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PubMed1992

Contribution of the human kidney to the metabolic clearance of drugs.

OBJECTIVE: To demonstrate that the human kidney is capable not only of filtering and secreting drugs and their metabolites, but also of carrying out conjugation reactions such as acyl glucuronidation, N-glucuronidation, and glycination. DATA SOURCES: Plasma concentrations and renal excretion rates of drugs are measured and renal clearance is calculated in a series of selected pharmacokinetic studies in healthy human volunteers (some studies were conducted in the authors' laboratory and others were reported in the literature). BACKGROUND THEORY: It is generally agreed that the liver plays the dominant role in drug metabolism, and that the function of the kidneys is limited to excretion of parent drug and metabolites. This can be easily understood when a metabolite is present in both plasma and urine. When the metabolite is present in urine but is not measurable in plasma, then the possibility exists that the metabolite is formed by the kidneys. RESULTS: "Simple" excretion by the kidneys is demonstrated for sulfatroxazole/sulfamethoxazole. Ether glucuronides of codeine are formed in the liver, and the resulting glucuronide is excreted by the kidneys. Possible formation of N1- and N2-glucuronides by the kidneys is demonstrated for sulfadimethoxine, sulfametomidine, and sulfaphenazole. Acyl glucuronidation of probenecid and nalidixic acid is carried out by the kidneys. The acyl glucuronidation of probenecid shows a capacity-limited formation/excretion rate of 46 mg/h, which is subject dependent. During this process, the acyl glucuronidation of co-administered nalidixic acid is reduced from 53 to 16 percent compared with that of nalidixic acid alone. Probenecid and its acyl glucuronidation do not inhibit the ether glucuronidation of codeine in the liver, but only interfere with the active tubular secretion process. The acyl glucuronidation of the nonsteroidal antiinflammatory drug naproxen and its metabolite, O-desmethylnaproxen, may be carried out by the liver and kidneys. Glycination of benzoic acid and salicylic acid is carried out in both the liver and kidneys. CONCLUSIONS: It is difficult to recognize renal drug metabolism in the intact human body (in vivo); the glucuronides or conjugates must be measured via direct HPLC analysis. In cases where the metabolite is present in high concentrations in urine but not in blood, there may be an indication that the kidneys are responsible for the formation of the metabolite. Impaired kidney function not only affects renal excretion but may also affect renal metabolism.

Glucuronates↗
PubMed1993

Harvesting bone marrow in an outpatient setting using newer anesthetic agents.

PURPOSE: To evaluate the results of outpatient bone marrow harvest (BMH). PATIENTS AND METHODS: Seventy-two adult patients with various malignancies had 79 BMH procedures performed for future autologous bone marrow transplantation (BMT) in our institution's outpatient surgical facility. All patients were evaluated and educated before the procedure. Newer anesthetic agents specifically developed to have shorter half-lives, more rapid recovery from general anesthesia, and fewer unpleasant side effects were chosen. Propofol was used for induction of anesthesia in 76 patients, the other three were induced with sodium pentothal. The blood volume removed was replaced by colloid (6% hydroxyethyl starch). Also, a new parenteral nonnarcotic pain medication, ketoroloc, was used during the last part of general anesthesia to help with expected postoperative pain in 76 patients. RESULTS: BMH took 111 +/- 24 minutes and patients were in postanesthesia care unit (PACU) for 220 +/- 72 minutes before being sent home with a companion and Tylenol with codeine (acetaminophen with codeine; McNeil Pharmaceutical, Spring House, PA). PACU complications were minor and included transient mild dizziness (7.6%), vomiting (3.8%), and fever (2.6%). No life-threatening complication was observed. Only one patient was hospitalized for observation (fever) and then sent home. Seventy-five patients (94.9%) were contacted at home by the hospital nursing staff the day following the procedure. Five (6.7%) complained of nausea or vomiting, and four (5.3%) developed fever at home (temperature, 37.2 to 38.3 degrees C). Only 36% of patients actually took oral narcotic pain medication at home. CONCLUSION: Autologous BMH (AuBMH) is a safe outpatient procedure with minimal side effects when newer anesthetic agents are used.

Adolescent↗
PubMed2004

Drug interactions in dentistry: the importance of knowing your CYPs.

BACKGROUND: The hepatic and intestinal cytochrome, or CY, P450 enzyme system is responsible for the biotransformation of a multitude of drugs. Certain medications used in dentistry can act as substrates, inducers or inhibitors of this system. METHODS: The authors conducted a MEDLINE search of articles appearing between 1976 and the present using the keywords "drug interactions" and "cytochrome P450," and reviewed reports involving dental therapeutic agents using PubMed links from an Indiana University CYP450 drug interaction table on the World Wide Web. RESULTS: The antibiotics erythromycin and clarithromycin are potent inhibitors of CYP3A4 and can increase blood levels and toxicity of CYP3A4 substrates. Likewise, quinolone antibiotics such as ciprofloxacin inhibit the metabolism of CYP1A2 substrates. Other dental therapeutic agents are substrates for CYP2C9 (celecoxib, ibuprofen and naproxen), CYP2D6 (codeine and tramadol), CYP3A4 (methylprednisolone) and CYP2E1 (acetaminophen). Because codeine and tramadol are prodrugs, inhibition of their metabolism can lead to a diminution of their analgesic effects. While inducers of acetaminophen metabolism, including alcohol, theoretically can increase the proportion of it that is biotransformed into a potentially hepatotoxic metabolite, recent research suggests that concomitant alcohol intake does not increase the hepatotoxic potential of therapeutic doses of acetaminophen. CONCLUSIONS: A number of clinically significant drug interactions can arise with dental therapeutic agents that act as substrates or inhibitors of the CYP450 system. Clinical Implications. As polypharmacy continues to increase, the likelihood of adverse drug interactions in dentistry will increase as well. Ensuring that patients' medical histories are up to date and acquiring knowledge of the various substrates, inducers and inhibitors of the CYP450 system will help practitioners avoid potentially serious adverse drug interactions.

Cytochrome P-450 Enzyme Inhibitors↗
PubMed1999

Analgesic nephropathy: is it caused by multi-analgesic abuse or single substance use?

Analgesic nephropathy is a slowly progressive renal disease, characterised by renal papillary necrosis. Recently, diagnostic criteria for this disease have been defined based on renal computed tomography scanning performed without contrast. The observation of a decreased renal mass of both kidneys, combined with either bumpy contours or papillary calcifications, has been found to have high diagnostic specificity and sensitivity. However, the question remains as to what kind of analgesics can cause analgesic nephropathy. In the majority of early reports about this condition, phenacetin was singled out as the nephrotoxic culprit. However, during the last decade the nephrotoxic potential of nonphenacetin-containing preparations has become apparent. It is clear that people who abuse analgesics prefer combination analgesics containing 2 analgesics combined with caffeine and/or codeine. In contrast, abuse of products containing only aspirin (acetylsalicylic acid) or paracetamol (acetaminophen) is seldom described and associated renal disease is only occasionally reported. Experimental evidence of the nephrotoxicity of analgesic preparations is not well established. The results of studies involving analgesic administration in animals remain contradictory. Clinical evidence linking high consumption of analgesic preparations with analgesic nephropathy is overwhelming. Most patients who admit to over-consuming analgesics have taken preparation containing more than one compound. In recent years, it has become more apparent that preparations not containing phenacetin also have the potential to cause nephrotoxicity manifesting as identical renal lesions. Further epidemiological evidence of the nephrotoxic potential of analgesic combinations has come from case-control studies published during the last decade and from 2 prospective cohort studies. Effective prevention of analgesic nephropathy consists of the prohibition of over-the-counter sales of preparation containing at least 2 analgesics associated with caffeine and/or codeine.

Analgesics↗
PubMed1998

Analgesic abuse in the elderly. Renal sequelae and management.

Nephropathy caused by the use of 'classical' analgesics [paracetamol (acetaminophen), salicylates and pyrazolone derivatives] and renal impairment associated with nonsteroidal anti-inflammatory drugs (NSAIDs) are important health problems in the elderly. Classical analgesic nephropathy is a chronic renal disease characterised by renal papillary necrosis and chronic interstitial nephritis. The nephropathy is caused by the excessive consumption of analgesic mixtures containing at least 2 antipyretic analgesics combined with caffeine and/or codeine. The use of NSAIDs is associated with a wide range of tubular, interstitial, glomerular and vascular renal lesions. Despite the well-characterised acute biological effects of NSAIDs on the kidney, there is only limited evidence that they are associated with an increased risk of chronic renal failure. Classical analgesic toxicity can be effectively prevented by limiting the availability of over-the-counter analgesic mixtures containing 2 analgesic compounds in combination with potentially addictive substances (e.g. caffeine and/or codeine). In the elderly in particular, the prolonged, regular use of NSAIDs should be discouraged. Patients starting NSAID therapy should be monitored regularly and drug interactions should be avoided.

Aged↗
PubMed2004

Pharmacological treatments for persistent non-malignant pain in older persons.

Persistent non-malignant pain is common, often neglected and under-treated among older persons. Some older adults do not complain because they consider chronic pain to be a characteristic of normal aging. Physicians have concerns regarding adverse effects of pharmacological treatment. The model of the World Health Organization for treatment of cancer pain is generally accepted and also recommended for persistent non-cancer pain. Furthermore, non-pharmacological treatment should complement drug treatment whenever possible. An initial assessment and possible treatment of underlying causes of pain are pertinent. Modern pharmacological pain management is based on non-opioid and opioid analgesics. NSAIDs are among the most widely prescribed class of drugs in the world. The new cyclo-oxygenase-2 inhibitors such as celecoxib and rofecoxib offer an alternative for the treatment of mild-to-moderate pain in patients with a history of gastric ulcers or bleeding. Paracetamol (acetaminophen) is being used widely for the management of mild pain across all age groups as it has moderate adverse effects at therapeutic dosages. For moderate pain, a combination of non-opioid analgesics and opioid analgesics with moderate pain relief properties (e.g. oxycodone, codeine, tramadol and tilidine/naloxone) is recommended. For severe pain, a combination of non-opioid analgesics and opioid analgesics with strong pain relief properties (e.g. morphine, codeine) is recommended. The least toxic means of achieving systemic pain relief should be used. For continuous pain, sustained-release analgesic preparations are recommended. Drugs should be given on a fixed time schedule, and possible adverse effects and interactions should be carefully monitored. Adjuvant drugs, such as antidepressants or anticonvulsants, can be very effective especially in the treatment of certain types of pain, such as in diabetic neuropathy. Effective pain management should result in decreased pain, increased function and improvement in mood and sleep.

Aged↗
PubMed2002

Drug interactions with patient-controlled analgesia.

Patient-controlled analgesia (PCA) has become standard procedure in the clinical treatment of pain. Its widespread use in patients with all kinds of diseases opens a variety of possible interactions between analgesics used for PCA and other drugs that might be administered concomitantly to the patient. Many of these drug interactions are of little clinical importance. However, some drug interactions have been reported to result in serious clinical problems. Drug interactions can either predominantly affect the pharmacokinetics or pharmacodynamics of the drug. Most important pharmacokinetic drug interactions occur at the level of drug metabolism or protein binding. Acceleration of methadone metabolism caused by cytochrome P450 (CYP) 3A4 induction by antiretroviral drugs or rifampicin (rifampin) has caused methadone withdrawal symptoms. Lack of morphine formation from codeine as a result of CYP2D6 inhibition by quinidine results in an almost complete loss of the analgesic effects of codeine. Alterations of methadone protein binding caused by an inhibition of alpha1-acid glycoprotein synthesis by alkylating substances are another possibility for predominantly pharmacokinetically based drug interactions during PCA. Furthermore, inhibition of P-glycoprotein by anticancer drugs could result in altered transmembrane transport of morphine, methadone or fentanyl, although this has not been shown to be of clinical relevance. Synergistic effects of systemically administered opioids with spinally or topically delivered opioids or anaesthetics have been reported frequently. The same is true for the opioid-sparing effects of coadministered non-opioid analgesics. Antidepressants, anticonvulsants or alpha2-adrenoreceptor agonists have also been shown to exert additive analgesic effects when administered together with an opioid. Inconsistent findings, however, are reported regarding the treatment of patients with opioid-induced nausea and sedation, since coadministration of antiemetics either increased or decreased the respective adverse effects or revealed additional unwanted drug effects.

Analgesia, Patient-Controlled↗
PubMed2004

Genetic predictors of the clinical response to opioid analgesics: clinical utility and future perspectives.

This review uses a candidate gene approach to identify possible pharmacogenetic modulators of opioid therapy, and discusses these modulators together with demonstrated genetic causes for the variability in clinical effects of opioids. Genetically caused inactivity of cytochrome P450 (CYP) 2D6 renders codeine ineffective (lack of morphine formation), slightly decreases the efficacy of tramadol (lack of formation of the active O-desmethyl-tramadol) and slightly decreases the clearance of methadone. MDR1 mutations often demonstrate pharmacogenetic consequences, and since opioids are among the P-glycoprotein substrates, opioid pharmacology may be affected by MDR1 mutations. The single nucleotide polymorphism A118G of the mu opioid receptor gene has been associated with decreased potency of morphine and morphine-6-glucuronide, and with decreased analgesic effects and higher alfentanil dose demands in carriers of the mutated G118 allele. Genetic causes may also trigger or modify drug interactions, which in turn can alter the clinical response to opioid therapy. For example, by inhibiting CYP2D6, paroxetine increases the steady-state plasma concentrations of (R)-methadone in extensive but not in poor metabolisers of debrisoquine/sparteine. So far, the clinical consequences of the pharmacogenetics of opioids are limited to codeine, which should not be administered to poor metabolisers of debrisoquine/sparteine. Genetically precipitated drug interactions might render a standard opioid dose toxic and should, therefore, be taken into consideration. Mutations affecting opioid receptors and pain perception/processing are of interest for the study of opioid actions, but with modern practice of on-demand administration of opioids their utility may be limited to explaining why some patients need higher opioid doses; however, the adverse effects profile may be modified by these mutations. Nonetheless, at a limited level, pharmacogenetics can be expected to facilitate individualised opioid therapy.

Analgesics, Opioid↗
PubMed1991

Opioid agonist-antagonist drugs in acute and chronic pain states.

The agonist-antagonist opioid analgesics are a heterogeneous group of drugs with moderate to strong analgesic activity comparable to that of the pure agonist opioids such as codeine and morphine but with a limited effective dose range. The group includes drugs which act as an agonist or partial agonist at one receptor and an antagonist at another (pentazocine, butorphanol, nalbuphine, dezocine) and drugs acting as a partial agonist at a single receptor (buprenorphine). These drugs can be classified as nalorphine-like or morphine-like. Meptazinol does not fit into either classification and occupies a separate category. Pentazocine, butorphanol and nalbuphine are weak mu-antagonists and kappa-partial-agonists. All three drugs are strong analgesics when given by injection: pentazocine is one-sixth to one-third as potent as morphine, nalbuphine is slightly less potent than morphine, and butorphanol is 3.5 to 7 times as potent. The duration of analgesia is similar to that of morphine (3 to 4 hours). Oral pentazocine is closer in analgesic efficacy to aspirin and paracetamol (acetaminophen) than the weak opioid analgesics such as codeine. Neither nalbuphine nor butorphanol is available as an oral formulation. At usual therapeutic doses nalbuphine and butorphanol have respiratory depressant effects equivalent to that of morphine (though the duration of such effects with butorphanol may be longer). Unlike morphine there appears to be a ceiling to both the respiratory depression and the analgesic action. All of these 3 drugs have a lower abuse potential than the pure agonist opioid analgesics such as morphine. However, all have been subject to abuse and misuse, and pentazocine (but not the others) is subject to Controlled Drug restrictions. Buprenorphine is a potent partial agonist at the mu-receptor, and by intramuscular injection is 30 times as potent as morphine. A ceiling to the analgesic effect of buprenorphine has been demonstrated in animals and it is also claimed in humans. However, there are no reliable data available to define the maximal dose of buprenorphine in humans. A practical ceiling exists for sublingual use in that the only available formulation is a 2 micrograms tablet and few patients will accept more than 3 or 4 of these in a single dose. The duration of analgesia is longer than that of morphine, at 6 to 9 hours. There have been suggestions that buprenorphine causes less respiratory depression than morphine, but viewed overall it appears that in equianalgesic doses the 2 drugs have similar respiratory depressant effects.(ABSTRACT TRUNCATED AT 400 WORDS)

Analgesics↗
PubMed1993

Propiram. A review of its pharmacodynamic and pharmacokinetic properties, and clinical use as an analgesic.

Propiram is an orally administered opioid analgesic with partial morphine-like agonist and weak antagonist properties. Analgesic efficacy of propiram, usually 50 or 100mg, appears comparable to that of standard dosages of other oral opioid drugs [i.e. pentazocine, pethidine (meperidine)] in patients with acute pain of moderate to severe intensity arising from various gynaecological and surgical procedures, and may be superior to codeine in gynaecological and postoperative dental pain. Some evidence of a more rapid onset of action for propiram than for these opioid agents, and a longer duration of action for propiram than for codeine, is encouraging but remains to be substantiated in more extensive clinical use. The tolerability profile of propiram resembles those of others in its class, with drowsiness, nausea and vomiting, and dizziness experienced most frequently in controlled trials. The apparently low propensity of propiram for development of physical dependence and psychotomimetic effects requires confirmation with wider clinical experience. Available data thus indicate that propiram is an effective, orally administered opioid analgesic suitable for providing relief of acute moderate to severe pain arising from various surgical or gynaecological procedures, and that the drug is likely to become a useful alternative in such conditions where opioid analgesia is appropriate.

Administration, Oral↗
PubMed1991

Thebaine O-demethylation to oripavine: genetic differences between two rat strains.

1. Codeine O-demethylation to morphine is mediated by cytochrome P450 IID1 (rat), or P450 IID6 (man), and exhibits genetic polymorphism. Thebaine is a precursor in the formation of endogenous morphine and codeine in man, being O-demethylated to oripavine. 2. The objective of the present study was to ascertain whether the O-demethylation of thebaine to oripavine was mediated by cytochrome P450 IID1 in rat liver microsomes. 3. Thebaine O-demethylation showed strain differences in female Sprague-Dawley (SD) and female Dark-Agouti (DA) rats, which serve as a model for the human debrisoquine/sparteine metabolism phenotypes. 4. The total intrinsic clearance of thebaine to oripavine was high (19.7 ml/h per mg protein) in SD rats, indicating that oripavine is a major metabolite of thebaine. A 3-fold lower intrinsic clearance was observed in DA rats (6.7 ml/h per mg protein). 5. Thebaine O-demethylation was inhibited by quinine and known substrates of cytochrome P450 IID1/P450 IID6, supporting the major involvement of cytochrome P450 IID1 in oripavine formation in rats.

Animals↗
PubMed1993

Patterns of drug use by participants in the Western Australian methadone program, 1984-1991.

OBJECTIVES: To establish the extent to which participants in the WA methadone treatment program used opiates, cannabinoids, benzodiazepines, cocaine and amphetamines, and to define the pattern of such use over time. In addition, the relationships between methadone daily dose and the use of the various drug groups was examined. DESIGN: A retrospective analysis of data from 1678 samples from urinalysis screening over 13 separate surveys between 1984 and 1991. A mean of 35.9% of patients in the program was sampled on each occasion with each patient contributing only one sample in any one survey. Analytical techniques used included enzyme-multiplied immunoassay, thin-layer chromatography and gas chromatography-mass spectrometry. RESULTS: Methadone and/or its major metabolite were detected in most urine samples, indicating satisfactory compliance by patients. The detection of opiates increased from a mean of 27.1% of samples in 1984-1989 to a mean of 44.2% of samples in 1990-1991. Codeine or morphine were most frequently detected (94% of all opiate-positive samples) and were found together in 38.2% of opiate-positive samples. Detection of cannabinoids also increased from a mean of 45.2% of all samples during 1984-1987 to a mean of 56.4% of samples during 1990-1991. Benzodiazepines were found in a mean of 26.7% of samples but use was not time-related. Detection of amphetamine-class drugs doubled from a mean of 8.3% of all samples (mid 1989 to mid 1990) to 16.8% of samples (mid 1990 to mid 1991). The major representatives of the latter group were methylamphetamine (47.3% of amphetamine-positive urines), amphetamine (15.7%) and ephedrine/pseudoephedrine (44.6%). Opiate use was significantly lower (P < 0.05) in those patients taking more than 80 mg methadone/day. In addition, benzodiazepine use increased significantly (P < 0.05) with increasing methadone daily dose. There was no relationship between methadone daily dose and use of cannabinoids or amphetamines. CONCLUSIONS: The increase in the use of opiates, cannabinoids and amphetamines over the period 1984-1991 occurred about four years after the adoption of a harm minimisation treatment philosophy by the WA methadone program. The high prevalence of codeine and morphine in opiate-positive urine samples strongly suggested the use of "home-bake" heroin. In addition, the data showed that methylamphetamine and ephedrine/pseudoephedrine were the most frequently used psychostimulants. Suppression of opiate use in those clients receiving more than 80 mg methadone/day was consistent with earlier studies. However, the significant increase in use of benzodiazepines with increasing methadone daily dose requires further study.

Adult↗
PubMed1999

Risk of drug dependence and abuse posed by barbiturate-containing analgesics.

Concern has been raised that the barbiturate component of barbiturate-containing analgesics constitutes a public and individual health problem because of information from literature before 1966 concerning preclinical and clinical abuse liability, and the dependence risk of barbiturates. The safety of barbiturates alone and in combination in analgesics was reviewed. In addition, information from manufacturers of combination products were evaluated. A meta-analysis was not possible because of the paucity of formal clinical trials. Even though barbiturates have a narrow margin of safety and substantial abuse potential, there is no evidence that barbiturate-containing analgesics without codeine represent a public health or social problem because of their abuse potential. However, proper studies to confirm this theory have not been performed. In the absence of better data concerning efficacy and lack of dependence potential, barbiturate-containing analgesics are not first-line medications for the initiation of treatment for pain. Codeine-containing combination analgesics have the potential to be a more important public health problem than those with only barbiturate in the combination.

Analgesics↗
PubMed1999

The extent of postmortem drug redistribution in a rat model.

The aim of this study was to investigate the postmortem redistribution of several drugs in a rat model and to examine if any of the pharmacological properties was related to the extent of this phenomenon. One of the following drugs: phenobarbital (phenobarbitone), acetaminophen (paracetamol), carbamazepine, codeine, verapamil, amphetamine, mianserin, trimeprazine (alimemazine) or chloroquine was administered together with nortriptyline orally to rats 90 min prior to sacrifice. Heart blood was sampled immediately before sacrifice and after 2 h postmortem, as it has previously been shown that this is sufficient time for postmortem concentration changes to occur in heart blood. Blood was also sampled from the clamped abdominal inferior vena cava (representing peripheral blood) and tissue samples were taken from lungs, myocardium, liver, kidney, thigh muscle, forebrain, and vitreous humor together with a specimen from the minced carcass. Drugs were analyzed by high performance liquid or gas chromatography. For phenobarbital, acetaminophen and carbamazepine the postmortem to antemortem blood drug concentration ratios were close to 1.0 and tissue concentrations were low. The postmortem to antemortem heart blood drug concentration ratio for chloroquine (6.9 +/- 1.5) was higher than for nortriptyline (3.5 +/- 0.3), and the remaining drugs (codeine, verapamil, amphetamine, mianserin, and trimeprazine) showed ratios of the same magnitude as nortriptyline. The postmortem to antemortem blood drug concentration ratios for both heart blood and blood from the vena cava and also the lung to antemortem blood drug concentration ratio were closely related to the apparent volume of distribution for the drugs studied (p < 0.001). Accordingly, an apparent volume of distribution of more than 3-4 L/kg is a good predictor that a drug is liable to undergo postmortem redistribution with significant increments in blood levels. The postmortem drug concentration in blood from vena cava was closely related to the antemortem blood level, confirming that among the postmortem samples, the peripheral blood sample was the most representative for the antemortem blood concentration.

Animals↗
PubMed2000

Mechanistic studies of morphine dehydrogenase and stabilization against covalent inactivation.

Morphine dehydrogenase (MDH) of Pseudomonas putida M10 catalyses the NADP(+)-dependent oxidation of morphine and codeine to morphinone and codeinone. This enzyme forms the basis of a sensitive detection and assay method for heroin metabolites and a biotransformation process for production of hydromorphone and hydrocodone. To improve these processes we have undertaken a thorough examination of the kinetic mechanism of MDH. Sequence comparisons indicated that MDH belongs within the aldose reductase enzyme family. MDH was shown to be specific for the pro-R hydrogen of NADPH. In steady-state kinetic studies, product inhibition patterns suggested that MDH follows a Theorell-Chance mechanism for codeinone reduction at pH 7, and a non-Theorell-Chance sequential ordered mechanism for codeine oxidation at pH 9.5. Residues corresponding to the catalytically important Tyr-48, Lys-77 and Asp-43 of aldose reductase were modified by site-directed mutagenesis, resulting in substantial loss of activity consistent with a catalytic role for these residues. Loss of activity of MDH in the presence of the reaction product morphinone was found to be due to the formation of a covalent adduct with Cys-80; alteration of Cys-80 to serine resulted in an enzyme with greatly enhanced stability.

Alcohol Oxidoreductases↗
PubMed1999

[How we use opioid drugs on patients with neoplasms].

OBJECTIVE: To find the pattern of use of opiate drugs for treating pain in terminal cancer patients. DESIGN: Retrospective descriptive study. SETTING: Gavà 2 Health Centre, located in Barcelona's industrial belt. MATERIAL AND METHOD: Systematic review of the clinical records for the deaths recorded between May 1993 and March 1998. The following variables were recorded: age, sex, cause and place of death, professional attending patient during terminal phase, use of opiates (type, how they were taken, dosage and length of treatment) and prescribing doctor. RESULTS: Of the 429 deaths reviewed, 100 (23%) were caused by neoplasm (68% males), with an average age of 69 +/- 3 years. More than half the patients (55%) died at home. In the terminal phase they were mainly attended (69%) by their Primary Care team. 52% of the patients were given opiates, with morphine being the most common (71.1%), followed by codeine (40.3%) and tramadol (17.3%). The general practitioner was the prescribing agent in 69.2% of the cases. 76% of the patients who took codeine did so at infra-therapeutic doses (< 120 mg per day). Similarly, insufficient doses of morphine (< 60 mg per day) were given to half the patients who received it. 21.62% only took it during a period of 5 days or less before death. CONCLUSIONS: Primary care teams are taking on steadily greater protagonism in caring for terminal cancer patients. Although a large number of these patients are treated with opiates, these are given at often insufficient doses and for too short time periods.

Aged↗
PubMed2001

[The history of heroin].

The discovery of heroin and the development of heroin abuse are introduced. Heroin, the hydrochloride of diacetylmorphine, was discovered by acetylation of morphine. Heroin, in pharmacological studies, proved to be more effective than morphine or codeine. The Bayer Company started the production of heroin in 1898 on a commercial scale. The first clinical results were so promising that heroin was considered a wonder drug. Indeed, heroin was more effective than codeine in respiratory diseases. It has turned out, however, that repeated administration of heroin results in the development of tolerance and the patients become heroin-addicts soon. In the early 1910s morphine addicts "discovered" the euphorising properties of heroin and this effect was enhanced by intravenous administration. Heroin became a narcotic drug and its abuse began to spread quickly. Restrictions on its production, use and distribution were regulated by international treties. The total ban on heroin production was also proposed. As a result of the strict regulations the production and cosumption of heroin showed a significant decrease after 1931. At the same time the underworld recognized the shortage of heroin and started the illicit production and trafficking. The quantity of heroin seized by law enforcement agencies in the past decades rose gradually. As an indicator of the worldwide heroin market, the quantity of confiscated heroin underwent a tenfold increase since 1970. The paper surveys the most important heroin-producing and trafficking countries. Heroin, prepared in clandestine ("kitchen" or "jungle") laboratories, is diluted ("cut") by every member of the illegal heroin distributing chain, i.e. smugglers, traffickers, dealers and vendors.

Heroin↗
PubMed2002

Meta-analysis of the effectiveness of nonsteroidal anti-inflammatory drugs in a standardized pain model.

A comprehensive meta-analysis using strict inclusion criteria examined 8 studies comparing the efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) and codeine-based oral analgesics for treating moderate to severe oral surgery pain. The studies involved 1,163 patients, drawn from a literature search of more than 300 studies published since 1990. Of the 8, 5 showed significantly better outcomes (P < .05) with NSAIDs, while 3 showed no differences in outcomes (P > .05). Adverse reactions were greater in the opiate group (P < .001). Data from the 8 studies were subjected to standardized data transformation and analysis procedures using preselected pain measurement inventories. An oral surgery pain model was used because it is relatively free of confounding variables, thereby leading to clearer results. Results of the meta-analysis revealed that NSAIDs were either as effective or more effective than codeine-based analgesics for treating the moderate to severe pain associated with oral surgery. NSAIDs also were associated with fewer complications. Based on this analysis, NSAIDs should be considered for the control of postoperative oral surgery pain. Generalizability to other forms of postoperative pain remains speculative.

Anti-Inflammatory Agents, Non-Steroidal↗