absolute value of serum immunoglobulin was not significantly reduced. It inhibits the viability of T cells in vitro, but has no effect on B cells. This product can also inhibit the cross-linking of newly synthesized procollagen, so it is also used to treat skin and soft tissue collagen diseases. ^[4]

Penicillamine pharmacokinetics

It is reported in the literature that about 57% of the drug is absorbed by the gastrointestinal tract after oral administration (which can affect the absorption of the drug when suffering from gastrointestinal diseases), and the peak time of the blood concentration is about 2 hours. The drug is distributed to all tissues of the body after absorption, but is mainly distributed in plasma and skin and can pass through the placenta. Most of this drug is metabolized in the liver. Penicillamine can be excreted in the urine within a few hours (50% in 24 hours), and 20% can be excreted in the feces. The main form of urine excretion is disulfide. One intravenous injection of penicillamine can excrete 80% of the disulfide in the urine within 24 hours. The half-life of penicillamine in plasma can reach 90 hours, and 3 months after withdrawal. There are still residues in the body.

Penicillamine indications:

1. For the treatment of heavy metal poisoning and hepatolenticular degeneration (Wilson disease).

2. It is also used for severe active rheumatoid arthritis in which other drugs are not effective.

Penicillamine Usage and Dosage:

Routine dosage for adults: Oral administration, usually 1g (8 tablets) a day, divided into 4 oral administrations.

1. Hepatolenticular degeneration, rheumatoid arthritis: 125-250mg (1-2 tablets) a day at the beginning, and 125-250mg (1-2 tablets) will be added every 1-2 months thereafter, the usual maintenance amount is 250mg once (2 tablets), 4 times a day, the maximum daily amount generally does not exceed 1.5g (12 tablets). When the symptoms improve and blood copper and ceruloplasmin are normal, they can be halved, 500-750mg (4-6 tablets) a day or intermittently. When treatment is still ineffective for 3-4 months, other drugs should be used instead.

2. Heavy metal poisoning: 1.5g (8-12 tablets), divided into 3-4 times. 5-7 is a course of treatment; 3 days after stopping the medicine, the next course of treatment can be started. It usually takes 1-4 courses depending on the amount of poison in the body.

Penicillamine adverse reactions:

The adverse reaction of this drug is related to the dosage, with a high incidence and seriousness. Some patients discontinued the drug because of intolerance within 18 months. The initial adverse reactions were mostly gastrointestinal dysfunction, decreased taste, and moderate platelet count reduction, but severe cases were rare. Taking large doses for a long time will damage the skin collagen and elastin, leading to increased skin fragility, and sometimes perforated tissue tumors and skin relaxation. Most of the adverse reactions can resolve and disappear by themselves after discontinuation.

1, allergic reactions can occur allergic reactions such as pruritus, rash, urticaria, fever, joint pain and lymphadenopathy. In severe cases, lupus-like erythema and exfoliative dermatitis can occur.

2. The digestive system may have nausea, vomiting, loss of appetite, abdominal pain, diarrhea, decreased taste, oral ulcers, glossitis, gingivitis, and recurrence of ulcers. A few patients have abnormal liver function (elevated aminotransferase).

3. Proteinuria occurs in some patients of the genitourinary system, and a small number of patients may develop nephrotic syndrome. Six months after treatment, some patients developed severe nephrotic syndrome.

4. Blood can cause bone marrow suppression, mainly manifested by platelet and leukopenia, agranulocytosis, and severe cases may have aplastic anemia. Eosinophilia and hemolytic anemia can also be seen.

5. The nervous system may have drooping eyelids, strabismus, and oculomotor nerve palsy. A small number of patients may develop peripheral neuropathy at the beginning of administration. Long-term use can cause optic neuritis. When treating hepatolenticular degeneration, it is easy to aggravate the symptoms of the nervous system, which can lead to spasm, muscle contracture, coma and even death.

6. Metabolic / endocrine system The drug can form complexes with various metals, which may lead to a deficiency of copper, iron, zinc or other trace elements.

7. The respiratory system may worsen or induce asthma attacks.

8. Other medicines can make the skin brittle and bleeding, and affect wound healing. According to reports, the drug can still cause lupus-like syndrome, myasthenia gravis, Goodpasture syndrome, polymyositis, and tinnitus. It can also cause a decrease in IgA test values.

Penicillamine contraindications:

1. Renal insufficiency, pregnant women and patients allergic to tetracycline are prohibited.

2. Granulocytic deficiency, disabled patients with aplastic anemia.

3. Patients with lupus erythematosus, myasthenia gravis and patients with severe skin diseases are prohibited.

Precautions:

1. Patients who are allergic to tetracycline may have an allergic reaction to this product. Penicillin skin test should be done before using this product.

2. This medicine should be taken 1.5 hours after a meal.

3. If the patient must use iron, it should be taken 2 hours before taking iron to avoid reducing the efficacy of this medicine. If iron is discontinued, the possible toxic effects of increased absorption of the drug should be considered, and the dose of the drug should be appropriately reduced if necessary.

4, white blood cell count and classification, hemoglobin, platelets, and urine tests should be checked every 2 weeks within the first 6 months of medication, and then every month thereafter.

5. When minor adverse reactions such as slight proteinuria, slight leukopenia, or rash occur, you can often use the "titration" method to gradually adjust the dosage of this drug. When the urine protein output is greater than 1g a day, the white blood cell count is less than 3x10 The drug should be discontinued when the / L or platelet count is less than 100x10 / L.

6. In the case of abnormal taste (except for patients with hepatolenticular degeneration), 5-10 drops of 4% copper sulfate solution can be added to the juice orally, twice a day, which will help restore the taste.

7. Liver function tests should be performed every 6 months in order to detect toxic liver disease and bile retention early.

8. Patients with Wilson disease should use urine for 24 hours to measure urine ketone on the day of taking the drug, and then measure it every 3 months.

9. This product should be taken daily continuously. Even if the drug is temporarily stopped for a few days, allergic reactions may occur when the drug is re-used, so it should be started from a small dose. Long-term use of this product should be added with vitamin B6 25mg per day to compensate for the required increase.

10. When the wound is not healed, the daily dose is limited to 250mg.

11. Reduce the dosage or discontinue the drug if there are adverse reactions.

12. Hematopoietic system and renal dysfunction should be regarded as serious adverse reactions, and the drug must be discontinued.

13. Wilson takes 1-3 months before taking effect. Rheumatoid arthritis service this product works for 2-3 months, if treatment is not effective for 3-4 months, you should stop taking this product and switch to other drugs.

Penicillamine for pregnant and lactating women:

This product can affect embryo development. Animal experiments have found skeletal deformities and cleft palate. Pregnant women with rheumatoid arthritis and cystineuria have reported developmental defects in their born babies when taking this product during pregnancy. Therefore, pregnant women should avoid taking it. If necessary, the dosage should not exceed 1g per day. It is expected that pregnant women who need a caesarean section should start at the end of 6 weeks of pregnancy and the dose should be limited to 250 mg per week before the post-partum wound healing. It is unclear whether this drug can be secreted into milk and it is recommended to ban it during breastfeeding.

Penicillamine for children:

The experiment was not performed and there are no reliable references.

Penicillamine for elderly:

Elderly people over 65 years of age are prone to toxic reactions to the hematopoietic system.

Penicillamine Drug Interactions:

1. Pyrazoles can increase the incidence of adverse reactions in the blood system of this drug.

2. This medicine can aggravate the toxicity of antimalarial drugs, gold preparations, immunosuppressive agents, butaisone to the blood system and kidneys.

3. Taking with iron can reduce the absorption of this medicine by 2/3.

4. Antacids containing aluminum hydroxide or magnesium hydride can reduce the absorption of this medicine. If this medicine must be used in combination with antacids, the time between taking the two medicines is preferably 2 hours.

5. This medicine can antagonize the effect of vitamin B6. For those who take this medicine for a long time, the demand for vitamin B6 increases, and 25mg of vitamin B6 can be taken in a day.

6. When combined with digoxin, the blood concentration of digoxin can be significantly reduced. ^[4]

Penicillamine Expert Reviews

It is still the drug of choice for the treatment of various types of hepatolenticular degeneration (Wilson's disease). Asymptomatic patients can also take maintenance amounts for a long time. The drug is not suitable for acute or severe, advanced patients, such as abdominal hepatolenticular degeneration, because of its slow copper displacing effect on tissues. Clinical application of penicillamine in the treatment of liver fibrosis, but the efficacy is uncertain, and many adverse reactions. The drug can inhibit the activity of the enzyme and prevent the newly secreted collagen from cross-linking with each other. It has good curative effect on hepatolenticular degeneration. Larger. ^[5]