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Cancer Cell Oct 2022Glioblastoma (GBM) is poorly responsive to therapy and invariably lethal. One conceivable strategy to circumvent this intractability is to co-target distinctive...
Glioblastoma (GBM) is poorly responsive to therapy and invariably lethal. One conceivable strategy to circumvent this intractability is to co-target distinctive mechanistic components of the disease, aiming to concomitantly disrupt multiple capabilities required for tumor progression and therapeutic resistance. We assessed this concept by combining vascular endothelial growth factor (VEGF) pathway inhibitors that remodel the tumor vasculature with the tricyclic antidepressant imipramine, which enhances autophagy in GBM cancer cells and unexpectedly reprograms immunosuppressive tumor-associated macrophages via inhibition of histamine receptor signaling to become immunostimulatory. While neither drug is efficacious as monotherapy, the combination of imipramine with VEGF pathway inhibitors orchestrates the infiltration and activation of CD8 and CD4 T cells, producing significant therapeutic benefit in several GBM mouse models. Inclusion up front of immune-checkpoint blockade with anti-programmed death-ligand 1 (PD-L1) in eventually relapsing tumors markedly extends survival benefit. The results illustrate the potential of mechanism-guided therapeutic co-targeting of disparate biological vulnerabilities in the tumor microenvironment.
Topics: Animals; Antidepressive Agents, Tricyclic; Autophagy; B7-H1 Antigen; Glioblastoma; Imipramine; Immune Checkpoint Inhibitors; Immunotherapy; Macrophages; Mice; Neoplasm Recurrence, Local; Programmed Cell Death 1 Receptor; Tumor Microenvironment; Vascular Endothelial Growth Factor A
PubMed: 36113478
DOI: 10.1016/j.ccell.2022.08.014 -
Alzheimer's Research & Therapy Jun 2022The apolipoprotein E (APOE) ε4 allele confers the strongest risk for late-onset Alzheimer's disease (AD) besides age itself, but the mechanisms underlying this risk are...
BACKGROUND
The apolipoprotein E (APOE) ε4 allele confers the strongest risk for late-onset Alzheimer's disease (AD) besides age itself, but the mechanisms underlying this risk are debated. One hypothesis supported by evidence from multiple labs is that apoE4 binds to the amyloid-β (Aβ) peptide and catalyzes its polymerization into neurotoxic oligomers and fibrils. Inhibiting this early step in the amyloid cascade may thereby reduce or prevent neurodegeneration and AD.
METHODS
Using a design of experiments (DOE) approach, we developed a high-throughput assay to identify inhibitors of apoE4-catalyzed polymerization of Aβ into oligomers and fibrils. We used it to screen the NIH Clinical Collection of small molecule drugs tested previously in human clinical trials. We then evaluated the efficacy and cytotoxicity of the hit compounds in primary neuron models of apoE4-induced Aβ and phosphorylated tau aggregation. Finally, we performed retrospective analyses of the National Alzheimer's Coordinating Center (NACC) clinical dataset, using Cox regression and Cox proportional hazards models to determine if the use of two FDA-approved hit compounds was associated with better cognitive scores (Mini-Mental State Exam), or improved AD clinical diagnosis, when compared with other medications of the same clinical indication.
RESULTS
Our high-throughput screen identified eight blood-brain barrier (BBB)-permeable hit compounds that reduced apoE4-catalyzed Aβ oligomer and fibril formation in a dose-dependent manner. Five hit compounds were non-toxic toward cultured neurons and also reduced apoE4-promoted Aβ and tau neuropathology in a dose-dependent manner. Three of the five compounds were determined to be specific inhibitors of apoE4, whereas the other two compounds were Aβ or tau aggregation inhibitors. When prescribed to AD patients for their normal clinical indications, two of the apoE4 inhibitors, imipramine and olanzapine, but not other (non-hit) antipsychotic or antidepressant medications, were associated with improvements in cognition and clinical diagnosis, especially among APOE4 carriers.
CONCLUSIONS
The critical test of any proposed AD mechanism is whether it leads to effective treatments. Our high-throughput screen identified two promising FDA-approved drugs, imipramine and olanzapine, which have no structural, functional, or clinical similarities other than their shared ability to inhibit apoE4-catalyzed Aβ polymerization, thus identifying this mechanism as an essential contribution of apoE4 to AD.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Apolipoprotein E4; Catalysis; Cognition; Humans; Imipramine; Olanzapine; Polymerization; Retrospective Studies
PubMed: 35768831
DOI: 10.1186/s13195-022-01020-9 -
Revista Brasileira de Psiquiatria (Sao... 2020
Topics: Antipsychotic Agents; Bipolar Disorder; Humans; Imipramine; Lithium; Lithium Carbonate
PubMed: 32321064
DOI: 10.1590/1516-4446-2020-1007 -
The Primary Care Companion For CNS... Mar 2022To describe a novel case of imipramine-induced hyperpigmentation and characterize the literature pertaining to imipramine-induced hyperpigmentation to this point.... (Review)
Review
To describe a novel case of imipramine-induced hyperpigmentation and characterize the literature pertaining to imipramine-induced hyperpigmentation to this point. PubMed and Google Scholar were searched through July 2021 utilizing various combinations of , , and . The references of initial articles were searched for more case reports and imipramine-related literature. Also, articles that cited the references identified in the literature search were reviewed using Google Scholar. Only articles published in English were included. A total of 19 cases of imipramine-induced hyperpigmentation were found in 15 publications to date. All cases were included to determine the variation in clinical presentations of this rare condition. The case reports were reviewed in their entirety for information concerning patient demographic, clinical presentation, histologic findings on biopsy, and treatment options for imipramine-induced hyperpigmentation. : This presentation, to our knowledge, represents the third case of imipramine-induced iris hyperpigmentation, the first case of iris hyperpigmentation occurring in a blue-eyed individual, and the first report to include pictures of the hyperpigmented irides. A novel proposed pathophysiologic mechanism is also provided. Imipramine is a tricyclic antidepressant with a rare side effect of cutaneous and iris hyperpigmentation. Granular dermal deposits in microscopy appear to be the cause of this discoloration. Treatment primarily focuses on discontinuing imipramine or laser therapy.
Topics: Antidepressive Agents, Tricyclic; Humans; Hyperpigmentation; Imipramine; Iris; Skin
PubMed: 35364629
DOI: 10.4088/PCC.21r03161 -
Canadian Medical Association Journal Aug 1973
Topics: Child; Child, Preschool; Electric Stimulation; Enuresis; Humans; Imipramine; Sleep, REM
PubMed: 4353981
DOI: No ID Found -
European Review For Medical and... Dec 2020Doxorubicin (DOX) is a chemotherapeutic agent widely used to treat cancers, particularly breast cancer. DOX has side effects, including cardiotoxicity, hepatotoxicity,...
OBJECTIVE
Doxorubicin (DOX) is a chemotherapeutic agent widely used to treat cancers, particularly breast cancer. DOX has side effects, including cardiotoxicity, hepatotoxicity, and nephrotoxicity. Imipramine is an antidepressant that increases the release of neurotransmitters. This study aimed to investigate the effect of co-administration of imipramine and DOX on DOX-induced toxicity.
MATERIALS AND METHODS
Forty female mice (10-12-weeks-old, 30-38 g) were divided into four groups (n = 10 per group). The animals in the control group received a single-dose saline injection. The animals in the DOX group received a single dose of DOX (20 mg/kg) by intraperitoneal (i.p.) injection. The animals in the imipramine group received the drug daily in their drinking water (0.13 mg/mL) for 9 days, starting 1 day before the DOX injection received by the DOX group. The animals in the combination group (DOX+imipramine) received a single dose of DOX (20 mg/kg, i.p. injection), and a daily dose of imipramine in their drinking water (0.13 mg/mL) for 9 days starting 1 day before the DOX injection. The animals were observed daily to record mortality, and their body weights were recorded every alternate day.
RESULTS
DOX treatment increased the rate of mortality compared with that for control animals. Imipramine co-administration with DOX increased the rate of mortality significantly (p < 0.05) compared with DOX treatment alone. The mortality rate in both the control and imipramine-treatment groups was zero. DOX co-administered with imipramine resulted in significantly reduced body weight compared with control animals.
CONCLUSIONS
The combination of DOX and imipramine reduced the survival rate of female mice, suggesting that imipramine increases the toxic effects of DOX.
Topics: Animals; Body Weight; Doxorubicin; Drug Therapy, Combination; Female; Imipramine; Injections, Intraperitoneal; Mice; Survival Rate
PubMed: 33378049
DOI: 10.26355/eurrev_202012_24202 -
Biomolecules Dec 2023Lysosomes are degradative organelles that facilitate the removal and recycling of potentially cytotoxic materials and mediate a variety of other cellular processes, such...
Lysosomes are degradative organelles that facilitate the removal and recycling of potentially cytotoxic materials and mediate a variety of other cellular processes, such as nutrient sensing, intracellular signaling, and lipid metabolism. Due to these central roles, lysosome dysfunction can lead to deleterious outcomes, including the accumulation of cytotoxic material, inflammation, and cell death. We previously reported that cationic amphiphilic drugs, such as imipramine, alter pH and lipid metabolism within macrophage lysosomes. Therefore, the ability for imipramine to induce changes to the lipid content of isolated macrophage lysosomes was investigated, focusing on sphingomyelin, cholesterol, and glycerophospholipid metabolism as these lipid classes have important roles in inflammation and disease. The lysosomes were isolated from control and imipramine-treated macrophages using density gradient ultracentrifugation, and mass spectrometry was used to measure the changes in their lipid composition. An unsupervised hierarchical cluster analysis revealed a clear differentiation between the imipramine-treated and control lysosomes. There was a significant overall increase in the abundance of specific lipids mostly composed of cholesterol esters, sphingomyelins, and phosphatidylcholines, while lysophosphatidylcholines and ceramides were overall decreased. These results support the conclusion that imipramine's ability to change the lysosomal pH inhibits multiple pH-sensitive enzymes in macrophage lysosomes.
Topics: Humans; Sphingomyelins; Imipramine; Cholesterol; Macrophages; Lysosomes; Inflammation; Lipid Metabolism; Glycerophospholipids
PubMed: 38136603
DOI: 10.3390/biom13121732 -
International Journal of Molecular... Aug 2019From the past, we know how much "serendipity" has played a pivotal role in scientific discoveries. The definition of serendipity implies the finding of one thing while...
From the past, we know how much "serendipity" has played a pivotal role in scientific discoveries. The definition of serendipity implies the finding of one thing while looking for something else. The most known example of this is the discovery of penicillin. Fleming was studying "Staphylococcus influenzae" when one of his culture plates became contaminated and developed a mold that created a bacteria-free circle. Then he found within the mold, a substance that proved to be very active against the vast majority of bacteria infecting human beings. Serendipity had a key role in the discovery of a wide panel of psychotropic drugs as well, including aniline purple, lysergic acid diethylamide, meprobamate, chlorpromazine, and imipramine. Actually, many recent studies support a step back in current strategies that could lead to new discoveries in science. This change should seriously consider the idea that to further focus research project milestones that are already too focused could be a mistake. How can you observe something that others did not realize before you? Probably, one pivotal requirement is that you pay a high level of attention on what is occurring all around you. But this is not entirely enough, since, specifically talking about scientific discoveries, you should have your mind sufficiently unbiased from mainstream infrastructures, which normally make you extremely focused on a particular endpoint without paying attention to potential "unexpected discoveries". Research in medicine should probably come back to the age of innocence and avoid the age of mainstream reports that do not contribute to real advances in the curing of human diseases. Max Planck said "Science progresses not because scientists change their minds, but rather because scientists attached to erroneous views die, and are replaced", and Otto Warburg used the same words when he realized the lack of acceptance of his ideas. This editorial proposes a series of examples showing, in a practical way, how unfocused research may contribute to very important discoveries in science.
Topics: Chlorpromazine; Humans; Imipramine; Lysergic Acid Diethylamide; Meprobamate; Psychotropic Drugs
PubMed: 31443232
DOI: 10.3390/ijms20163973 -
The Cochrane Database of Systematic... May 2014Antidepressants are widely used to treat chronic neuropathic pain (pain due to nerve damage), usually in doses below those at which they exert antidepressant effects. An... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Antidepressants are widely used to treat chronic neuropathic pain (pain due to nerve damage), usually in doses below those at which they exert antidepressant effects. An earlier review that included all antidepressants for neuropathic pain is being replaced by new reviews of individual drugs examining individual neuropathic pain conditions.Imipramine is a tricyclic antidepressant that is occasionally used to treat neuropathic pain.
OBJECTIVES
To assess the analgesic efficacy of imipramine for chronic neuropathic pain in adults, and to assess the associated adverse events.
SEARCH METHODS
We searched CENTRAL, MEDLINE, and EMBASE on 18 November 2013, as well as the reference lists of retrieved papers and other reviews. We also used our own handsearched database for older studies, and two clinical trials databases.
SELECTION CRITERIA
We included randomised, double-blind studies of at least two weeks' duration comparing imipramine with placebo or another active treatment in chronic neuropathic pain. Participants were adults aged 18 and over. We included only articles with full journal publication and extended trial abstracts and summaries.
DATA COLLECTION AND ANALYSIS
Two review authors independently extracted efficacy and adverse event data, and examined issues of study quality. We performed analysis using three tiers of evidence. First tier evidence was derived from data meeting current best standards and subject to minimal risk of bias (outcome equivalent to substantial pain intensity reduction, intention-to-treat analysis without imputation for dropouts; at least 200 participants in the comparison, 8 to 12 weeks duration, parallel design); second tier from data that failed to meet one or more of these criteria and were considered at some risk of bias but with adequate numbers in the comparison; and third tier from data involving small numbers of participants which was considered very likely to be biased or used outcomes of limited clinical utility, or both.
MAIN RESULTS
Five studies treated 168 participants with painful diabetic neuropathy or polyneuropathy. The mean age in individual studies was between 47 and 56 years. Four studies used a cross-over, and one a parallel group design; 126 participants were randomised to receive imipramine 25 mg to 350 mg daily (most took 100 mg to 150 mg daily). Comparators were placebo (an active placebo in one study), paroxetine, mianserin, venlafaxine, and amitriptyline, and treatment was given for 2 to 12 weeks. All studies had one or more sources of potential major bias.No study provided first or second tier evidence for any outcome. No data were available on the proportion of people with at least 50% or 30% reduction in pain or equivalent, and data were available from only one study for our other primary outcome of Patient Global Impression of Change, reported as patient evaluation of pain relief of complete or good. No pooling of data was possible, but third tier evidence in individual studies indicated some improvement in pain relief with imipramine compared with placebo, although this is was very low quality evidence, derived mainly from group mean data and completer analyses, in small, short duration studies where major bias is possible.Four studies reported some information about adverse events, but reporting was inconsistent and fragmented, and the quality of evidence was very low. Participants taking imipramine generally experienced more adverse events, notably dry mouth, and a higher rate of withdrawal due to adverse events, than did participants taking placebo.
AUTHORS' CONCLUSIONS
This review found little evidence to support the use of imipramine to treat neuropathic pain. There was very low quality evidence of benefit but this came from studies that were methodologically flawed and potentially subject to major bias. Effective medicines with much greater supportive evidence are available.
Topics: Adult; Analgesics; Antidepressive Agents, Tricyclic; Diabetic Neuropathies; Humans; Imipramine; Middle Aged; Neuralgia; Randomized Controlled Trials as Topic
PubMed: 24838845
DOI: 10.1002/14651858.CD010769.pub2 -
Journal of the Royal Society of Medicine Aug 1983
Topics: Behavior Therapy; Child; Enuresis; Humans; Imipramine
PubMed: 6887185
DOI: 10.1177/014107688307600802