Imatinib - Wikipedia
Morphine, the most common opioid used in the treatment of cancer which contribute to morphine's analgesic activity In addition, Oxycodone serum concentrations are increased by imatinib and nilotinib. Tapentadol is another pain medication with structural similarity and mechanism to tramadol. Imatinib, sold under the brand names Gleevec among others, is a medication used to treat . Crystallographic structure of tyrosine-protein kinase ABL ( rainbow colored, An example of a drug that increases imatinib activity and therefore side . of a difference in therapeutic efficacy between the final form of Gleevec and the. Imatinib is a small molecule kinase inhibitor used to treat certain types of cancer. Morphine, The serum concentration of Morphine can be increased when it is inducers, inhibitors and structure-activity relationships of human Cytochrome .
This lead compound was then tested and modified by the introduction of methyl and benzamide groups to give it enhanced binding properties, resulting in imatinib. However, favorable results in studies with monkeys and in vitro human cells allowed testing to continue in humans. The "beta crystalline form" of the molecule is a specific polymorph of imatinib mesylate; a specific way that the individual molecules pack together to form a solid. Inmore than cancer specialists published a letter in Blood saying that the prices of many new cancer drugs, including imatinib, are so high that people in the United States couldn't afford them, and that the level of prices, and profits, was so high as to be immoral.
Other physicians have complained about the cost.SAR of morphine - ring modification
When competitive drugs came on the market, they were sold at a higher price to reflect the smaller population,[ clarification needed ] and Novartis raised the price of Gleevec to match them.
The patent application at the center of the case was filed by Novartis in India inafter India had agreed to enter the World Trade Organization and to abide by worldwide intellectual property standards under the TRIPS agreement. As part of this agreement, India made changes to its patent law, the biggest of which was that prior to these changes, patents on products were not allowed, while afterwards they were, albeit with restrictions.
These changes came into effect inso Novartis' patent application waited in a "mailbox" with others until then, under procedures that India instituted to manage the transition. India also passed certain amendments to its patent law injust before the laws came into effect. The solid form of imatinib mesylate in Gleevec is beta crystalline. The application was rejected by the patent office and by an appeal board. The key basis for the rejection was the part of Indian patent law that was created by amendment indescribing the patentability of new uses for known drugs and modifications of known drugs.
That section, 3d, specified that such inventions are patentable only if "they differ significantly in properties with regard to efficacy. Novartis lost that case and did not appeal. The Supreme Court case hinged on the interpretation of Section 3d. The Supreme Court issued its decision inruling that the substance that Novartis sought to patent was indeed a modification of a known drug the raw form of imatinib, which was publicly disclosed in the patent application and in scientific articlesthat Novartis did not present evidence of a difference in therapeutic efficacy between the final form of Gleevec and the raw form of imatinib, and that therefore the patent application was properly rejected by the patent office and lower courts.
Imatinib was initially thought to have a potential role in the treatment of pulmonary hypertension.
Structure-activity relationships of some opiate glycosides.
It was shown to reduce both the smooth muscle hypertrophy and hyperplasia of the pulmonary vasculature in a variety of disease processes, including portopulmonary hypertension. These included 6 subdural hematomas and 17 deaths during or within 30 days of study end. One of its effects is delaying atherosclerosis in mice without  or with diabetes.
GSAP selectively increases the production and accumulation of neurotoxic beta-amyloid plaques, which suggests that molecules which target GSAP and are able to cross blood—brain barrier are potential therapeutic agents for treating Alzheimer's disease. Tests on mice indicate that imatinib is effective at reducing beta-amyloid in the brain. M3G has no analgesic effects but may cause some of the side effects of morphine.
Morphine and its congeners hydromorphone, fentanyl, etc. However, MORs are recycled back to the cell membrane following endocytosis. Morphine has a high RAVE value as a consequence of its inability to promote receptor desensitization and endocytosis [ 34 ].
The implication is that short-term, repeated, or chronic morphine treatment may lead to sustained effects on target tissues. Molecular and Cellular Effects of Opioids That May Influence SCD Pathophysiology In addition to analgesia induction, opioids activate growth, survival, and cytoprotection via opioid receptors in multiple cell types in the peripheral organs and in the central nervous system [ 636 ].
Morphine stimulates diverse neural and nonneural molecular targets. Thus, morphine administration may amplify endothelial activation and promote organ dysfunction such as retinopathy, strokes, and pulmonary hypertension, in SCD, as discussed below Figure 1.
Proposed model of morphine-induced signaling leading to organ damage. Independent of opioid receptors, morphine can induce inflammation and potentiate hyperalgesia in rodents via TLR4 [ 47 ]. Our group found that TLR4 expression is increased in the spinal cord and cutaneous mast cells of mice expressing human sickle hemoglobin as compared to control mice [ 2124 ]. Morphine treatment in vitro leads to the activation of cutaneous mast cells from control and sickle mice and in vivo in breast tumors in mice, leading to the release of inflammatory cytokines and neuropeptides, substance P SPand calcitonin-gene related peptide CGRP [ 24 ].
In sickle mice activation of TLR4 underlies vasoocclusion and acute lung injury [ 4849 ]. Increased levels of neuropeptide SP were described in sickle patients at steady state, which increased further during VOC [ 50 ].
Pain was not evaluated in this study. Thus, while providing analgesia via MOR, morphine may simultaneously play a detrimental role in SCD by promoting neuroinflammation, vascular dysfunction, and hyperalgesia via TLR4 activation. These experimental data argue for examining the cotreatment strategies of inhibition of TLR4 with morphine and evaluate the contribution of opioids to the exaggeration of inflammatory and neuroinflammatory microenvironment in SCD.
Renal Disease Renal complications that start early in age and may progress to end-stage renal disease ESRD are a leading cause of morbidity and mortality in adults with SCD [ 5152 ]. Survival is estimated to be 4 years following the onset of ESRD even when receiving dialysis. The pathophysiology of sickle nephropathy is not clearly understood but it involves both glomerular and tubular injury accompanied by proteinuria, hyperfiltration, increased glomerular filteration rate GFRblood flow and tubular resorption, and glomerulosclerosis.
Early renal disease includes glomerular hyperfiltration, increased proximal tubular function, and hematuria. Subsequently the concentrating ability is reduced; there is focal segmental glomerulosclerosis with proteinuria, papillary necrosis, and reduced glomerular filtration [ 53 ]. Influence of Opioids on Renal Disease Clinical and experimental studies have demonstrated the toxic effects of the chronic use of opioids on the kidney.
We and others have observed that clinical doses of morphine and hydromorphone incite kidney pathology, glomerular enlargement, and albuminuria in wild type and transgenic sickle mice [ 105455 ]. Opioids cause renal damage as evidenced by renal tubular vacuolization, mononuclear cell infiltration, and focal necrosis in rats receiving morphine or levo-alpha-noracetylmethadol, a metabolite of levo-alpha-acetylmethadol, a long-acting MOR agonist [ 5657 ]. Morphine and opioid peptides have direct effects on mesangial and glomerular epithelial cells, kidney fibroblast, and the interaction of mesangial cells with circulating macrophages and PMNs via the production of superoxide [ 5859 ].
Through this interaction, morphine has the potential to directly impair slit diaphragm cell membranes in podocytes, contributing to kidney injury. Morphine-induced generation of reactive oxygen species ROS and production of superoxide by macrophages and mesangial cells induce podocyte DNA damage [ 58 ].
Morphine-induced podocyte injury leads to albuminuria in wild type mice [ 10 ]. Morphine treatment led to albuminuria and podocyte injury as well as diminished expression of podocyte markers, synaptopodin, and nephrin, in wild type FVBN mice [ 10 ], and increased podocyte foot process effacement accompanied by albuminuria in sickle mice [ 60 ]. Morphine stimulates proliferation of glomerular mesangial cells [ 9 ] and superoxide production [ 58 ], enhances deposition of ferritin-antiferritin complexes in the glomerulus [ 61 ], amplifies nitrite production [ 62 ], and stimulates COX-2 in the kidneys of mice treated with morphine [ 54 ].
Morphine amplifies renal pathology, stimulates albuminuria, and impairs renal function, in sickle mice, which share the disease phenotype with humans [ 55 ]. Proposed model of morphine activity in the kidney. These molecular changes are accompanied by albuminuria and glomerular pathology in morphine treated mice. Together, these morphine-induced cellular, molecular, and pathological effects may stimulate and exacerbate existent renal damage in sickle cell disease.
We Gupta et al. Higher expression of MOR and KOR in sickle mouse kidneys may further augment the activity of morphine manifested as renal dysfunction demonstrated by proteinuria, higher BUN, and reduced BUN clearance in sickle mice and increased BUN in Wistar rats following chronic morphine treatment [ 5556 ]. Morphine-induced tubular damage observed in mice and rats [ 5660 ] may additionally contribute to renal dysfunction. Pain and opioid use were not evaluated in this study.
However, heroin-associated nephropathy was recognized in chronic drug users more than three decades ago [ 63 ] but the possibility of a similar nephropathy in chronic morphine a metabolite of heroin users remains unexamined. Moreover, intravenous opiate addiction has been considered a risk factor for the development of human immunodeficiency virus HIV associated nephropathy [ 5658 ].
Data suggest both central and sympathetic nervous system dependent and independent effects of opioids on renal function [ 64 ]. Therefore, whether morphine contributes to sickle nephropathy in humans merits careful examination.
Morphine for the Treatment of Pain in Sickle Cell Disease
Pulmonary Disease Pulmonary disease is another major cause of morbidity and mortality in adults with SCD but its etiology is not well understood. In sickle patients, morphine is associated with an increased risk of developing acute chest syndrome ACS [ 765 ]. Acute chest syndrome is closely associated with VOCs, especially in adults [ 186970 ]. These hospitalized patients were given opioids, mostly morphine for pain management.
This is further supported by three observational reports showing that the use of morphine in patients with SCD seems to be associated with acute chest syndrome [ 77475 ].
Potent morphiceptin analogs: structure activity relationships and morphine-like activities.
As discussed above, morphine stimulates TLR4 activity, and TLR4 has been implicated in acute lung injury and vasoocclusion in sickle mice [ 4849 ]. Moreover, the patient discussed above who died of fentanyl toxicity may have had fentanyl-related ACS, although the autopsy findings were not entirely convincing [ 27 ].
The association of morphine with increased frequency of ACS, therefore, merits further investigation. Right heart catheterization is the gold standard for the diagnosis of pulmonary hypertension [ 7778 ]. Yet, the pathogenesis of pulmonary hypertension in patients with SCD is not known.
Several mechanisms have been proposed including hemolysis leading to nitric oxide NO deficiency, interstitial fibrosis secondary to ACS and vasculopathy characterized by endothelial dysfunction, increased vascular tone, inflammation, hypercoagulability, and vascular remodeling and destruction of pulmonary vasculature [ 79 — 81 ]. In pulmonary hypertension, the initial apoptotic injury of pulmonary endothelial cells followed by hyperproliferation of apoptosis-resistant cells is believed to be one of the causes.
Morphine treatment led to pulmonary vascular remodeling caused by enhanced apoptosis and endothelial proliferation in SIV-infected macaques [ 8 ]. It is noteworthy that morphine did not stimulate vascular remodeling in uninfected macaques.
This clearly indicates that vascular responsiveness to morphine is distinct in a proinflammatory microenvironment, as compared to normal conditions. Similarly, in a tumor microenvironment replete with inflammatory cytokines, morphine promotes angiogenesis [ 682 ].
It is therefore possible that the vasculopathic effects of morphine may contribute to development of PAH in an inflammatory microenvironment encountered in SCD. Hemin-induced acute lung injury in sickle mice is mediated by TLR4 [ 49 ]. TLR4 gene expression is upregulated severalfold in cutaneous mast cells from sickle mice as compared to control mice.
Morphine activated the release of tryptase and neuropeptides from mast cells from both control and sickle mice [ 24 ]. Mast cell proliferation and activation may contribute to PAH in humans [ 83 ]. In sickle mice, mast cell inhibitors reduce inflammation and improve morphine analgesia [ 24 ]. Other Organ Systems We speculate that the activity of morphine on the vasculature may exacerbate preexisting endothelial vasculopathy and multiorgan dysfunction leading to devastating complications such as retinopathy and cerebral strokes in SCD.
Proangiogenic signaling and angiogenesis stimulated by morphine may promote proliferative sickle retinopathy and collateralization in ischemic strokes, while morphine-induced vascular permeability may contribute to hemorrhagic strokes in SCD. Morphine use was associated with a 4. Morphine-induced pruritis is another common feature in SCD patients [ 85 ]. Significantly less itching was observed with controlled release oxycodones as compared to controlled release morphine in cancer patients with pain [ 86 ].
Drug Interactions in Cancer Patients Requiring Concomitant Chemotherapy and Analgesics (Page 4)
The contribution of mast cell activation described above, therefore, deserves consideration in morphine-induced pruritis. Opioid-induced clinical manifestations of the gastrointestinal system have been well known. Another side effect induced by opioid analgesia in patients is vomiting, which persists upon intrathecal delivery as well [ 9091 ].
Therefore, careful usage of MOR antagonists needs to be explored for these side effects while using opioids.