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The Hematology dsg recognizes that thalidomide is an active agent in multiple myeloma patients who have relapsed after autologous stem-cell transplantation or who are refractory to alkylating agent-based chemotherapy. To date, no reported. The combination of bortezomib , melphalan, and prednisone is a standard treatment for patients with newly diagnosed multiple myeloma who are ineligible for autologous stem-cell transplantation.
Daratumumab has shown efficacy in combination with standard-of-care regimens in patients with relapsed or refractory multiple myeloma. In this phase 3 trial, we randomly assigned patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation to receive nine cycles of bortezomib , melphalan, and prednisone either alone control group or with daratumumab daratumumab group until disease progression.
The primary end point was progression-free survival. At a median follow-up of Purpose To examine the combination of bortezomib and vorinostat in multiple myeloma cells U and xenografts, and to assess the nature of their potential interactions with semi-mechanistic pharmacodynamic models and biomarkers.
Methods U proliferation was examined for a range of bortezomib and vorinostat exposure times and concentrations alone and in combination. A non-competitive interaction model was used with interaction parameters that reflect the nature of drug interactions after simultaneous and sequential exposures. Results Estimated model parameters for simultaneous in vitro and xenograft treatments suggested additive drug effects. The sequence of bortezomib preincubation for 24 hours, followed by vorinostat for 24 hours, resulted in an estimated interaction term significantly less than 1, suggesting synergistic effects.
Conclusions Semi-mechanistic pharmacodynamic modeling suggests synergistic pharmacodynamic interactions for the sequential administration of bortezomib followed by vorinostat.
Chemotherapy agents were the same as those used in the TACL trial, consisting of dexamethasone, doxorubicin, vincristine and pegylated asparaginase. Addition of cyclophosphamide and higher doses of dexamethasone do not improve outcomes of patients with AL amyloidosis treated with bortezomib. Bortezomib , in combination with dexamethasone VD or with the addition of cyclophosphamide VCD , is highly effective in patients with amyloid light-chain AL amyloidosis.
Currently, VCD is considered as a primary regimen for patients with AL, but it is not clear whether the addition of cyclophosphamide to VD further and significantly improves efficacy, given the substantial activity of bortezomib itself. Early mortality after adjustment for Mayo stage was similar. Organ responses occurred in similar rates between the two groups.
In conclusion, bortezomib even with low doses of dexamethasone is effective for the treatment of AL amyloidosis; higher doses of dexamethasone and addition of cyclophosphamide do not seem to have a profound effect on efficacy and survival. Panobinostat plus bortezomib and dexamethasone: Panobinostat in combination with bortezomib and dexamethasone demonstrated a significant and clinically meaningful progression-free survival benefit compared with placebo, bortezomib and dexamethasone in the phase 3 PANORAMA 1 Panobinostat Oral in Multiple Myeloma 1 trial.
Despite this benefit, patients in the panobinostat arm experienced higher rates of adverse events AEs and higher rates of discontinuation due to AEs. The incidences of several key AEs were lower in both arms following the planned reduction of bortezomib dosing frequency in TP2.
Dose intensity analysis of panobinostat and bortezomib by cycle in the panobinostat arm showed reductions of both agent doses during cycles due to dose adjustments for AEs. Exposure-adjusted analysis demonstrated a reduction in thrombocytopenia frequency in TP1 following dose adjustment. These results suggest that optimization of dosing with this regimen could improve tolerability, potentially leading to improved patient outcomes.
The present global, open-label, single-arm, multicenter, phase IIb study was designed to determine the efficacy and tolerability of oral vorinostat combined with standard doses of bortezomib in patients with multiple myeloma considered refractory to novel myeloma agents. The patients received day cycles of bortezomib 1. Oral dexamethasone, 20 mg, on the day of and the day after each dose of bortezomib could be added for patients with progressive disease after 2 cycles or no change after 4 cycles.
The primary endpoint was the objective response rate. The objective response rate was The median overall survival duration was The frequently reported adverse events were thrombocytopenia The combination of vorinostat and bortezomib is active in patients with multiple myeloma refractory to novel treatment modalities and offers a new therapeutic option for this difficult-to-treat patient population ClinicalTrials.
Overall survival of patients with relapsed multiple myeloma treated with panobinostat or placebo plus bortezomib and dexamethasone the PANORAMA 1 trial: Panobinostat plus bortezomib and dexamethasone significantly increased median progression-free survival compared with placebo plus bortezomib and dexamethasone in the phase 3 PANORAMA 1 trial.
Here, we present the final overall survival analysis for this trial. PANORAMA 1 is a randomised, placebo-controlled, double-blind, phase 3 trial of patients with relapsed or relapsed and refractory multiple myeloma with one to three previous treatments. Patients were randomly assigned 1: In treatment phase 1 eight 3-week cycles , patients received: During treatment phase 2 four 6-week cycles with a 2 weeks on, 1 week off schedule , panobinostat or placebo was given three times a week, bortezomib was administered once a week, and dexamethasone was given on the days of and following bortezomib administration.
The primary endpoint was progression-free survival; overall survival was a key secondary endpoint. This study is registered at ClinicalTrials. At data cutoff June 29, , patients had died. Background Based on preclinical studies and a phase I trial of the combination of bortezomib and pegylated liposomal doxorubicin PLD , which both showed activity in breast cancer, we conducted a phase II study of this regimen in patients with metastatic breast cancer.
Patients and Methods Patients received bortezomib 1. The primary objective was to evaluate the response rate of this combination, while secondary objectives were to obtain further safety data about this combination, to evaluate the time to disease progression TTP , and to evaluate response by the breast cancer subtype. At 26 months follow-up, the median overall survival was 4.
The combination was well tolerated, with the most common events including low-grade nausea and vomiting, neutropenia, and neuropathy, and no cardiac toxicity was seen.
Of the 7 tumors subtyped, no association was seen between intrinsic subtype or receptor status and response. Conclusion The combination of PLD and bortezomib was well tolerated but has minimal activity in heavily pretreated unselected metastatic breast cancer.
A Phase I study of intermittently dosed vorinostat in combination with bortezomib in patients with advanced solid tumors.
Accumulating evidence shows evidence of efficacy with the combination of vorinostat and bortezomib in solid tumors. We previously examined a once-daily continuous dosing schedule of vorinostat in combination with bortezomib which was well tolerated in cycles 1 and 2; however, there was concern regarding the tolerability through multiple cycles. This study was conducted to evaluate an intermittent dosing schedule of vorinostat with bortezomib. Vorinostat was initially administered orally twice daily on days with bortezomib IV on days 1, 4, 8, and 11 of a 21 day cycle.
Two DLTs elevated ALT and fatigue were observed at dose level 1, thus the protocol was amended to administer vorinostat intermittently twice daily on days and Common cancer types included sarcoma, pancreatic, colorectal, GIST, and breast. DLTs in the intermittent dosing scheduled included thrombocytopenia and fatigue.
The Cmax and AUC for the intermittent dosing regimen were similar to those observed in the daily dosing. In this heavily pretreated population, stable disease was observed in patients with sarcoma, colorectal adenocarcinoma and GIST.
Tolerability was not improved with the intermittent dosing schedule of vorinostat when compared to continuous dosing. Retreatment with bortezomib alone or in combination for patients with multiple myeloma following an initial response to bortezomib.
This clinical trial was conducted to determine the safety and efficacy of bortezomib retreatment in patients with multiple myeloma MM who had previously responded to bortezomib. Patients were allowed to receive bortezomib on retreatment in combination with dexamethasone, thalidomide, or doxorubicin.
Thirty-two patients received bortezomib retreatment most with added dexamethasone. The median treatment-free interval last dose of initial bortezomib treatment to first dose of retreatment was 9. The median duration of retreatment was 2. The median time from start of retreatment to progressive disease PD was 6.
Retreatment with bortezomib alone or in combination is effective and well tolerated in patients with MM who have responded to their initial bortezomib treatment. Bortezomib with chemotherapy is highly active in advanced B-precursor acute lymphoblastic leukemia: Therapy of relapsed pediatric acute lymphoblastic leukemia ALL is hampered by low remission rates and high toxicity, especially in second and subsequent relapses. Our phase 1 study, T, showed that the combination of bortezomib with vincristine, dexamethasone, pegylated asparaginase, and doxorubicin had acceptable toxicity.
We report the phase 2 expansion of this combination in patients with relapsed ALL who failed previous regimens. After 3 patients died from bacterial infections, treatment with vancomycin, levofloxacin, and voriconazole prophylaxis resulted in no further infectious mortality in the last 6 patients. Thus, this combination of bortezomib with chemotherapy is active in B-precursor ALL, and prophylactic antibiotics may be useful in reducing mortality.
Bortezomib merits further evaluation in combination therapy in pediatric B-precursor ALL. This study is registered at http: Bortezomib -induced Sweet's syndrome confirmed by rechallenge. Sweet's syndrome, also known as acute febrile neutrophilic dermatosis, is characterized predominantly by fever, elevated neutrophil count, and erythematous skin lesions composed of plaques and nodules that appear on upper extremities, face, or neck.
The incidence of Sweet's syndrome in the general population is unknown due to the rarity of the condition and potential lack of reporting. Bortezomib , an antineoplastic agent that is the standard of care in patients with multiple myeloma, has been reported to be associated with Sweet's syndrome. We describe a year-old man who developed Sweet's syndrome during his initial course after cycle 4 of bortezomib for treatment of multiple myeloma; he again experienced Sweet's syndrome 3.
The patient's signs, symptoms, and biopsy results were identical during both presentations of Sweet's syndrome. In both instances, the syndrome spontaneously resolved without incident and without supportive treatment with corticosteroids or antihistamines.
To our knowledge, this is the first case report of a patient who developed Sweet's syndrome during an initial course of treatment with bortezomib and after rechallenge with bortezomib for relapsed disease.
As proteasome inhibitors continue to be a mainstay of therapy for both treatment and salvage therapy for multiple myeloma, this case demonstrates that rechallenge with bortezomib is an option for patients who develop Sweet's syndrome. Utility of bortezomib retreatment in relapsed or refractory multiple myeloma patients: Bortezomib therapy has become an important part of the standard of care for patients with relapsed multiple myeloma, and preliminary clinical evidence suggests that bortezomib retreatment in patients previously treated with the drug may prolong disease control.
This retrospective study was designed to clarify the utility of bortezomib as a repeat therapy. We found 22 patients who received bortezomib retreatment following a 60 or more day gap between bortezomib treatments. Twelve patients had intervening therapy between initial bortezomib treatment and bortezomib retreatment.
During retreatment, 14 of 22 patients received bortezomib in combination with another antineoplastic agent. The median length of retreatment was 5. Therapy was terminated due to unmanageable toxicity in 2 patients during retreatment, compared with 6 patients during initial treatment. During retreatment, no patients required dose reduction due to peripheral neuropathy, compared to 4 patients during their initial treatment.
Thus, bortezomib retreatment appears to be safe and effective. Favorable observed response rates with bortezomib retreatment suggest that it may be a viable option for relapsed or refractory multiple myeloma, even in patients previously exposed to bortezomib.
Outcomes with two different schedules of bortezomib , melphalan, and prednisone VMP for previously untreated multiple myeloma: Bortezomib -melphalan-prednisone VMP is a standard-of-care for previously untreated, transplant-ineligible multiple myeloma MM. Median overall survival OS was similar We aimed to assess efficacy and tolerability of vorinostat in combination with bortezomib for treatment of patients with relapsed or refractory multiple myeloma.
Eligible patients had to have non-refractory multiple myeloma that previously responded to treatment one to three regimens but were currently progressing, ECOG performance statuses of 2 or less, and no continuing toxic effects from previous treatment. We excluded patients with known resistance to bortezomib.
We randomly allocated patients 1: The primary endpoint was progression-free survival PFS in the intention-to-treat population. We assessed adverse events in all patients who received at least one dose of study drug.
This study is registered with ClinicalTrials. Between Dec 24, , and Sept 8, , we randomly allocated eligible patients to the vorinostat group of whom received at least one dose and to the placebo group all of whom received at least one dose. Combination therapy of intravenous immunoglobulin IVIG and rituximab showed a good transplant rate in highly sensitized wait-listed patients for deceased donor kidney transplantation DDKT , but carried the risk of antibody-mediated rejection.
The authors investigated the impact of a new combination therapy of bortezomib , IVIG, and rituximab on transplantation rate. This study was a prospective, open-labeled clinical trial. The transplant rate was analyzed. Anti-Human leukocyte antigen HLA DRB antibodies were determined by a Luminex solid-phase bead assay at baseline and after 2, 3, and 6 months in the desensitized patients. There were 19 highly sensitized patients who received desensitization and 17 patients in the control group.
Deceased donor kidney transplantation was successfully performed in 8 patients Multivariate time-varying covariate Cox regression analysis showed that desensitization increased the probability of DDKT hazard ratio, Desensitization decreased mean fluorescence intensity values of class I panel reactive antibody by In addition, a liberal mismatch strategy in post hoc analysis increased the benefit of desensitization in donor-specific antibody reduction.
Desensitization was well tolerated, and acute rejection occurred only in the control group. In conclusion, a desensitization protocol using bortezomib , high-dose IVIG, and rituximab increased the DDKT rate in highly sensitized, wait-listed patients.
Abstract Combination therapy of intravenous immunoglobulin IVIG and rituximab showed a good transplant rate in highly sensitized wait-listed patients for deceased donor kidney transplantation DDKT , but carried the risk of antibody-mediated rejection.
Bortezomib is an antitumor drug that competitively inhibits proteasome beta-1 and beta-5 subunits. While the impact of bortezomib on protein stability is known, the effect of this drug on intracellular peptides has not been previously explored.
A quantitative peptidomics technique was used to examine the effect of treating human embryonic kidney T HEKT cells with 5— nM bortezomib for various lengths of time 30 minutes to 16 hours , and human neuroblastoma SH-SY5Y cells with nM bortezomib for 1 hour.
Although bortezomib treatment decreased the levels of some intracellular peptides, the majority of peptides were increased by 50— nM bortezomib. Peptides requiring cleavage at acidic and hydrophobic sites, which involve beta-1 and -5 proteasome subunits, were among those elevated by bortezomib. In contrast, the proteasome inhibitor epoxomicin caused a decrease in the levels of many of these peptides.
Although bortezomib can induce autophagy under certain conditions, the rapid bortezomib -mediated increase in peptide levels did not correlate with the induction of autophagy.
Taken together, the present data indicate that bortezomib alters the balance of intracellular peptides, which may contribute to the biological effects of this drug.
Six day cycles were planned. Thirty patients 7 with mantle cell lymphoma were enrolled and treated. Eight patients experienced serious adverse events, including one event of grade 5 sepsis. On the basis of these promising results, the US cooperative groups have initiated randomized trials to evaluate this regimen in follicular and mantle cell lymphoma.
This trial was registered at www. Light or Heavy Flow? Pads come in different sizes for heavier Naturally, if your period is heavy, you should change pads more often because they Sequential cyclophosphamide- bortezomib -dexamethasone unmasks the harmful cardiac effect of dexamethasone in primary light-chain cardiac amyloidosis.
The benefit is limited in patients with cardiac amyloidosis mainly because of adverse cardiac events. A new escalation-sequential regimen was set to improve the outcomes.
The results show that corticoids may destabilise the heart through fluid retention. Thus, a sequential protocol may be a promising approach to treat these patients. Multiple Myeloma MM is a haematologic malignancy characterized by the accumulation of clonal plasma cells in the bone marrow. Over the last y the introduction of the proteasome-inhibitor bortezomib has improved MM prognosis, however relapse due to bortezomib -resistance is inevitable and the disease, at present, remains incurable.
We identified enhanced Bruton's tyrosine kinase BTK activity in bortezomib -resistant MM cells and found that inhibition of BTK, either pharmacologically with ibrutinib 0. Over the last 10—15 y the introduction of the proteasome-inhibitor bortezomib has improved MM prognosis, however relapse due to bortezomib -resistance is inevitable and the disease, at present, remains incurable. Targeting the insulin-like growth factor-1 receptor to overcome bortezomib resistance in preclinical models of multiple myeloma.
Proteasome inhibition with bortezomib is a validated approach to the treatment of multiple myeloma, but drug resistance often emerges and limits its utility in the retreatment setting. Exogenous IGF-1 reduced cellular sensitivity to bortezomib , whereas pharmacologic or small hairpin RNA-mediated IGF-1R suppression enhanced bortezomib sensitivity in cell lines and patient samples.
In vitro studies with OSI, a clinically relevant dual IGF-1R and insulin receptor inhibitor, showed it acted synergistically with bortezomib , and potently resensitized bortezomib -resistant cell lines and patient samples to bortezomib. Importantly, OSI in combination with bortezomib also overcame bortezomib resistance in an in vivo model of myeloma.
Promising new drugs are being evaluated for treatment of multiple myeloma MM , but their impact should be measured against the expected outcome in patients failing current therapies. However, the natural history of relapsed disease in the current era remains unclear. The date patients satisfied the entry criteria was defined as time zero T0.
The median age at diagnosis was 58 years and time from diagnosis to T0 was 3. The median overall survival and event free survival from T0 were 9 and 5 months respectively. This study confirms the poor outcome once patients become refractory to current treatments.
The results provide context for interpreting ongoing trials of new drugs. Knuckle pads , first described by Garrod in , 1 are benign, asymptomatic, well- circumscribed, smooth, firm, skin colored papules, nodules, or plaques. They most commonly occur on the dorsal aspect of the proximal interphalangeal joint of the finger, 2 but also may occur on the dorsal aspects of the foot over joints. Neuropathy and efficacy of once weekly subcutaneous bortezomib in multiple myeloma and light chain AL amyloidosis.
Introduction Randomized studies have shown that bortezomib BTZ can be given weekly via intravenous IV route or twice weekly via subcutaneous SC route with lower neuropathy risk and no loss of anti-myeloma efficacy compared to original standard IV twice weekly schedule.
Weekly SC should therefore yield the best therapeutic index and is widely used but has not been compared to established administration schedules in the context of a clinical trial. Methods Comprehensive electronic medical record review was done for disease control and neuropathy symptoms of consecutive patients who received their first BTZ-containing regimen for myeloma or AL amyloidosis before or after we changed to SC weekly in December Univariate and multivariable analyses were carried out that adjusted for age, underlying disease, concurrently used anticancer agents, underlying conditions predisposing to neuropathy, and number of prior regimens compared SC weekly to other schedules.
Risk for neuropathy of any grade was higher with other schedules compared to SC weekly Multivariable analyses upheld higher neuropathy risk Odds ratio 2. Bortezomib induces apoptosis and suppresses cell growth and metastasis by inactivation of Stat3 signaling in chondrosarcoma. However, diverse antitumor mechanisms of bortezomib have been identified in many investigations and preclinical studies. Understanding the molecular and cellular mechanisms through which bortezomib acts will improve the therapeutic utility of this drug in different cancer types.
Bortezomib selectively inhibited cell growth in chondrosarcoma cells but not in normal articular cartilage cells. In addition to growth inhibition, apoptosis and cell cycle arrest, bortezomib triggered alleviation of migratory and invasive properties of chondrosarcoma cells. Accordingly, small interfering RNA siRNA -mediated Stat3 knockdown enhanced bortezomib -induced apoptosis, and concomitantly enhanced the inhibitory effect of bortezomib on cell viability, migration and invasion.
Together, inactivation of Stat3 signaling contributes to bortezomib -induced inhibition of tumor growth, migration and invation on chondrosarcoma. These beneficial effects can be explained by bortezomib -mediated Stat3 supression.
The present study suggests a promising therapeutics target in chondrosarcoma and probably in other kinds of metastatic malignant tumors. Abdominal wall fat pad biopsy. Amyloidosis - abdominal wall fat pad biopsy; Abdominal wall biopsy; Biopsy - abdominal wall fat pad The health care provider cleans the Bortezomib alters microtubule polymerization and axonal transport in rat dorsal root ganglion neurons. Bortezomib is part of a newer class of chemotherapeutic agents whose mechanism of action is inhibition of the proteasome-ubiquitination system.
There are no established useful preventative agents for bortezomib -induced peripheral neuropathy BIPN , and the molecular mechanisms of BIPN are unknown. We have developed an in vitro model of BIPN using rat dorsal root ganglia neuronal cultures. At clinically—relevant dosages, bortezomib produces a sensory axonopathy as evidenced by whole explant outgrowth and cell survival assays.
This sensory axonopathy is associated with alterations in tubulin and results in accumulation of somatic tubulin without changes in microtubule ultrastructure.
Furthermore, we observed an increased proportion of polymerized tubulin, but not total or acetylated tubulin, in bortezomib -treated DRG neurons. Similar findings are observed with lactacystin, an unrelated proteasome-inhibitor, which argues for a class effect of proteasome inhibition on dorsal root ganglion neurons. Finally, there is a change in axonal transport of mitochondria induced by bortezomib in a time-dependent fashion.
In summary, we have developed an in vitro model of BIPN that recapitulates the clinical sensory axonopathy; this model demonstrates that bortezomib induces an alteration in microtubules and axonal transport. This robust model will be used in future mechanistic studies of BIPN and its prevention. Cancerous inhibitor of protein phosphatase 2A determines bortezomib -induced apoptosis in leukemia cells. The multiple cellular targets affected by proteasome inhibition implicate a potential role for bortezomib , a first-in-class proteasome inhibitor, in enhancing antitumor activities in hematologic malignancies.
Here, we examined the antitumor activity and drug targets of bortezomib in leukemia cells. Human leukemia cell lines were used for in vitro studies. Drug efficacy was evaluated by apoptosis assays and associated molecular events assessed by Western Blot. Gene silencing was performed by small interference RNA. Drug was tested in vivo in xenograft models of human leukemia cell lines and in primary leukemia cells.
Clinical samples were assessed by immunohistochemical staining. Bortezomib differentially induced apoptosis in leukemia cells that was independent of its proteasome inhibition. Cancerous inhibitor of protein phosphatase 2A, a cellular inhibitor of protein phosphatase 2A, mediated the apoptotic effect of bortezomib. Furthermore, cancerous inhibitor of protein phosphatase 2A negatively regulated protein phosphatase 2A activity.
Importantly, bortezomib exerted in vivo antitumor activity in HL xenografted tumors and induced cell death in some primary leukemic cells.
Cancerous inhibitor of protein phosphatase 2A was expressed in leukemic blasts from bone marrow samples. Cancerous inhibitor of protein phosphatase 2A plays a major role in mediating bortezomib -induced apoptosis in leukemia cells. Some users either do not appreciate this or do not care and have been known to clock up rather large quarterly bills. This software package allows a system manager to determine who has used PAD to call where and most importantly how much it has cost. The system manager can then take appropriate action - either charging the individuals, warning them to use the facility with more care or even denying access to a greedy user to one or more sites.
Effectiveness of bortezomib in cardiac Al amyloidosis: Cardiac involvement is a major prognostic determinant in patients with primary AL amyloidosis. The clinical results of standard therapeutic approaches are suboptimal. It has been recently shown that bortezomib , an inhibitor of the proteasome, can induce rapid favourable responses in AL amyloidosis improving cardiac function and survival.
Herein we report on two patients with cardiac amyloidosis treated by bortezomib who experienced partial or total remission of hematologic disease and of cardiac involvement.
However, death of one patient, suffering from chronic kidney disease stage 5, due to fulminant respiratory syndrome suggests the need for caution in bortezomib use if patients have this comorbid condition. A Report of Two Cases. S Astronauts John W. Young left , pilot, and Virgil I.
Grissom, command pilot, for the Gemini-Titan 3 flight, are shown leaving the launch pad after simulations in the Gemini-3 spacecraft. Cellular homeostasis requires routine degradation of key regulatory proteins, including tumor suppressor gene products, transcription factors, cell-cycle proteins and their inhibitors, as well as damaged and misfolded proteins.
A critical part of this process is mediated by the 26S proteasome, a multi-subunit enzyme found in the nucleus and cytoplasm of all eukaryotic cells. Because of its essential role in many cellular processes controlling growth and survival, the proteasome has been identified as a potential target for cancer therapy. Drugs known to inhibit proteasome activity have been shown to induce cell-cycle arrest and programmed cell death apoptosis.
The impact of this finding is heightened by research showing that cancer cells are more sensitive to the proapoptotic effects of proteasome inhibition than normal cells. Preclinical evidence using bortezomib , the only proteasome inhibitor to enter clinical trials, suggests that proteasome inhibition may be effective in the treatment of hematologic and solid malignancies by promoting apoptosis, retarding angiogenesis, and inhibiting tumor cell adhesion and production of growth factors by acting on molecules such as nuclear factor-kappaB.
Further preclinical evidence suggests that the antitumor effects of cytotoxic chemotherapy or radiotherapy may be enhanced by the addition of a proteasome inhibitor. Bortezomib was recently approved for the treatment of multiple myeloma. It is currently being investigated, both as a single agent and in combination, in phase I and II trials in a variety of tumor types. Unlike conventional treatments for cancer, Bortezomib -induced acute pancreatitis: Case report and review of the literature.
Acute pancreatitis is a rare complication of chemotherapy agents. We describe the case of a patient with multiple myeloma who developed acute pancreatitis after treatment with bortezomib , a proteasome inhibitor commonly used in the treatment of this disease. We reviewed the available medical literature on this topic, and found other seven similar cases, all after intravenous bortezomib. Our case is the first one occurring with the subcutaneous route of administration. The possibility that cytokine administration could enhance the antitumor effects of proteasome inhibition was explored.
Patients were treated on a 5-week cycle. There was a treatment break during week 5. Bortezomib was administered in escalating doses 1. Sixteen patients were treated 8 women, 8 men; median age 59 y. Common grade 3 toxicities included fatigue 5 , vomiting 3 , and diarrhea 3. Grade 4 toxicities included fatigue 3 and lymphopenia 1. The maximum tolerated dose for bortezomib was 1. One patient had a partial response, and 7 had stable disease.
Progression-free survival was 2. With no FDA approved therapeutics available to treat RVFV infection, understanding the interactions between the virus and the infected host is crucial to developing novel therapeutic strategies. Using the FDA-approved proteasome inhibitor Bortezomib , we observed robust inhibition of intracellular and extracellular viral loads. In silico ubiquitination prediction analysis predicted that known NSs interactors SAP30, YY1, and mSin3A have multiple putative ubiquitination sites, while NSs itself was not predicted to be ubiquitinated.
Bortezomib treatment, however, resulted in increased ubiquitination of mSin3A, suggesting that Bortezomib dynamically affects the ubiquitination status of host proteins that interact with NSs.
Cancer immunotherapy shows great promise but many patients fail to show objective responses, including in cancers that can respond well, such as melanoma and renal adenocarcinoma. The proteasome inhibitor bortezomib sensitizes solid tumors to apoptosis in response to TNF-family death ligands. Because T cells provide multiple death ligands at the tumor site, we investigated the effects of bortezomib on T-cell responses in immunotherapy models involving low-avidity antigens.
Notably, bortezomib increased tumor cell surface expression of Fas in mice as well as human melanoma tissue from a responsive patient. Our findings highlight the potential of proteasome inhibitors to enhance antitumor T-cell function in the context of cancer immunotherapy.
Proteasome inhibitor bortezomib enhances the effect of standard chemotherapy in small cell lung cancer. Small cell lung cancer SCLC is an aggressive cancer showing a very poor prognosis because of metastasis formation at an early stage and acquisition of chemoresistance. One key driver of chemoresistance is the transcription factor Forkhead box protein M1 FOXM1 that regulates cell cycle proliferation, maintenance of genomic stability, DNA damage response, and cell differentiation in numerous tumor entities.
Both proteasome inhibitors successfully inhibited FOXM1 expression leading to a significantly reduced proliferation and a decreased mitotic rate along with cell cycle arrest and apoptosis induction. These effects were further enhanced by addition of bortezomib to standard chemotherapy. In conclusion, we demonstrate the effect of bortezomib in inhibiting FOXM1 expression and thus in sensitizing resistant SCLC cells to standard chemotherapy. Thus, addition of bortezomib to standard chemotherapy might potently improve SCLC therapy, particularly in an extensive cancer stage.
This image was acquired on the 3rd sol, or martian day, of Opportunity's mission Jan. The upper left image is a monochrome single filter image from the rover's panoramic camera, showing regions from which spectra were extracted from the 'Lily Pad ' area. As noted by the line graph on the right, the green spectra is from the undisturbed surface and the red spectra is from the airbag bounce mark. The orbiter is scheduled to fly the final mission of the Space Shuttle Program, launching on July 8.
The mortality rate among patients on hemodialysis HD is extremely high. Remaining life expectancy for a patient initiating HD is only approximately one quarter of that of the general population at the same age bracket.
The conventional HD regimen based on four-hour sessions three times a week was empirically established nearly four decades ago and needs to be revisited. Short daily HD and long nocturnal HD stand out as the most promising alternative regimens. Economical obstacles which could hinder the clinical application of emerging knowledge in the field should be overcome. GRP78 is also a member of the heat shock protein 70 gene family and induces tumor cell survival and resistance to chemotherapeutics.
Bortezomib is a highly specific 26S proteasome inhibitor that has been approved as treatment for patients with multiple myeloma. The present study first examined the dose- and time-dependent effects of bortezomib on GRP78 expression levels in the highly metastatic mouse breast cancer 4T1 cell line using western blot analysis.
The analysis results revealed that GRP78 levels were significantly increased by bortezomib at a dose as low as 10 nM. Time-dependent experiments indicated that the accumulation of GRP78 was initiated after a 24 h incubation period following the addition of 10 nM bortezomib. Overall, the present results suggest that bortezomib and BAPTA-AM combination therapy may be a novel therapeutic strategy for breast cancer treatment.
Hilderbrand has been working for the space program since Bortezomib -related neuropathy may mask CNS relapse in multiple myeloma: A call for diligence. Neuropathy is a common adverse effect of bortezomib. Isolated central nervous system CNS relapse in MM remains exceedingly rare and carries a dismal prognosis. A year-old female was diagnosed with standard-risk MM with clinical and cytogenetic features not typically associated with CNS involvement.
Six months after ASCT she developed symptoms suggestive of peripheral neuropathy which was attributed to bortezomib. However the symptoms persisted despite discontinuation of bortezomib. Imaging and cerebrospinal fluid analysis subsequently confirmed a CNS relapse. Recently published literature has reported biomarkers with prognostic potential. However, isolated CNS relapse is even less common; an event which carries a very poor prognosis.
Given the heterogeneous neurologic manifestations associated with MM, clinical suspicion may be masked by confounding factors such as bortezomib -based therapy.
The disease may further remain incognito if the patient does not exhibit any of the high risk features and biomarkers associated with CNS involvement. This case further highlights the need for more robust biomarkers to predict CNS relapse and use of newer novel agents which demonstrate potential for CNS penetration.
Bortezomib reverses the proliferative and antiapoptotic effect of neuropeptides on prostate cancer cells. Neuropeptides are important signal initiators in advanced prostate cancer, partially acting through activation of nuclear factor kappa B.
Central to nuclear factor kappa B regulation is the ubiquitin-proteasome system, pharmacological inhibition of which has been proposed as an anticancer strategy. We investigated the putative role of the proteasome inhibitor bortezomib in neuropeptides signaling effects on prostate cancer cells.
Furthermore, 20S proteasome activity, subcellular localization of nuclear factor kappa B and transcription of nuclear factor kappa B target genes, interleukin-8 and vascular endothelial growth factor, were assessed. Neuropeptides endothelin-1, bombesin increased cell proliferation, whereas bortezomib decreased proliferation and induced apoptosis, an effect maintained after cotreatment with neuropeptides. Bad, p53, p21 and p27 were downregulated by neuropeptides in PC-3, and these effects were reversed with the addition of bortezomib.
Neuropeptides increased proteasomal activity and nuclear factor kappa B levels in PC-3, and these effects were prevented by bortezomib. Interleukin-8 and vascular endothelial growth factor transcripts were induced after neuropeptides treatment, but downregulated by bortezomib.
These results coincided with the ability of bortezomib to reduce mitogen-activated protein kinase signaling in both cell lines. These findings are consistent with bortezomib -mediated abrogation of neuropeptides-induced proliferative and antiapoptotic signaling. Thus, the effect of the drug on the neuropeptides axis needs to be further investigated, as neuropeptide action in prostate cancer might entail involvement of the proteasome.
Phase 2 randomized study of bortezomib -melphalan-prednisone with or without siltuximab anti—IL-6 in multiple myeloma. Because interleukin-6 IL-6 is considered important in the proliferation of early multiple myeloma MM , we hypothesized that the addition of the anti-IL-6 monoclonal antibody siltuximab to the bortezomib -melphalan-prednisone VMP regimen would improve outcomes in transplant-ineligible patients with newly diagnosed MM.
Baseline characteristics were well balanced except for immunoglobulin A subtype and 17p deletions. Maintenance therapy with siltuximab was well tolerated. This study was registered at http: However, its favorable therapeutic and safety profile, and the prognostic role of pre-transplant PET negativity in patients receiving IGEV-based regimens are confirmed.
Phase I trial of bortezomib and dacarbazine in melanoma and soft tissue sarcoma. Preclinical studies in human melanoma cell lines and murine xenograft tumor models suggest that the proteasome inhibitor bortezomib enhances the activity of the cytotoxic agent dacarbazine. We performed a phase I trial of bortezomib and dacarbazine in melanoma, soft tissue sarcoma, and amine precursor uptake and decarboxylation tumors.
The primary objective was to identify recommended phase II doses for the combination. Bortezomib and dacarbazine were both administered intravenously once weekly.
All patients received prophylactic antiemetics. Twenty eight patients were enrolled to six dose levels. The combination was generally well tolerated.
Among 15 patients with melanoma there was one durable complete response in a patient with an exon cKIT mutation, and one partial response. Among 12 patients with soft tissue sarcoma there was one partial response.
An international, multicenter phase II trial of bortezomib in patients with hepatocellular carcinoma. This phase II study evaluated the activity and tolerability of bortezomib in unresectable hepatocellular carcinoma HCC patients. The primary endpoint was confirmed tumor response rate RR with secondary endpoints including duration of response, time to disease progression, survival and toxicity.
Treatment consisted of bortezomib , 1. Thirty-five patients enrolled and received a median of 2 cycles of treatment range Overall, 24 and 4 patients had a maximum severity of grade 3 and 4 adverse events AEs , respectively.
No treatment related deaths occurred. One patient achieved a partial response, lasting 13 weeks during treatment and progressed Median time-to-progression was 1.
This international, multicenter trial evaluated bortezomib as monotherapy in unresectable HCC patients. And, despite the lack of significant activity, this report serves as a baseline clinical experience for the development of future dual biologic approaches including bortezomib. Outcome measures included quantitative muscle morphology, gene and miRNA expression analyses, proteasome activity, motor activity, and survival.
In addition, bortezomib reduced proteasome activity in congenital muscular dystrophy type 1A myoblasts and myotubes. Investigation of the clinical efficacy of bortezomib administration in congenital muscular dystrophy type 1A clinical trials may be warranted. Published by Elsevier Inc. Use of bortezomib in heavy-chain deposition disease: Heavy-chain deposition disease HCDD is a rare complication of plasma cell dyscrasia in which monoclonal heavy chains deposit in glomerular and tubular basement membranes of the kidney.
Clinical and pathologic features of HCDD have been well described in case reports and series, but evidence supporting specific therapies is sparse.
Historically, the disease has had a poor prognosis, intensifying the need to clarify optimal treatments. We describe 3 cases of HCDD with biopsy-proven glomerular involvement, severe nephrotic syndrome, and decline in kidney function that were treated successfully with bortezomib , a proteasome inhibitor.
None of these patients had multiple myeloma. In all cases, bortezomib -based therapy resulted in sustained resolution of nephrotic syndrome and improvement in kidney function. All 3 patients developed peripheral neuropathy; otherwise, treatment was well tolerated. To our knowledge, this is the first description of the clinical effectiveness of bortezomib against HCDD.
Venetoclax is a selective, orally bioavailable small-molecule BCL-2 inhibitor; bortezomib can indirectly inhibit MCL In preclinical studies, venetoclax enhanced bortezomib activity, suggesting that cotargeting of BCL-2 and MCL-1 could be an effective treatment strategy in myeloma.
A total of 66 patients were enrolled 54 in the dose-escalation cohorts and 12 in the safety expansion. Median time to progression and duration of response were 9. Meta-analysis of incidence and risk of peripheral neuropathy associated with intravenous bortezomib. Bortezomib is a proteasome inhibitor which has demonstrated activity against recurrent or newly diagnosed multiple myeloma MM and mantle cell lymphoma. Peripheral neuropathy has been described with this agent, although the overall incidence and relative risk remain unclear.
We performed a meta-analysis to calculate the incidence of peripheral neuropathy associated with the use of intravenous bortezomib in MM and lymphoma and to compare the relative risk compared with placebo. Eligible studies included prospective phase 2 and 3 clinical trials with toxicity profile on peripheral neuropathy associated with intravenous bortezomib in patients with MM and lymphoma.
Altogether, 34 clinical trials were selected for the meta-analysis, yielding a total of patients. The incidence of peripheral neuropathy all grades was Our analysis was also stratified by different underlying diseases, and patients with lymphoma had an increased incidence of all-grade peripheral neuropathy than those with MM when treated with intravenous bortezomib. Treatment with intravenous bortezomib is associated with an increased risk of developing peripheral neuropathy.
Morpheus Launch Pad Move. The launch pad is being moved to a different location to support the next phase of flight testing. Morpheus completed its seventh free flight test on March The second test began at 3: EDT with the Morpheus lander launching from the ground over a flame trench and ascending to feet. Morpheus then flew its fastest downrange trek at 30 mph, travelling farther than before, feet. The lander performed a foot divert to emulate a hazard avoidance maneuver before descending and touching down on Landing Site 2, at the northern landing pad inside the automated landing and hazard avoidance technology ALHAT hazard field.
Morpheus landed within one foot of its intended target. The landing facility provides the lander with the kind of field necessary for realistic testing, complete with rocks, craters and hazards to avoid.
The efforts in AES pioneer new approaches for rapidly developing prototype systems, demonstrating key capabilities and validating operational concepts for future human missions beyond Earth orbit. For more information on Project Morpheus, visit http: The launch pad is being moved to a different location at the landing facility to support the next phase of flight testing. The launch pad was moved to a different location to support the next phase of flight testing. The launch pad will be moved to a different location at the landing facility to support the next phase of flight testing.
The seventh free flight test of Morpheus occurred on March This film covers both the Big Joe and a Little Joe Project Mercury flight test with a research and development version of the Mercury capsule. Big Joe was an Atlas missile that successfully launched a boilerplate model of the Mercury capsule on September 9, The scenes include coverage of the assembly and erection of the boosters, delivery of the capsules, mating of the capsules to the boosters, prelaunch views of the capsule and boosters on launchers, mission control, the launches, and recovery.
We investigated the procoagulant effects of lenalidomide Len -based regimens in vitro focusing on tissue factor TF and phosphatidylserine PS.
We examined the effects of a pharmacological concentration of Len with or without the corticosteroid dexamethasone Dex and the proteasome inhibitor bortezomib Bor using the human vascular endothelial cell line EAhy and the monocytic cell lines THP-1 and U Cell-surface procoagulant activity PCA was induced by Dex-containing regimens in all lines.
PS exposure was increased modestly by a Len-based regimen. Activation of coagulation by lenalidomide-based regimens for the treatment of multiple myeloma. A Bim-targeting strategy overcomes adaptive bortezomib resistance in myeloma through a novel link between autophagy and apoptosis. Bim contributes to resistance to various standard and novel agents.
Whereas short hairpin RNA Bim knockdown conferred bortezomib resistance in Bim hi cells, adaptive bortezomib -resistant cells displayed marked Bim downregulation. These events were correlated with Bim-associated autophagy attenuation, whereas Bim knockdown sharply increased autophagy in Bim hi cells.
Thus, Bim deficiency represents a novel mechanism of adaptive bortezomib resistance in MM cells, and Bim-targeting strategies combining HDACIs which upregulate Bim and BH3 mimetics which unleash Bim from antiapoptotic proteins overcomes such resistance, in part by disabling cytoprotective autophagy. Whereas short hairpin RNA Bim knockdown conferred bortezomib resistance in Bimhi cells, adaptive bortezomib -resistant cells displayed marked Bim downregulation.
These events were correlated with Bim-associated autophagy attenuation, whereas Bim knockdown sharply increased autophagy in Bimhi cells. Preferential cytotoxicity of bortezomib toward highly malignant human liposarcoma cells via suppression of MDR1 expression and function. Liposarcoma is the most common soft tissue sarcoma with a high risk of relapse. Few therapeutic options are available for the aggressive local or metastatic disease. Here, we report that the clinically used proteasome inhibitor bortezomib exhibits significantly stronger cytotoxicity toward highly malignant human liposarcoma SWS cells compared with its parental SW cells, which is accompanied by enhanced activation of apoptotic signaling both in vitro and in vivo.
Treatment of cells with Jun-N-terminal kinase JNK inhibitor SP or the translation inhibitor cycloheximide ameliorated this enhanced apoptosis. These results show that bortezomib exhibits preferential cytotoxicity toward SWS cells possibly via highly expressed SERCA2-associated MDR1 suppression and suggest that bortezomib may serve as a potent agent for treating advanced liposarcoma. Superiority of bortezomib , thalidomide, and dexamethasone VTD as induction pretransplantation therapy in multiple myeloma: Patients with high-risk cytogenetics had a shorter PFS and overall survival in the overall series and in all treatment groups.
In conclusion, VTD resulted in a higher pre- and posttransplantation CR rate and in a significantly longer PFS although it was not able to overcome the poor prognosis of high-risk cytogenetics. The study was registered with http: Managing Complex Medication Regimens.
This article is the first in a series, Supporting Family Caregivers: Results of focus groups conducted as part of the AARP Public Policy Institute's No Longer Home Alone video project supported evidence that family caregivers aren't being given the information they need to manage the complex care regimens of their family members.
This series of articles and accompanying videos aims to help nurses provide caregivers with the tools they need to manage their family member's medications. Each article explains the principles nurses should consider and reinforce with caregivers and is accompanied by a video for the caregiver to watch. The first video can be accessed at http: Results of focus groups conducted as part of the AARP Foundation's No Longer Home Alone video project supported evidence that family caregivers aren't being given the information they need to manage the complex care regimens of their family members.
Sixteen patients entered the trial, 4 had gastric MALT-lymphoma, 7 of the ocular adnexa, one of the colon, and 2 of the parotid, and one patient each the lung and the breast. There is a perception that cannabis may affect disease course in MS Consroe et al. Cannabinoids for the control of experimental multiple sclerosis. It is raised, however, that the cannabinoids may also induce or exacerbate such symptoms as spasticity, ataxia or muscle debilitation, and the adverse effects are very frequent.
In multiple sclerosis patients, cannabis brings improvement of depression and anxiety . Cannabinoids have anxiolytic, sedative and a soporific activity, which may be valuable, as many patients with advanced cancer tend to have adaptation disorders, such as depression or anxiety.
A Review of the Evidence. There is an increased interest in the use of cannabinoids in the treatment of symptoms in cancer and palliative care patients. Their multimodal action, in spite of limited efficacy, may make them an attractive alternative, particularly in patients with multiple concomitant symptoms of mild and moderate intensity.
There is evidence to indicate cannabis in the treatment of pain, spasticity, seizures, sleep disorders, nausea and vomiting, and Tourette syndrome. Although the effectiveness of cannabinoids is limited, it was confirmed in neuropathic pain management and combination with opioids.
A relatively favorable adverse effects profile, including no depressive effect on the respiratory system, may make cannabis complement a rather narrow armamentarium that is in the disposition of a palliative care professional. The results of these studies were cited in the AAN review.
Review of the neurological benefits of phytocannabinoids. Background Numerous physical, psychological, and emotional benefits have been attributed to marijuana since its first reported use in 2, BC in a Chinese pharmacopoeia. Through direct and indirect actions, intrinsic endocannabinoids and plant-based phytocannabinoids modulate and influence a variety of physiological systems influenced by the ECS.
Methods In , Cunha et al. Since then neurological applications have been the major focus of renewed research using medical marijuana and phytocannabinoid extracts.
Results Recent neurological uses include adjunctive treatment for malignant brain tumors, Parkinson's disease, Alzheimer's disease, multiple sclerosis, neuropathic pain, and the childhood seizure disorders Lennox-Gastaut and Dravet syndromes. In addition, psychiatric and mood disorders, such as schizophrenia, anxiety, depression, addiction, postconcussion syndrome, and posttraumatic stress disorders are being studied using phytocannabinoids.
We will emphasize the neuroprotective, antiinflammatory, and immunomodulatory benefits of phytocannabinoids and their applications in various clinical syndromes. The Cannabis is constituted by compounds with therapeutic properties, obsered in distinct contexts.
Some Cannabis-based products are already available in the international market, and here we will highlight those already in use, which are supported by solid scientific evidence, including phytocannabinoids, synthetic cannabinoids and herbal extracts. The biggest challenge is to balance the beneficial effects of Cannabis and the potential adverse effects, which may happen after chronic high-dose use.
Despite the equivalente efficacy, smoked Cannabis is not well tolerated by patients without previous recreative use.
On the other hand, the herbal product is preferred by recreative users that become patients. In this case, one should vaporize the plant, to avoid the harms caused by the smoke. Considering cost-effectiveness, therapeutic efficacy and quality control, the standardized herbal extracts seem to be the best option, so far available. In fact , the rela - tion of cannabinoids with MS is not new and has its origin in the late s and early s when it was evident that MS patients frequently self - medicated with illegal cannabis to alleviate pain , spasticity , sleep disturbance and other specific MS symptoms Consroe et al.
This anecdotal evidence was extensively investigated , with the generation of solid pre - clinical Baker et al. In fact, the relation of cannabinoids with MS is not new and has its origin in the late s and early s when it was evident that MS patients frequently self-medicated with illegal cannabis to alleviate pain, spasticity, sleep disturbance and other specific MS symptoms Consroe et al.
This anecdotal evidence was extensively investigated, with the generation of solid preclinical Baker et al. However, further evidence suggest that it could be also active as disease-modifying therapy given the immunomodulatory, anti-inflammatory and cytoprotective properties of their two major components.
In this study, we investigated this potential in the experimental autoimmune encephalitis EAE model of MS in mice. Treatments were initiated at the time that symptoms appear and continued up to the first relapse of the disease.
The results show that the treatment with a Sativex-like combination significantly improved the neurological deficits typical of EAE mice, in parallel with a reduction in the number and extent of cell aggregates present in the spinal cord which derived from cell infiltration to the CNS.
With the advent of the internet, use of CAM can be widely publicised and adopted even before scientific evidence can support or refute the claims of efficacy.
Indeed PwMS perceived benefit from taking cannabis for the control of sleep disturbances, pain and spasticity Consroe et al. This was subsequently supported by biology, experimental and clinical class I evidence in humans to support the role of cannabinoid control of spasticity and pain in PwMS Baker et al. Multiple sclerosis MS is the major immune-mediated, demyelinating, neurodegenerative disease of the central nervous system.
However, the biology indicates that the endocannabinoid system may offer the potential to control other aspects of disease. Although there is limited evidence that the cannabinoids from cannabis are having significant immunosuppressive activities that will influence relapsing autoimmunity, we and others can experimentally demonstrate that they may limit neurodegeneration that drives progressive disability.
Here we show that synthetic cannabidiol can slow down the accumulation of disability from the inflammatory penumbra during relapsing experimental autoimmune encephalomyelitis EAE in ABH mice, possibly via blockade of voltage-gated sodium channels. They also appear to slow down clinical progression during MS in humans. Patients have also reported previously irrelevant visual patterns to become potent distracters after the intravenous injection of THC in a study relating the CB system with psychosis D' Souza et al.
Cannabinoid CB receptors are widely distributed through the central nervous system, where they play a relevant role in various cognitive processes such as learning, memory, or attention.
However, despite the distortion in sensory perception caused by cannabis, it has not been until recently that the effect of CB activation on visual physiology and pathophysiology has been studied in detail. These studies reflect a critical role for CB in visual perception, modulating not only the processing of visual information by the retina, but also further processing and computation of visual signals by the thalamus and cortex. Interestingly, activation of cannabinoid receptors in therapies can result in some cases in an improvement of visual function.
Administration of AEA to HD rats caused hypokinesia and decreased nigrostriatal dopaminergic activity, but this effect was mediated through activation of vanilloid-like receptor rather than CB1R de Lago et al. Cannabis sativa and its components have been shown to provide protection against many movement disorders, such as tremor Gapen ;Clifford ; Consroe et al. However, in several clinical trials, cannabinoids failed to provide protection against HD.
Endocannabinoid System in Neurodegenerative Disorders. Jun J Neurochem. Most neurodegenerative disorders NDDs are characterized by cognitive impairment and other neurological defects. The definite cause of and pathways underlying the progression of these NDDs are not well defined. Several mechanisms have been proposed to contribute to the development of NDDs.
These mechanisms may proceed concurrently or successively, and they differ among cell types at different developmental stages in distinct brain regions. The endocannabinoid system, which involves cannabinoid receptors type 1 CB1R and type 2 CB2R , endogenous cannabinoids and the enzymes that catabolize these compounds, has been shown to contribute to the development of NDDs in several animal models and human studies.
In this review, we discuss the functions of the endocannabinoid EC system in NDDs and converse the therapeutic efficacy of targeting the endocannabinoid system to rescue NDDs.
This article is protected by copyright. Higher doses of THC can produce side efects, including blur vision , double vision, and vision dimness . Numerous reports claim that smoking marijuana improves dim light vision . Although the ability of cannabinoids to suppress signs and symptoms of multiple sclerosis MS are in line with some traditional medical applications of cannabis, the claims from MS patients about the benefits of self-medicating with cannabis promoted the study of cannabinoids for such indications .
The first studies made by Lyman and collaborators indicated that THC may reduce the signs of experimental autoimmune encephalomyelitis EAE and delay the progression into generalized atonia to death . Modern Medicines Derived from Cannabis. There is much anecdotal evidence that patients self-medicate with marijuana with the intention of palliating pain, tremor, spasticity, ataxia, and other symptoms associated with MS, an autoimmune disease typified by demyelination and remyelination, and associated with neuroaxonal damage and inflammation [67, 69, 85, 86].
More recent controlled studies, both in animal models of MS and in humans, have begun to validate these preclinical and uncontrolled observations. Cannabinoids and Tremor Induced by Motor-related Disorders: In the wake of anecdotal, largely uncontrolled, observations claiming the amelioration of some symptoms among cannabis smokers, and the high density of cannabinoid receptors in the areas responsible for motor function, including basal ganglia and cerebellum, many researchers have pursued the question of whether cannabinoid-based compounds could be used therapeutically to alleviate tremor associated with central nervous system diseases.
In this review, we focus on possible effects of cannabinoid-based medicines, in particular on Parkinsonian and multiple sclerosis-related tremors and the common probable molecular mechanisms. While, at present, inconclusive results have been obtained, future investigations should extend preclinical studies with different cannabinoids to controlled clinical trials to determine potential benefits in tremor. Phytocannabinoid use in management of multiple sclerosis MS symptoms Consroe et al.
MS, a demyelinating disease characterized by persistent neuroinflammation and progressive central nervous system CNS demyelination Kutzelnigg and Lassmann, , is only one of many demyelinating neurodegenerative diseases involving oligodendrocytes, the myelinating cells of the CNS.
Cannabinoid-based interventions are being explored for central nervous system CNS pathologies such as neurodegeneration, demyelination, epilepsy, stroke, and trauma. In this review, we examine research reports on the effects of the endocannabinoid system ECS components on oligodendrocytes and their precursors, with a focus on therapeutic implications. Cannabinoid ligands and modulators of the endocannabinoid system promote cell signaling in oligodendrocyte precursor survival, proliferation, migration and differentiation, and mature oligodendrocyte survival and myelination.
CB1 receptors in radial glia promote proliferation and conversion to progenitors fated to become oligodendroglia, whereas CB2 receptors promote OPC migration in neonatal development. OPCs produce 2-arachidonoylglycerol 2-AG , stimulating cannabinoid receptor-mediated ERK pathways responsible for differentiation to arborized, myelin basic protein MBP -producing oligodendrocytes.
In cell culture models of excitotoxicity, increased reactive oxygen species, and depolarization-dependent calcium influx, CB1 agonists improved viability of oligodendrocytes. In transient and permanent middle cerebral artery occlusion models of anoxic stroke, WIN increased OPC proliferation and maturation to oligodendroglia, thereby reducing cerebral tissue damage.
In several models of rodent encephalomyelitis, chronic treatment with cannabinoid agonists ameliorated the damage by promoting OPC survival and oligodendrocyte function. Pharmacotherapeutic strategies based upon ECS and oligodendrocyte production and survival should be considered.
Canna- bis users have consistently reported anecdotal evidence for symptom improvement, although the proportion reporting benefit has varied widely. Clinical trials of medicinal cannabis for appetite-related symptoms from advanced cancer: A survey of preferences, attitudes and beliefs among patients willing to consider participation.
Aug Intern Med J. Background Australian clinical trials are planned to evaluate medicinal cannabis in a range of clinical contexts. AimsTo explore the preferences, attitudes and beliefs of patients eligible and willing to consider participation in a clinical trial of medicinal cannabis for poor appetite and appetite-related symptoms from advanced cancer. Survey items focused on medicinal rather than recreational cannabis use and did not specify botanical or pharmaceutical products.
Items asked about previous medicinal cannabis use and preferences for delivery route and invited comments and concerns. Six respondents volunteered a belief that cannabis might cure cancer, while two wanted assurance of efficacy before participating in a trial. Cannabinoids, a heterogenous group of endogenous molecules and others that are metabolites of phytocannabinoids , have been reported to improve tremor and spasticity in animal models  and questionnaire-based reports have suggested beneficial effects of recreational cannabis use in patients with MS who have NLUTD .
Cannabinoids are presumed to reduce detrusor contractility via cannabinoid receptors [7,8] expressed both in the detrusor and CNS ; however, cannabinoid-mediated actions on lower urinary tract function are complex and not yet fully understood. Cannabinoids for treating neurogenic lower urinary tract dysfunction in patients with multiple sclerosis: A systematic review and meta-analysis.
Jan BJU Int. To systematically review all available evidence on efficacy and safety of cannabinoids for treating neurogenic lower urinary tract dysfunction NLUTD in patients with multiple sclerosis MS. Studies were identified by electronic search of Cochrane register, Embase, Medline, Scopus last search on 11 November After screening articles, two randomized controlled trials and one open label study enrolling a total of patients, were included. Cannabinoids relevantly decreased incontinence episodes in all three studies.
Pooling data showed mean difference in incontinence episodes per 24 hours to be However, evidence base is poor and more high-quality, well-designed, adequately powered and sampled studies are urgently needed to reach definitive conclusions. Prevalence, Predictors, Pharmacology and Psychopharmacology. This is a brief review of polydrug use the simultaneous or concurrent usage of more than one drug.
Reviewed areas are listed below. As a result of its nature and structure, this review provides a superficial yet wide-ranging review of polydrug use as a behavioural and psychological phenomenon, covering an extensive body of research spanning decades.
Identifying and discussing the populations that exhibit these particular behaviours, and discriminating between populations that use one drug from another.
Identifying and discussing some of the risk factors and at-risk populations for polydrug use, especially problematic use. Examining research into the effects of combining multiple drugs on the body.
Pharmacodynamics and pharmacokinetics are discussed but not specified. Examining research into the effects of combining multiple drugs on behaviour, cognition and psychopathology, and the mechanisms behind these effects. Different reports have showed that cannabinoids can affect uterine and bladder motility . It has been reported that cannabis can improve nocturia, bladder hyperactivity, and pain in MS patients .
Cannabinoid-1 receptors CB1 have been found in mouse urinary bladder as well as terminals of peripheral sensory afferent and sympathetic fibers [95,96], which can reduce bladder motility when activated .
Pharmacological treatments available for the management of underactive bladder in neurological conditions. Dec Expet Rev Clin Pharmacol. Underactive bladder UAB is a common cause of lower urinary tract dysfunction which has an increasing incidence with aging. UAB is observed in both men and women. The exact definition, classification, and pathophysiological mechanism responsible for UAB is still debatable, however neurologic, myogenic, and iatrogenic causes are explained. The symptom complex related to UAB includes hesitancy, diminished sensation of bladder filling, a slow urinary stream, increased post-void residue, and etc.
We reviewed the current understanding of UAB with special focus on pharmacological treatments and potential pharmacotherapy options particularly in neurological conditions.
Also, the definition, etiology, symptoms, diagnosis and management of UAB were discussed in this review. The underlying mechanism of UAB is not clear yet.
Therefore; the lack of efficient pharmacotherapies is evident in such patients. Prior to any decision for pharmacological or surgical interventions, the underlying causes of UAB and detrusor impairment in each patient should be distinguished. Future researches need to address the exact dynamics of detrusor contraction and the muscular and neurological contributors to UAB.
In a double-blind crossover study of a single MS patient, nabilone treatment improved muscle spasms, nocturia, and general well-being . Although these encouraging reports have triggered numerous larger, population-based clinical trials of cannabis-based medicines in MS, mixed results have been reported   . Neuroprotection by Cannabinoids in Neurodegenerative Diseases. Publications detailing this headache, migraine, and facial pain literature, as well as described mechanisms of pain relief with cannabis and cannabinoids are available and should be reviewed, but are beyond the scope of this paper [1,2,28,51,65].
Patterns of medicinal cannabis use, strain analysis, and substitution effect among patients with migraine, headache, arthritis, and chronic pain in a medicinal cannabis cohort. Background Medicinal cannabis registries typically report pain as the most common reason for use.
It would be clinically useful to identify patterns of cannabis treatment in migraine and headache, as compared to arthritis and chronic pain, and to analyze preferred cannabis strains, biochemical profiles, and prescription medication substitutions with cannabis. Methods Via electronic survey in medicinal cannabis patients with headache, arthritis, and chronic pain, demographics and patterns of cannabis use including methods, frequency, quantity, preferred strains, cannabinoid and terpene profiles, and prescription substitutions were recorded.
Results Of patients, 21 illnesses were treated with cannabis. Pain syndromes accounted for Across all 21 illnesses, headache was a symptom treated with cannabis in Many pain patients substituted prescription medications with cannabis Conclusions Chronic pain was the most common reason for cannabis use, consistent with most registries. The majority of headache patients treating with cannabis were positive for migraine.
Prospective studies are needed, but results may provide early insight into optimizing crossbred cannabis strains, synergistic biochemical profiles, dosing, and patterns of use in the treatment of headache, migraine, and chronic pain syndromes. Cannabinoids have been reported to be helpful in reducing the symptoms of MS. For in- stance, patients with spasticity arising due to degradation of myelin and nerve fibers  claimed improvement in their condition upon in- haling cannabis and upon receiving escalating doses of THC  Symptoms like ataxia , tremors, chronic pain in extremities, an- orexia, double vision, sexual dysfunctions etc were also reduced upon marijuana smoking .
Therapeutic applications of cannabinoids. The psychoactive property of cannabinoids is well known and there has been a continuous controversy regarding the usage of these compounds for therapeutic purposes all over the world. Their use for medical and research purposes are restricted in various countries. However, their utility as medications should not be overshadowed by its negative physiological activities. This review article is focused on the therapeutic potential and applications of phytocannabinoids and endocannabinoids.
We further highlights their mode of action, overall effects on physiology, various in vitro and in vivo studies that have been done so far and the extent to which these compounds can be useful in different disease conditions such as cancer, Alzheimer's disease, multiple sclerosis, pain, inflammation, glaucoma and many others.
Thus, this work is an attempt to make the readers understand the positive implications of these compounds and indicates the significant developments of utilizing cannabinoids as therapeutic agents. Sativex is licensed for this indication in patients with multiple sclerosis. Cannabinoids and the Urinary Bladder. The study was approved by the institutional review boards, and all the participating patients agreed to answer questions by telephone. The design of the structured questionnaire was based on the published MC surveys in multiple sclerosis 4 and PD.
Medical Cannabis in Parkinson Disease: The use of medical cannabis MC is controversial. Support for its benefits is based on small clinical series.
The aim of this study was to report the results of a standardized interview study that retrospectively assessed the effects of MC on symptoms of Parkinson disease PD and its adverse effects in patients treated for at least 3 months.
Forty-seven nondemented patients with PD 40 men participated. Their mean age was The duration of MC use was The delivery of MC was mainly by smoking cigarettes 38 cases, Effect size r improvement for falls was 0.
The most frequently reported adverse effects from MC were cough Medical cannabis was found to improve symptoms of PD in the initial stages of treatment and did not cause major adverse effects in this pilot, 2-center, retrospective survey.
The extent of use and the reported effects lend support to further development of safer and more effective drugs derived from Cannabis sativa. Cannabinoid System Contribution to Control Micturition. Cannabinoid compounds, such as those that can be extracted from the Cannabis sativa plant marijuana , produce a very wide array of central and peripheral effects, some of which may be of importance for the control of lower urinary tract function. Thus, stimulation of cannabinoid receptors, located both in the central nervous system and in different components of the lower urinary tract, has been shown to affect both normal micturition and various disturbances of bladder function.
It is clear that systemically administered cannabinoids may be able to become clinically useful; however, a much greater understanding of the mechanisms of cannabinoid receptors in the control of the human lower urinary tract is necessary to facilitate development of novel cannabinoid drugs for the treatment of micturition disorders such as overactive bladder syndrome.
The use of cannabis, or marijuana, for medicinal purposes is deeply rooted though history, dating back to ancient times. It once held a prominent position in the history of medicine, recommended by many eminent physicians for numerous diseases, particularly headache and migraine. Through the decades, this plant has taken a fascinating journey from a legal and frequently prescribed status to illegal, driven by political and social factors rather than by science.
The Perceived Effects of Smoked Cannabis on Patients with Multiple Sclerosis