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Frontiers in Oncology 2023Multiple myeloma (MM) is an incurable cancer of malignant plasma cells that engraft in the bone marrow (BM). It is more than likely that the poorly investigated physical...
INTRODUCTION
Multiple myeloma (MM) is an incurable cancer of malignant plasma cells that engraft in the bone marrow (BM). It is more than likely that the poorly investigated physical parameters of hypoxia and pH in the tumor microenvironment (TME) is critical for MM survival. Here, we explore the effects of a hypoxic environment on pH regulation and its role in MM survival.
METHODS
We used in vitro models of MM, in which the culturing medium was modified to specific pH and pO2 levels and then measured the effects on cell survival that was correlated with changes in intracellular (pHi) and extracellular pH (pHe). In a MM xenograft model, we used PET/CT to study hypoxia-mediated effects on tumor growth.
RESULTS
Hypoxia-mediated apoptosis of MM cells is correlated with acidic intracellular pHi (less than < 6.6) that is dependent on HIF activity. Using a polyamide HIF responsive element binding compound, a carbonic anhydrase inhibitor (acetazolamide), and an NHE-1 inhibitor (amiloride) acidified the pHi and lead to cell death. In contrast, treatment of cells with an alkalization agent, Na-lactate, rescued these cells by increasing the pHi (pH > 6.6). Finally, treatment of mice with acetazolamide decreased cell growth in the tumor nodules.
DISCUSSION
Targeting hypoxia and HIF have been proposed as an anti-tumor therapy but the clinical efficacy of such strategies are modest. We propose that targeting the pHi may be more effective at treating cancers within a hypoxic TME.
PubMed: 38023253
DOI: 10.3389/fonc.2023.1268421 -
Investigative Ophthalmology & Visual... Mar 2024The purpose of this study was to test the hypothesis that optical coherence tomography (OCT) bioenergy-linked and anatomical biomarkers are responsive to an...
PURPOSE
The purpose of this study was to test the hypothesis that optical coherence tomography (OCT) bioenergy-linked and anatomical biomarkers are responsive to an acetazolamide (ACZ) provocation.
METHODS
C57BL/6J mice (B6J, a strain with relatively inefficient mitochondria) and 129S6/ev mice (S6, a strain with relatively efficient mitochondria) were given a single IP injection of ACZ (carbonic anhydrase inhibitor) or vehicle. In each mouse, the Mitochondrial Configuration within Photoreceptors based on the profile shape Aspect Ratio (MCP/AR) index was determined from the hyper-reflective band immediately posterior to the external limiting membrane (ELM). In addition, we tested for ACZ-induced acidification by measuring contraction of the external limiting membrane-retinal pigment epithelium (ELM-RPE) thickness; the hyporeflective band (HB) signal intensity at the photoreceptor tips was also examined. Finally, the nuclear layer thickness was measured.
RESULTS
In response to ACZ, MCP/AR was greater-than-vehicle in B6J mice and lower-than-vehicle in S6 mice. ACZ-treated B6J and S6 mice both showed ELM-RPE contraction compared to vehicle-treated mice, consistent with dehydration in response to subretinal space acidification. The HB intensity at the photoreceptor tips and the outer nuclear layer thickness (B6J and S6), as well as the inner nuclear layer thickness of B6J mice, were all lower than vehicle following ACZ.
CONCLUSIONS
Photoreceptor respiratory efficacy can be evaluated in vivo based on distinct rod mitochondria responses to subretinal space acidification measured with OCT biomarkers and an ACZ challenge, supporting and extending our previous findings measured with light-dark conditions.
Topics: Mice; Animals; Tomography, Optical Coherence; Acetazolamide; Mice, Inbred C57BL; Retina; Biomarkers
PubMed: 38488413
DOI: 10.1167/iovs.65.3.21 -
Polish Archives of Internal Medicine Dec 2023
Topics: Humans; Diuretics; Acetazolamide; Chlorides; Heart Failure
PubMed: 38126245
DOI: 10.20452/pamw.16629 -
Polish Archives of Internal Medicine Dec 2023
Topics: Humans; Acetazolamide; Heart Failure; Disease Progression
PubMed: 38126242
DOI: 10.20452/pamw.16632 -
Ophthalmology. Glaucoma Apr 2024To identify and quantify medications causing angle-closure glaucoma through the FDA Adverse Event Reporting System (FAERS).
OBJECTIVE
To identify and quantify medications causing angle-closure glaucoma through the FDA Adverse Event Reporting System (FAERS).
DESIGN
National retrospective database analysis.
SUBJECTS
There were 11 737 133 total adverse event reports from the FDA Federal Adverse Event Reporting System (FAERS) database 2004 to third quarter of 2023 (2023Q3), which included 1629 reports of angle-closure glaucoma.
METHODS
Drugs associated with reports of angle-closure glaucoma were identified in FAERS through disproportionality analysis MAIN OUTCOME MEASURES: To ascertain if these reports yielded statistically significant signals, we used the proportional reporting ratio (PRR), reporting odds ratio (ROR), empirical Bayes geometric mean (EBGM), and information component (IC). We considered a signal to be detected when all 4 disproportionality analysis metrics were positive.
RESULTS
We identified a total of 1629 adverse event reports linked to 611 suspected drugs over the course of 20 years (2004-2023Q3). Frequently reported drugs included topiramate (520 reports) and citalopram (69 reports), amongst many others. Eighteen medications yielded a positive signal, including lesser-known medications like olanzapine, phentermine, and ranibizumab. Tropicamide exhibited the most robust statistical significance (n = 18; PRR: 164.263; ROR [95% confidence interval {CI}]: 167.95 [104.994-268.655]; EBGM [EBGM05]: 162.421 [109.5]; IC [IC05]: 7.344 [4.591]), while acetazolamide was the second strongest (n = 51; PRR: 113.088; ROR 95% CI: 114.782 [86.665-152.021]; EBGM [EBGM05]: 109.506 [86.501]; IC [IC05]: 6.775 [5.115]).
CONCLUSIONS
Drug-induced glaucoma included both well-known medications such as topiramate as well as lesser-known medications such as olanzapine, phentermine, and ranibizumab. Clinician awareness of these findings is important.
FINANCIAL DISCLOSURE(S)
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
PubMed: 38679326
DOI: 10.1016/j.ogla.2024.04.006 -
BMC Neurology Jun 2024We present a rare case of NeuroBehcet's-related intracranial hypertension without cerebral venous thrombosis (NBrIHwCVT), occurring as the first presentation of... (Review)
Review
BACKGROUND
We present a rare case of NeuroBehcet's-related intracranial hypertension without cerebral venous thrombosis (NBrIHwCVT), occurring as the first presentation of NeuroBehcet's. In addition, we describe the novel use of subcutaneous tocilizumab for this indication. This is followed by a review of the literature on this topic.
CASE
The patient was a 28-year-old lady of Southern Chinese origin with a known history of Behcet's disease with oral ulcers and ocular findings for which she was on mycophenolate mofetil and adalimumab. She presented with a headache and bilateral disc swelling associated with an intracranial pressure (ICP) of > 40cmH20. There were no structural lesions or cerebral venous thrombosis (CVT) on imaging. Initial lumbar puncture had raised leucocytes and protein. We discuss diagnostic challenges given persistently elevated ICP despite subsequent non-inflammatory cerebrospinal fluid (CSF) profiles and non-response to acetazolamide. She eventually showed a response to immunosuppressant therapy in the form of pulsed methylprednisolone, cyclophosphamide and subsequently subcutaneous tocilizumab, supporting the diagnosis of NBrIHwCVT. Complete normalization of ICP remains challenging. Her disease course was severe, unusual for her ethnicity.
LITERATURE REVIEW
We identified 34 patients (including ours) from 14 publications. We found that the majority of NBrIHwCVT patients were young (average age of 34 years), with a slight female preponderance. Of the 17 cases in the literature with available data on CSF profile, none had raised leucocytes whilst one patient had elevated protein. Patients were generally treated with steroids and occasionally azathioprine, in line with the suspected autoimmune pathophysiology. Of 22 patients with data on outcome, six (27%) were noted to have recurrence of symptoms generally occurring a few months later.
CONCLUSION
As demonstrated by this case, NBrIHwCVT can present with BD with raised ICP even if there is no prior history of NB, central Asian ethnicity, cerebral venous thrombosis or features of inflammation on the CSF. We demonstrated how novel use of Tocilizumab may have a role in the management of NBrIHwCVT. Based on our literature review, patients were more likely to be young, female, display a non-inflammatory CSF picture, be treated with steroids and harbour a possibility of recurrence.
Topics: Humans; Female; Adult; Intracranial Hypertension; Behcet Syndrome; Antibodies, Monoclonal, Humanized; Immunosuppressive Agents
PubMed: 38877431
DOI: 10.1186/s12883-024-03708-x -
Neuro-ophthalmology (Aeolus Press) 2024Nitrous oxide is used as an anaesthetic and analgesic agent in the medical setting and is known to cause raised intracranial pressure. The use of nitrous oxide...
Nitrous oxide is used as an anaesthetic and analgesic agent in the medical setting and is known to cause raised intracranial pressure. The use of nitrous oxide recreationally for the drug's euphoric and relaxant properties has been linked to multiple neurological and psychiatric sequelae including neuropathy, myelopathy, and psychosis. We describe a case of a young person who declared heavy nitrous oxide use resulting in vision-threatening papilloedema secondary to raised intracranial pressure. He underwent emergency lumbar drainage alongside high-dose acetazolamide and parenteral vitamin B injections. To our knowledge, there have yet to be other reports of cases where heavy nitrous oxide use has caused secondary pseudotumor cerebri syndrome.
PubMed: 38933749
DOI: 10.1080/01658107.2023.2301359 -
Journal of the American Board of Family... 2024Consider IV Acetazolamide in addition to standard IV loop diuretic therapy in patients hospitalized for acute decompensated heart failure..
Consider IV Acetazolamide in addition to standard IV loop diuretic therapy in patients hospitalized for acute decompensated heart failure..
Topics: Humans; Acetazolamide; Heart Failure; Acute Disease; Sodium Potassium Chloride Symporter Inhibitors; Diuretics; Carbonic Anhydrase Inhibitors
PubMed: 38740482
DOI: 10.3122/jabfm.2023.230379R0 -
Translational Vision Science &... Jan 2024To visualize and quantify structural patterns of optic nerve edema encountered in papilledema during treatment.
PURPOSE
To visualize and quantify structural patterns of optic nerve edema encountered in papilledema during treatment.
METHODS
A novel bi-channel deep-learning variational autoencoder (biVAE) model was trained using 1498 optical coherence tomography (OCT) scans of 125 subjects over time from the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT) and 791 OCT scans of 96 control subjects from the University of Iowa. An independent test dataset of 70 eyes from 70 papilledema subjects was used to evaluate the ability of the biVAE model to quantify and reconstruct the papilledema spatial patterns from input OCT scans using only two variables.
RESULTS
The montage color maps of the retinal nerve fiber layer (RNFL) and total retinal thickness (TRT) produced by the biVAE model provided an organized visualization of the variety of morphological patterns of optic disc edema (including differing patterns at similar thickness levels). Treatment effects of acetazolamide versus placebo in the IIHTT were also demonstrated in the latent space. In image reconstruction, the mean signed peripapillary retinal nerve fiber layer thickness (pRNFLT) difference ± SD was -0.12 ± 17.34 µm, the absolute pRNFLT difference was 13.68 ± 10.65 µm, and the RNFL structural similarity index reached 0.91 ± 0.05.
CONCLUSIONS
A wide array of structural patterns of papilledema, integrating the magnitude of disc edema with underlying disc and retinal morphology, can be quantified by just two latent variables.
TRANSLATIONAL RELEVANCE
A biVAE model encodes structural patterns, as well as the correlation between channels, and may be applied to visualize individuals or populations with papilledema throughout treatment.
Topics: Humans; Papilledema; Deep Learning; Optic Nerve; Retina; Edema
PubMed: 38231498
DOI: 10.1167/tvst.13.1.13 -
International Journal of Molecular... Mar 2024In this study, we designed two series of novel anthraquinone-based benzenesulfonamide derivatives and their analogues as potential carbonic anhydrase inhibitors (CAIs)...
Novel Anthraquinone-Based Benzenesulfonamide Derivatives and Their Analogues as Potent Human Carbonic Anhydrase Inhibitors with Antitumor Activity: Synthesis, Biological Evaluation, and In Silico Analysis.
In this study, we designed two series of novel anthraquinone-based benzenesulfonamide derivatives and their analogues as potential carbonic anhydrase inhibitors (CAIs) and evaluated their inhibitory activities against off-target human carbonic anhydrase II (hCA II) isoform and tumor-associated human carbonic anhydrase IX (hCA IX) isoform. Most of these compounds exhibited good inhibitory activities against hCA II and IX. The compounds that exhibited the best hCA inhibition were further studied against the MDA-MB-231, MCF-7, and HepG2 cell lines under hypoxic and normoxic conditions. Additionally, the compounds exhibiting the best antitumor activity were subjected to apoptosis and mitochondrial membrane potential assays, which revealed a significant increase in the percentage of apoptotic cells and a notable decrease in cell viability. Molecular docking studies were performed to demonstrate the presence of numerous hydrogen bonds and hydrophobic interactions between the compounds and the active site of hCA. Absorption, distribution, metabolism, excretion (ADME) predictions showed that all of the compounds had good pharmacokinetic and physicochemical properties.
Topics: Humans; Benzenesulfonamides; Molecular Structure; Structure-Activity Relationship; Carbonic Anhydrase Inhibitors; Molecular Docking Simulation; Sulfonamides; Carbonic Anhydrase IX; Protein Isoforms; Anthraquinones
PubMed: 38542320
DOI: 10.3390/ijms25063348