Once administered into the body, diamorphine undergoes deacetylation via various esterase enzymes to generate active metabolites like 6-monoacetylmorphine and morphine. In particular, when administered orally, diamorphine undergoes extensive first pass metabolism.
A 17-year-old girl was found dead in a public toilet with fresh needle puncture marks. She was 18-20 weeks pregnant with a male fetus. Drug screening of her blood and urine indicated recent heroin use. Chronic drug use was confirmed by hair analysis. Amniotic fluid as well as fetal and maternal tissues and body fluids were analyzed by GC/MS and HPLC. All the fetal specimens were investigated, and the following levels of drugs were found: 6-monoacetyl-morphine (blood: 152 ng/g; amniotic fluid: 128 ng/g; brain: 140 ng/g; lung: 110 ng/g; liver: 2 ng/g; kidney: 40 ng/g), morphine (blood: 1360 ng/g; amniotic fluid: 604 ng/g; brain: 710 ng/g; lung: 1030 ng/g; liver: 2060 ng/g; kidney: 1100 ng/g), codeine (blood: 70 ng/g; brain: 60 ng/g; lung: 60 ng/g; liver: 90 ng/g; kidney: 70 ng/g), and morphine-3-glucuronide (amniotic fluid: 209 ng/g; brain: 170 ng/g; lung: 325 ng/g; kidney: 231 ng/g). Morphine-6-glucuronide was present in the maternal circulation but could not be detected in the fetal circulation.
Heroin is a prodrug. After IV administration, it is rapidly converted to 6-acetylmorphine and then more slowly to morphine. .... With oral administration, first-pass metabolism results in only morphine being produced.
Heroin (diacetylmorphine) is rapidly hydrolyzed to 6-monoacetylmorphine, which, in turn, is hydrolyzed to morphine. Heroin and 6-monoacetylmorphine are more lipid soluble than morphine and enter the brain more readily. Evidence suggests that morphine and 6-monoacetylmorphine are responsible for the pharmacological actions of heroin. Heroin is excreted mainly in the urine largely as free and conjugated morphine.
Heroin is metabolized in the liver and other tissues and is cleared more rapidly than morphine. Deacetylation produces 6-o-acetylmorphine and morphine, which appear in the plasma of dogs within minutes.
IDENTIFICATION AND USE: Heroin is 3,6-diacetylmorpine (diamorphine) a semisynthetic morphine derivative. Dependence and abuse potential is high. It is a DEA Schedule I Controlled Substance (determined to have no therapeutic benefit and is not legally available for use in the US). The hydrochloride salt is available in the UK. The injectable form is used in the treatment of severe pain associated with surgical procedures, myocardial infarction or pain in the terminally ill and for the relief of dyspnea in acute pulmonary edema. The nasal spray is used for the treatment of acute severe nociceptive pain in children and adolescents 2 to 15 years of age in a hospital setting, while the oral form is used for the relief of severe pain particularly in terminal care, myocardial infarction, left ventricular pain, pulmonary edema. As a street drug, heroin has no quality control regarding purity, sterility, or dose. HUMAN EXPOSURE AND TOXICITY: Injection of a heroin solution produces a variety of sensations described as warmth, taste, or high and intense pleasure ("rush") compared with sexual orgasm. After intravenous injection, the effects begin in less than a minute. Heroin has high lipid solubility, crosses the blood-brain barrier quickly, and is deacetylated to the active metabolites 6-monoacetyl morphine (6-MAM) and morphine. After the intense euphoria, which lasts from 45 seconds to several minutes, there is a period of sedation and tranquility ("on the nod") lasting up to an hour. The effects of heroin wear off in 3 to 5 hours, depending on the dose. Experienced users may inject two to four times per day. Thus, the heroin addict is constantly oscillating between being "high" and feeling the sickness of early withdrawal. This produces many problems in the homeostatic systems regulated by endogenous opioids. For example, the hypothalamic-pituitary-gonadal axis and the hypothalamic-pituitary-adrenal axis are abnormal in heroin addicts. Women on heroin have irregular menses, and men have a variety of sexual performance problems. Mood also is affected. Heroin addicts are relatively docile and compliant after taking heroin, but during withdrawal, they become irritable and aggressive. Both morphine and 6-MAM are responsible for the pharmacological effects of diamorphine. The toxicity of heroin is similar to other opioids, with CNS and respiratory depression, miotic pupils, and possibly pulmonary edema. Miosis is a variable finding, depending on coingestants and secondary effects such as hypoxia. In addition, heroin may present with myoclonus, seizures, and the additional sequelae of illicit drug use. Seizures are uncommon and may be related to hypoxia or to naloxone use. Patients with reactive airway disease can have exacerbations in response to inhalational use. Rhabdomyolysis consequent to the overuse of heroin can result in acute renal failure. Myoglobinuria and hyperuricosuria, due to muscle injury, in a setting of severely compromised extracellular circulating fluid volume account for the acute renal failure. Use during pregnancy causes various problems in the newborn. A neonatal withdrawal syndrome may occur in up to 85% of cases. Symptoms appear between 48 hours and 6 days after birth. They usually peak between 3 to 6 weeks then diminish progressively over as long as 6 months. They manifest as hyperactivity, tremor, myoclonus, hyperirritability, anorexia, poor weight gain, and scratching. Sweating, sneezing, mucous secretion, yawning, vomiting, diarrhea and hyperthermia may also be present. Convulsions appear in 5% of the children. Withdrawal syndrome in the mother during pregnancy can cause an increase in fetal catecholamine concentration, an increase in fetal movement, a relative oxygen lack, acute fetal distress and an increase in intrauterine death rate. The principal obstetrical and pediatric sequelae were studied in 22 heroin addicts. The main effects were on the fetus with 45% showing growth retardation below the 10th percentile, 65% fetal distress, 9% prematurity; 33% had infections and 66% had the withdrawal syndrome. Diamorphine crosses the placenta and is found in breast milk. A large study of approximately 500 births failed to show any increase in malformation rate. Taking heroin during pregnancy has not been associated with any congenital malformation, and no characteristic group of malformations exists. One study found chromosomal aberration in a group of 16 children born to mothers who were heroin addicts. In one case the chromosomal damage was linked to a malformation. Heroin addicts have an increase in chromosomal damage with sister chromatid exchange and reduced DNA repair. ANIMAL STUDIES: Rats show reduction in lymphocyte proliferation, phagocytosis, and interferon production during chronic morphine administration. CNS malformations were observed in 12 hamsters. Birth weight was reduced in rabbits, without evidence of malformation.
Heroin is a mu-opioid agonist. It acts on endogenous mu-opioid receptors that are spread in discrete packets throughout the brain, spinal cord and gut in almost all mammals. Heroin, along with other opioids, are agonists to four endogenous neurotransmitters. They are beta-endorphin, dynorphin, leu-enkephalin, and met-enkephalin. The body responds to heroin in the brain by reducing (and sometimes stopping) production of the endogenous opioids when heroin is present. Endorphins are regularly released in the brain and nerves, attenuating pain. Their other functions are still obscure, but are probably related to the effects produced by heroin besides analgesia (antitussin, anti-diarrheal).
来源:Toxin and Toxin Target Database (T3DB)
毒理性
致癌物分类
对人类不具有致癌性（未被国际癌症研究机构IARC列名）。
No indication of carcinogenicity to humans (not listed by IARC).
◉ Summary of Use during Lactation:Heroin use during breastfeeding has not been systematically studied, but it has long been known that infants exposed via breastmilk can be affected and develop abstinence if breastmilk is discontinued. Heroin use by breastfeeding mothers can also prevent symptoms of withdrawal in their heroin-exposed breastfed infants. Use of heroin as a street drug by nursing mothers carries the risk of breastmilk contamination with a variety of possible chemical contaminants that may be present in illicit heroin. Heroin use by a nursing mother is generally considered to be a contraindication to breastfeeding. Mothers who discontinue heroin use and begin methadone or buprenorphine maintenance therapy should be encouraged to breastfeed with ongoing medical support.
Heroin (diamorphine) by the intrathecal or epidural route is recommended for analgesia during cesarean section and for postoperative analgesia in the United Kingdom where a standardized pharmaceutical product is commercially available. However, no research on the effect on the breastfed infant or lactation has been published with this use.
◉ Effects in Breastfed Infants:A paper from 1915 reported a breastfed newborn infant whose mother began using heroin as a snuff for abdominal pain. She continued to use the snuff and became dependent. Her breastfed (extent not stated, but probably nearly exclusive) infant slept excessively, but when awake would curl up with abdominal cramps and cry continuously until breastfed. When the mother was deprived of the drug, the infant would yawn, sneeze, sweat, cry and have cramps in addition to occasional diarrhea. The mother was arrested and the infant was examined by the prison physician. Upon examination, the infant was "pale and flabby looking." with almost colorless lips and pinpoint pupils that did not react to light. The infant slept for most of a day then awoke with sweating and cramps. The infant was treated with camphorated tincture of opium (paregoric) and tincture of nux vomica (containing strychnine) three times daily. After 4 days of therapy, the infant reportedly appeared more cheerful and had no more cramps.
A 2-month-old breastfed (extent not stated) infant presented to the hospital with irritability and a high-pitched cry. He developed hypertonia and opisthotonos and had an increased respiration and heart rate. Laboratory tests revealed a severe metabolic alkalosis. His mother admitted to using heroin 2 days prior to admission for the first time since delivery. The infant's stomach contents and blood were positive for opiates as was the breastmilk and urine of the mother. The infant developed bilateral pulmonary infiltrates and had two positive sweat tests, indicating cystic fibrosis. The authors attributed the infant's metabolic alkalosis to the profuse sweating from heroin withdrawal in the presence of undiagnosed cystic fibrosis.
An 8-year-old girl was brought to a hospital in Iran by her aunt. The girl's mother had used heroin throughout pregnancy and lactation. She continued to breastfeed the child up to the time of admission to prevent heroin withdrawal. The girl had also not been enrolled in school to avoid signs of withdrawal in the child. Both mother and child were treated with buprenorphine for opiate dependence.
A 1-month-old infant was brought to the emergency room with respiratory distress. Cyanosis, fixed and constricted pupils, muscular hypotony and respiratory failure were found on physical examination. Free and conjugated morphine and codeine were found in the infant's urine. Hair analysis of the infant was positive for morphine, codeine and 6-monoacetylmorphine as well as cocaine and its metabolite benzoylecgonine. The authors believed that the infant had been exposed to heroin and cocaine chronically via the placenta, breastmilk, and inhalation of smoked heroin and cocaine.
◉ Effects on Lactation and Breastmilk:Heroin and morphine can increase serum prolactin. However, the prolactin level in a mother with established lactation may not affect her ability to breastfeed.
One nursing mother was using heroin as a snuff and had an adequate milk supply. When she switched to using morphine by injection, her milk supply seemed to diminish and she needed to breastfeed more frequently.
The amenorrhea-galactorrhea syndrome with "copious galactorrhea" was reported in 3 heroin-dependent women in their early 20's. Serum prolactin was not measured, but all had hypoestrogenism and low gonadotropin levels.
◈ What is heroin?
Heroin is a highly addictive opioid (narcotic). It can be smoked, snorted, or injected. Some street names for heroin include smack, dope, mud, horse, skag, junk, H, black tar, and skunk, among others. In the United States, heroin is an illegal substance and is not available by prescription.
◈ I just found out I am pregnant. Should I stop taking heroin?
If you have been taking heroin regularly, please seek help right away. It is important to stop using during pregnancy, but you should not stop suddenly (also called “cold turkey”). Stopping an opioid suddenly could cause you to go into withdrawal. Going through withdrawal might increase risks to the pregnancy. Your healthcare providers can talk with you about how to stop using heroin gradually in pregnancy.
◈ I use heroin. Can it make it harder for me to get pregnant?
It is not known if heroin can make it harder to get pregnant.
◈ Does using heroin increase the chance for miscarriage?
Miscarriage can occur in any pregnancy. Studies have not been done to see if heroin increases the chance for miscarriage.
◈ Does using heroin increase the chance of birth defects?
Every pregnancy starts out with a 3-5% chance of having a birth defect. This is called the background risk. Overall, the studies on heroin do not suggest an increased chance of birth defects. However, heroin is often combined with other drugs, medications, and even chemicals that could increase the chance of birth defects. This makes it difficult to know the actual exposures and risks for each person who uses heroin.
◈ Does using heroin in pregnancy increase the chance of other pregnancy related problems?
Studies involving people who use heroin or misuse other opioids during their pregnancy (take them in higher amounts or for longer than prescribed by healthcare providers) have found an increased chance for adverse outcomes including poor growth of the baby, stillbirth, delivery before 37 weeks of pregnancy (preterm delivery), and fetal distress during labor. Using heroin close to the time of delivery can result in withdrawal symptoms in the baby (see the section of this fact sheet on Neonatal Abstinence Syndrome.) Some people who misuse opioids also have other habits that can result in health problems for themselves and their pregnancy. For example, poor diet choices can lead to not having enough nutrients to support a healthy pregnancy and could increase the chance of miscarriage and preterm birth. Sharing needles to inject opioids increases the chance of getting diseases like hepatitis C and/or HIV, which can cross the placenta and infect the baby.
◈ Will my baby have withdrawal (Neonatal Abstinence Syndrome) if I continue to use heroin?
Studies have reported an increased chance for neonatal abstinence syndrome (NAS) with some opioids, including heroin. NAS is the term used to describe withdrawal symptoms in newborns from medication(s) or substances that a person takes during pregnancy. For any opioid, symptoms can include difficulty breathing, extreme drowsiness (sleepiness), poor feeding, irritability, sweating, tremors, vomiting and diarrhea. Most often, symptoms of NAS appear two days after birth and may last more than two weeks. Most babies can be successfully treated for withdrawal while in the hospital. If you used heroin or other opioids in your pregnancy, it is important that your baby’s healthcare providers know to check for symptoms of NAS, so your newborn gets the best possible care.
◈ Does using heroin in pregnancy affect future behavior or learning for the child?
One small study found smaller head measurements and brain volume in infants exposed to heroin during the pregnancy. Some studies on opioids as a general group including heroin have found more problems with learning and behavior in children exposed to opioids for a long period of time during pregnancy.
◈ Breastfeeding while using heroin:
Heroin breaks down into morphine inside the body, and morphine enters the breast milk. Heroin is often combined with other medications, drugs, or chemicals that could also enter the breast milk. Use of some opioids while breastfeeding can cause babies to be very sleepy and they may have trouble latching on. Some opioids can cause difficulty with breathing. If you have used heroin while breastfeeding, contact the baby’s healthcare provider immediately if your baby has any problems such as increased sleepiness (more than usual), trouble feeding, trouble breathing, or limpness.It is usually recommended that people do not breastfeed while using heroin. Be sure to talk to your healthcare provider about all your breastfeeding questions.
◈ If a male uses heroin, could it affect fertility (ability to get partner pregnant) or increase the chance of birth defects?
Heroin use may affect the sperm, making it harder to get a partner pregnant. The use of heroin by a father or sperm donor is not expected to increase the chance of birth defects, but injecting heroin increases the chance of exposure to infections such as hepatitis C or HIV. These infections can be passed through the semen to the person who is pregnant and then to the baby. For more information, please see the MotherToBaby fact sheet Paternal Exposures at https://mothertobaby.org/fact-sheets/paternal-exposures-pregnancy/.
Bioavailability is less than 35% when orally administered. In particular, some studies have determined that the bioavailability of orally administered diamorphine could be as low as 22.9% (16.4-29.4%) on average in opioid-naive subjects. Nevertheless, diamorphine administered by any many medically indicated routes of administration leads to a rapid absorption. Peak serum levels are achieved five to ten minutes subcutaneously, three to five minutes intranasally and intramuscularly, and less than one minute intravenously.
The majority of the drug is excreted via the kidney as glucuronides and to a much lesser extent as morphine. About 7-10 % is eliminated via the biliary system into the faeces.
Data regarding the volume of distribution specific to diamorphine is not readily accessible or available. However, considering diamorphine is considered a prodrug for morphine, the volume of distribution of morphine has been determined to be approximately 1 to 6 L/kg.
Some studies have determined a relatively high systemic diacetylmorphine clearance of about 8.7 +/- 2.6 L/min, suggesting that the intestine, liver, and blood might all collectively take part in the first pass metabolism of diacetylmorphine to morphine, although such clearance observations were made only in opioid-addicted individuals. However, considering diamorphine is considered a prodrug for morphine, the mean adult plasma clearance of morphine is approximately 20 to 30 mL/min/kg.
A case of lethal overdose by heroin ingestion is presented. The concentrations of drugs were measured several hours after death. Heroin, 06-monoacetylmorphine, and morphine were identified and quantitated in blood, urine, and gastrointestinal contents by gas chromatography-mass spectrometry and high-performance liquid chromatography. Concentrations of heroin, 06-monoacetylmorphine, and morphine were 109, 168, and 1140 ng/mL, respectively, in blood and 17, 12, and 425 ng/g, respectively, in gastrointestinal content. In urine, however, only morphine was detected at 3650 ng/mL.
[EN] NOVEL HEPCIDIN MIMETICS AND USES THEREOF<br/>[FR] NOUVEAUX MIMÉTIQUES D'HEPCIDINE ET LEURS UTILISATIONS
申请人：BAYER HEALTHCARE LLC
公开号：WO2018128828A1
公开（公告）日：2018-07-12
The present invention relates to novel peptides acting as hepcidin mimetics, as well as analogues and derivatives thereof. The invention further relates to compositions comprising the peptides of the present invention, and to the use of the peptides in the prophylaxis and treatment of hepcidin-associated disorders, including prophylaxis and treatment of iron overload diseases such as hemochromatosis, iron-loading anemias such as thalassemia, and diseases being associated with ineffective or augmented erythropoiesis, as well as further related conditions and disorders described herein.
[EN] IMIDAZOLIUM REAGENT FOR MASS SPECTROMETRY<br/>[FR] RÉACTIF D'IMIDAZOLIUM POUR SPECTROMÉTRIE DE MASSE
申请人：HOFFMANN LA ROCHE
公开号：WO2021234004A1
公开（公告）日：2021-11-25
The present invention relates to compounds which are suitable to be used in mass spectrometry as well as methods of mass spectrometric determination of analyte molecules using said compounds.
本发明涉及适用于质谱的化合物，以及利用该化合物进行分析物分子的质谱测定方法。
The effect of temperature and pH on the deacetylation of diamorphine in aqueous solution and in human plasma
作者：David A Barrett、Astrid L P Dyssegaard、P Nicholas Shaw
DOI：10.1111/j.2042-7158.1992.tb05474.x
日期：2011.4.12
Abstract
The effect of temperature on the kinetics of the deacetylation of diamorphine and 6-monoacetylmorphine was studied in human plasma. Diamorphine was rapidly and quantitatively degraded to 6-monoacetylmorphine with initial half-lives of 354, 18 and 3 min at temperatures of 4, 25 and 37°C, respectively. Further deacetylation to morphine was not detected. In aqueous solution, diamorphine was quantitatively degraded to give 6-monoacetylmorphine as the major product and morphine as a minor product, the rate of deacetylation being dependent on temperature and pH. At pH 4·0 and 5·6 diamorphine had a half-life of greater than 14 days at all temperatures but at alkaline pH diamorphine was rapidly deacetylated. The rate of deacetylation of 6-monoacetylmorphine was consistently slower than that of diamorphine under identical conditions of pH and temperature. A method is described for the rapid stabilization and subsequent assay of diamorphine in plasma which will prevent errors in estimation of the drug due to unwanted hydrolysis.
A pharmaceutically active inventive compound comprises two independently active analgesic moieties covalently conjoined through a physiologically labile linker. A preferred embodiment comprises an opioid, such as morphine, covalently linked to at least one analgesic compound selected from the group consisting of an opioid or a non-opioid compound through a physiologically labile linker. Suitable covalent linkers are covalently bonded to the two independently active analgesic compounds through one or more lactone, lactam, or sulfonamido linkages. Suitable linkers include endogenous carboxylate, amido, and sulfonamido moieties, and exogenous moieties that form the aforementioned lactone, lactam or sulfonamido linkages.
Controlled-release compositions containing opioid agonist and antagonist
申请人：——
公开号：US20020010127A1
公开（公告）日：2002-01-24
Controlled-release dosage forms containing an opioid agonist; an opioid antagonist; and a controlled release material release during a dosing interval an analgesic or sub-analgesic amount of the opioid agonist along with an amount of said opioid antagonist effective to attenuate a side effect of said opioid agonist. The dosage form provides analgesia for at least about 8 hours when administered to human patients. In other embodiments, the dose of antagonist released during the dosing interval enhances the analgesic potency of the opioid agonist.
