Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0002895 (sickle cell disease)
 11,747 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pain in sickle cell anemia (SCA) is clinically managed with opioid analgesics. There are reports that SCA patients tolerate high doses of these drugs without adequate pain relief. The current study investigated the in vitro hepatic metabolism of opioids in mouse models of sickle cell anemia, with the hypothesis that higher dose requirements in SCA could be explained by an increased metabolism rate of opioids. Various rodent cytochrome P450 substrates, i.e., buprenorphine and codeine, and rodent uridine glucuronosyltransferase substrates, i.e., morphine, buprenorphine, and estradiol, were studied. The three groups used were: 1) control C57BL mice, 2) mice with the human alpha-globin and sickle beta-globin transgenes (SC), and 3) mice with the human alpha-globin and sickle beta-globin transgenes, and homozygous for the murine alpha-globin and heterozygous for the beta(major)-gene knockout (SCKO). In vitro hepatic microsomal incubations were carried out for each substrate, and data were fit to the Michaelis-Menten equation. Morphine formation had a higher V(max) in SCKO microsomes (0.4 +/- 0.009 nmol/min. mg; estimate +/- S.E.) than controls (0.25 +/- 0.007). Morphine-3-glucuronide formation had V(max) estimates of 18.9 +/- 0.6, 25.1 +/- 0.4, and 27.06 +/- 1.1 nmol/min. mg in control, SC, and SCKO microsomes, respectively. The control V(max) for estradiol-3-glucuronide formation was 2-fold greater than in SCKO microsomes. The control V(max) for estradiol 17-glucuronide formation was 3.4- and 2.2-fold greater than in SC and SCKO microsomes. Thus, in vitro metabolism of opioids is altered in SCA mouse models, which may lead to altered clearances of these drugs.
 ...
PMID:Metabolism of opioids is altered in liver microsomes of sickle cell transgenic mice. 1470 26

Morphine is frequently used to treat painful episodes associated with sickle cell disease (SCD) but may fail to provide adequate analgesia in many patients. This concise review focuses on unique disease related changes in physiologic variables associated with SCD that impacts pharmacokinetics and pharmacodynamics of morphine and may contribute to the variability in analgesia. Emerging evidence suggests that the allelic variants in the genes involving the opioid (UGT2B7, OPRM1, and ABCB1 genes) and nonopioid system (COMT gene) can alter the efficacy of morphine.
 ...
PMID:Pharmacogenetics of morphine: Potential implications in sickle cell disease. 1772 74

Morphine given by Patient Controlled Analgesia (PCA) is widely used in hospital settings to manage severe pain during acute painful episodes. Wide variations in prescription patterns occur and some patients are often self-administering sub- or low- therapeutic doses. In this preliminary study, a descriptive design with repeated measures was used to examine the effects of different PCA morphine regimens on the intensity, location and quality of pain as well as on the perceived amount of relief and side effects in patients with sickle cell disease (N=13; mean age 13.7 years; eight males; five females). The preliminary data showed that a regimen with a high background infusion rate and low intermittent push dose (Regimen B) may provide better response to PCA morphine. The difference in trends between the worst and least pain intensity ratings were narrower in this regimen, suggesting that pain peaks and troughs were not occurring as in a regimen with an around the clock nurse administered dosing schedule (Regimen C). The amount of morphine that was administered per day was not significantly different (p > 0.05) among the three morphine regimens. The combination of a high background infusion rate and low intermittent push dose (as in Regimen B) within the first 24 hours of admission, may provide improved response and possibly shorter recovery from the painful episode than the regimen that would routinely be prescribed with lower background infusion rate and high intermittent push dose (as in regimen A).
 ...
PMID:Analgesic Response to Morphine in Children with Sickle Cell Disease: A Pilot Study. 2010 57

Morphine-6-glucuronide, the active metabolite of morphine, and to a lesser extent morphine itself are known to accumulate in patients with renal failure. A number of cases on non-lethal morphine toxicity in patients with renal impairment report high plasma concentrations of morphine-6-glucuronide, suggesting that this metabolite achieves sufficiently high brain concentrations to cause long-lasting respiratory depression, despite its poor central nervous system penetration. We report a lethal morphine intoxication in a 61-year-old man with sickle cell disease and renal impairment, and we measured concentrations of morphine and morphine-6-glucuronide in blood, brain and cerebrospinal fluid. There were no measurable concentrations of morphine-6-glucuronide in cerebrospinal fluid or brain tissue, despite high blood concentrations. In contrast, the relatively high morphine concentration in the brain suggests that morphine itself was responsible for the cardiorespiratory arrest in this patient. Given the fatal outcome, we recommend to avoid repeated or continuous morphine administration in renal failure.
 ...
PMID:Lethal morphine intoxication in a patient with a sickle cell crisis and renal impairment: case report and a review of the literature. 2105 50

Patients with sickle cell disease (SCD) are often treated with opioids for severe pain. Although opioids are known to have renal-specific effects, their role in nephropathy in SCD remains unknown. Because a subset of patients receives opioids for long periods of time, we examined the influence of chronic morphine treatment on mice with pre-existing renal disease expressing varying amounts of sickle hemoglobin. Morphine treatment for 3-6 weeks resulted in a variety of defects in renal morphology observed using light and electron microscopy. Notably, morphine induced glomerular pathology, resulting in increased glomerular volume, mesangial expansion, mesangial cell proliferation, parietal cell metaplasia, podocyte effacement, and microvillus transformation. Cystic tubulopathy and hemeoxygenase-1 expression and activity were also increased in morphine-treated mice. Naloxone, a non-selective opioid receptor (OR) antagonist, ameliorated these effects. Functionally, the urine albumin to creatinine ratio was increased following acute as well as chronic morphine treatment. These results suggest that clinically relevant doses of morphine induce renal pathology and that OR antagonists may be effective for ameliorating morphine-induced renal disease.
 ...
PMID:Morphine promotes renal pathology in sickle mice. 2288 69

Sickle-cell anaemia is the most widespread genetic disease in the world. It manifests itself differently depending on the individual, but approximately 20% of patients affected suffer from very frequent and severe vaso-occlusive crises. The red blood cells, deformed into a sickle shape, obliterate the small blood vessels, reducing the oxygen supply to the organs. It is the main reason that patients with sickle-cell anaemia seek medical care in hospital emergency departments. Morphine is the basic treatment.
 ...
PMID:[Sickle-cell anemia and pain]. 2291 89

Sickle cell anemia is a manifestation of a single point mutation in hemoglobin, but inflammation and pain are the insignia of this disease which can start in infancy and continue throughout life. Earlier studies showed that mast cell activation contributes to neurogenic inflammation and pain in sickle mice. Morphine is the common analgesic treatment but also remains a major challenge due to its side effects and ability to activate mast cells. We, therefore, examined cannabinoid receptor-specific mechanisms to mitigate mast cell activation, neurogenic inflammation and hyperalgesia, using HbSS-BERK sickle and cannabinoid receptor-2-deleted sickle mice. We show that cannabinoids mitigate mast cell activation, inflammation and neurogenic inflammation in sickle mice via both cannabinoid receptors 1 and 2. Thus, cannabinoids influence systemic and neural mechanisms, ameliorating the disease pathobiology and hyperalgesia in sickle mice. This study provides 'proof of principle' for the potential of cannabinoid/cannabinoid receptor-based therapeutics to treat several manifestations of sickle cell anemia.
 ...
PMID:Cannabinoid receptor-specific mechanisms to alleviate pain in sickle cell anemia via inhibition of mast cell activation and neurogenic inflammation. 2670 65