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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 -
Molecular Diversity Jun 2024Pyrazoles are unique bioactive molecules with a versatile biological profile and they have gained an important place on pharmaceutical chemistry. Pyrazole compounds...
Synthesis, molecular docking and molecular dynamics simulations, drug-likeness studies, ADMET prediction and biological evaluation of novel pyrazole-carboxamides bearing sulfonamide moiety as potent carbonic anhydrase inhibitors.
Pyrazoles are unique bioactive molecules with a versatile biological profile and they have gained an important place on pharmaceutical chemistry. Pyrazole compounds containing sulfonamide nuclei also attract attention as carbonic anhydrase (CA) inhibitors. In this study, a library of pyrazole-carboxamides were synthesized and the structures of the synthesized molecules were characterized using FT-IR, H-NMR, C-NMR and HRMS. Then the inhibition effects of newly synthesized molecules on human erythrocyte hCA I and hCA II isoenzymes were investigated. K values of the compounds were in the range of 0.063-3.368 µM for hCA I and 0.007-4.235 µM for hCA II. Molecular docking studies were performed between the most active compounds 6a, 6b and the reference inhibitor, acetazolamide (AAZ) and the hCA I and hCA II receptors to investigate the binding mechanisms between the compounds and the receptors. These compounds showed better interactions than the AAZ. ADMET analyzes were performed for the compounds and it was seen that the compounds did not show AMES toxicity. The stability of the molecular docking results over time was analysed by 50 ns molecular dynamics simulations. Molecular dynamics simulations revealed that 6a and 6b exhibited good stability after docking to the binding sites of hCA I and hCA II receptors, with minor conformational changes and fluctuations.
PubMed: 38869737
DOI: 10.1007/s11030-024-10901-0 -
Journal of Neuro-ophthalmology : the... Jun 2024Among the symptoms seen in idiopathic intracranial hypertension (IIH), hemifacial spasm (HFS) is rare. Orthostatic-induced HFS preceding lumbar puncture (LP) is...
BACKGROUND
Among the symptoms seen in idiopathic intracranial hypertension (IIH), hemifacial spasm (HFS) is rare. Orthostatic-induced HFS preceding lumbar puncture (LP) is previously unreported. We treated two patients with unusual IIH presentations. This case series reviews the few reports of HFS in IIH and proposes a mechanism for spasm occurrence.
METHODS
Case 1: A woman in her mid-40s with previously controlled IIH developed daily headache, pulsatile tinnitus, right-sided trigeminal paresthesia, and right-sided HFS. The latter 2 symptoms occurred exclusively when moving from a sitting to a standing position. Imaging was unremarkable; opening pressure (OP) on LP was 46 cmH2O with normal cerebrospinal fluid (CSF) components. Case 2: A woman in her late 40s presented with severe daily headache, pulsatile tinnitus, and left-sided HFS following weight gain. Imaging was unremarkable; OP on LP was 32 cmH2O with normal CSF components.
RESULTS
HFS episodes persisted following LP in both patients. Increasing and initiating acetazolamide, respectively, resolved all symptoms.
CONCLUSIONS
Earlier suggested mechanisms of HFS are based on elevated intracranial pressure (ICP) shifting the facial nerve into proximity of a vascular structure. HFS appearing upon standing and continuing after LP, and thus a lower ICP, contradicts this. We propose a mechanism based on the degree of ICP change. This theory is grounded in the lack of intracranial compliance in IIH, wherein substantial pressure changes occur following small volume changes.
PubMed: 38863112
DOI: 10.1097/WNO.0000000000002187 -
Expert Opinion on Therapeutic Patents Jun 2024is a common sexually transmitted disease connected with extensive drug resistance to many antibiotics. Presently, only expanded spectrum cephalosporins (ceftriaxone and... (Review)
Review
INTRODUCTION
is a common sexually transmitted disease connected with extensive drug resistance to many antibiotics. Presently, only expanded spectrum cephalosporins (ceftriaxone and cefixime) and azithromycin remain useful for its management.
AREAS COVERED
New chemotypes for the classical antibiotic drug target gyrase/topoisomerase IV afforded inhibitors with potent binding to these enzymes, with an inhibition mechanism distinct from that of fluoroquinolones, and thus less prone to mutations. The α-carbonic anhydrase from the genome of this bacterium (NgCAα) was also validated as an antibacterial target.
EXPERT OPINION
By exploiting different subunits from the gyrase/topoisomerase IV as well as new chemotypes, two new antibiotics reached Phase II/III clinical trials, zoliflodacin and gepotidacin. They possess a novel inhibition mechanism, binding in distinct parts of the enzyme compared to the fluoroquinolones. Other chemotypes with inhibitory activity in these enzymes were also reported. NgCAα inhibitors belonging to a variety of classes were obtained, with several sulfonamides showing MIC values in the range of 0.25-4 µg/mL and significant activity in animal models of this infection. Acetazolamide and similar CA inhibitors might thus be repurposed as antiinfectives. The scientific/patent literature has been searched for on PubMed, ScienceDirect, Espacenet, and PatentGuru, from 2016 to 2024.
Topics: Neisseria gonorrhoeae; Anti-Bacterial Agents; Humans; Animals; Drug Repositioning; Patents as Topic; Gonorrhea; Drug Resistance, Bacterial; Topoisomerase II Inhibitors; Oxazolidinones; Microbial Sensitivity Tests; DNA Topoisomerase IV; DNA Gyrase; Morpholines; Isoxazoles; Spiro Compounds; Heterocyclic Compounds, 3-Ring; Barbiturates; Acenaphthenes
PubMed: 38856987
DOI: 10.1080/13543776.2024.2367005 -
Cureus May 2024Idiopathic intracranial hypertension (IIH) or benign intracranial hypertension affects the neuro-ophthalmological system and leads to elevated intracranial pressure....
Idiopathic intracranial hypertension (IIH) or benign intracranial hypertension affects the neuro-ophthalmological system and leads to elevated intracranial pressure. Elevated opening pressure during lumbar puncture is diagnostic of IIH. Here in, we present an interesting case of a 15-year-old girl, recently immigrated and with a high BMI, presenting with recurrent fever, abdominal issues, weight loss, and other symptoms, leading to a diagnosis of pelvic inflammatory disease (PID) and HIV infection. After treatment with antibiotics (doxycycline) and antiretroviral therapy, she developed IIH, manifesting as sudden-onset headache and vision problems. MRI and lumbar puncture confirmed the diagnosis. She responded well to acetazolamide and was discharged with continued medication and follow-up appointments. This case underscores the complexity of IIH development, especially in the setting of acute HIV infection and antibiotic treatment, highlighting the need for a comprehensive diagnostic approach and multidisciplinary management.
PubMed: 38854218
DOI: 10.7759/cureus.60001 -
MedRxiv : the Preprint Server For... May 2024Identifying risk protein targets and their therapeutic drugs is crucial for effective cancer prevention. Here, we conduct integrative and fine-mapping analyses of large...
Identifying risk protein targets and their therapeutic drugs is crucial for effective cancer prevention. Here, we conduct integrative and fine-mapping analyses of large genome-wide association studies data for breast, colorectal, lung, ovarian, pancreatic, and prostate cancers, and characterize 710 lead variants independently associated with cancer risk. Through mapping protein quantitative trait loci (pQTL) for these variants using plasma proteomics data from over 75,000 participants, we identify 365 proteins associated with cancer risk. Subsequent colocalization analysis identifies 101 proteins, including 74 not reported in previous studies. We further characterize 36 potential druggable proteins for cancers or other disease indications. Analyzing >3.5 million electronic health records, we uncover five drugs (Haloperidol, Trazodone, Tranexamic Acid, Haloperidol, and Captopril) associated with increased cancer risk and two drugs (Caffeine and Acetazolamide) linked to reduced colorectal cancer risk. This study offers novel insights into therapeutic drugs targeting risk proteins for cancer prevention and intervention.
PubMed: 38853880
DOI: 10.1101/2024.05.29.24308170 -
Surgical Neurology International 2024This study aimed to directly measure cerebrospinal fluid (CSF) gas tensions and pH before and after superficial temporal artery to middle cerebral artery (STA-MCA)...
BACKGROUND
This study aimed to directly measure cerebrospinal fluid (CSF) gas tensions and pH before and after superficial temporal artery to middle cerebral artery (STA-MCA) anastomosis for moyamoya disease.
METHODS
This study included 25 patients with moyamoya disease who underwent STA-MCA anastomosis combined with indirect bypass onto their 34 hemispheres. About 1 mL of CSF was collected before and after bypass procedures to measure CSF partial pressure of oxygen (PO), CSF partial pressure of carbon dioxide (PCO), and CSF pH with a blood gas analyzer. As the controls, the CSF was collected from 6 patients during surgery for an unruptured cerebral aneurysm. PO and PCO were expressed as the ratio to partial pressure of oxygen (PO) and partial pressure of carbon dioxide (PCO), respectively.
RESULTS
PO/PO was 0.79 ± 0.14 in moyamoya disease, being lower than 1.10 ± 0.09 in the controls ( < 0.0001). PCO/PCO was 0.90 ± 0.10 in moyamoya disease, being higher than 0.84 ± 0.07 in the controls ( = 0.0261). PO/PO was significantly lower in pediatric patients than in adult patients and in the hemispheres with reduced cerebral blood flow (CBF) and cerebrovascular reactivity (CVR) to acetazolamide than in those with normal CBF but reduced CVR. STA-MCA anastomosis significantly increased PO/PO from 0.79 ± 0.14 to 0.86 ± 0.14 ( < 0.01) and reduced PCO/PCO from 0.90 ± 0.10 to 0.69 ± 0.16 ( < 0.0001). There was no difference in CSF pH between moyamoya disease and the controls.
CONCLUSION
PO/PO was significantly lower in moyamoya disease than in the controls. Its magnitude was more pronounced in pediatric patients than in adult patients and depends on the severity of cerebral ischemia. STA-MCA anastomosis carries dramatic effects on CSF gas tensions in moyamoya patients. CSF may be a valuable biomarker to monitor the pathophysiology of cerebral ischemia/hypoxia in moyamoya disease.
PubMed: 38840605
DOI: 10.25259/SNI_281_2024 -
Veterinary Ophthalmology Jun 2024In equine glaucoma, topical treatment with carbonic anhydrase inhibitors (CAIs) is recommended. Oral acetazolamide, a systemic CAI, is used in horses with hyperkalemic...
OBJECTIVES
In equine glaucoma, topical treatment with carbonic anhydrase inhibitors (CAIs) is recommended. Oral acetazolamide, a systemic CAI, is used in horses with hyperkalemic periodic paralysis. Information regarding its effect on equine intraocular pressure (IOP) is scarce. The aim of the study was to determine the effect of oral acetazolamide treatment on IOP in horses, in a case-control study.
ANIMALS
Ten healthy horses.
PROCEDURES
Horses were treated with oral acetazolamide (4.4 mg/kg) BID for 1 week. Serum acetazolamide concentrations were determined by liquid chromatography/tandem mass spectrometry, and IOP were measured before treatment, daily during treatment, and at 48 and 72 h after treatment.
RESULTS
Acetazolamide serum levels reached steady state at 72 h after the first oral dose. In a mixed effect model logistic regression, there was a significant decrease in IOP on the third treatment day, of 2.4 mmHg (p = .012) and 2.7 mmHg (p = .006) in the left (OS) and right eye (OD), respectively. On the seventh day, there was a decrease in 2.5 mmHg (p = .008) and 2.7 mmHg (p = .007) OS and OD, respectively. A significant increase occurred 48 h following treatment discontinuation (3.6 mmHg, p < .001 and 3.5 mmHg, p < .001 OS and OD, respectively). The area under the concentration versus time curve (AUC) was 1.1 ± 0.5 μg/mL*h, mean residence time 6.7 ± 4.3 h, peak plasma concentration (C) 0.4 ± 0.4 μg/mL and time to reach C 1.8 h. There was a significant increase in serum concentrations 1, 2, 48, 72, and 156 h following the first drug administration (p < .05).
CONCLUSIONS
Further studies are required to determine whether acetazolamide is a potential treatment for equine glaucoma.
PubMed: 38839562
DOI: 10.1111/vop.13240 -
Molecular Pharmaceutics Jul 2024Carbonic anhydrase IX (CAIX), a zinc metal transmembrane protein, is highly expressed in 95% of clear cell renal cell carcinomas (ccRCCs). A positron emission tomography...
Carbonic anhydrase IX (CAIX), a zinc metal transmembrane protein, is highly expressed in 95% of clear cell renal cell carcinomas (ccRCCs). A positron emission tomography (PET) probe designed to target CAIX in nuclear medicine imaging technology can achieve precise positioning, is noninvasive, and can be used to monitor CAIX expression in lesions in real time. In this study, we constructed a novel acetazolamide dual-targeted small-molecule probe [Ga]Ga-LF-4, which targets CAIX by binding to a specific amino acid sequence. After attenuation correction, the radiolabeling yield reached 66.95 ± 0.57% ( = 5) after 15 min of reaction and the radiochemical purity reached 99% ( = 5). [Ga]Ga-LF-4 has good in vitro and in vivo stability, and in vivo safety and high affinity for CAIX, with a value of 6.62 nM. Moreover, [Ga]Ga-LF-4 could be quickly cleared from the blood in vivo. The biodistribution study revealed that the [Ga]Ga-LF-4 signal was concentrated in the heart, lung, and kidney after administration, which was the same as that observed in the micro-PET/CT study. In a ccRCC patient-derived xenograft (PDX) model, the signal significantly accumulated in the tumor after administration, where it was retained for up to 4 h. After competitive blockade with LF-4, uptake at the tumor site was significantly reduced. The SUVmax of the probe [Ga]Ga-LF-4 at the ccRCC tumor site was three times greater than that in the PC3 group with low CAIX expression at 30 min (ccRCC vs PC3:1.86 ± 0.03 vs 0.62 ± 0.01, = 48.2, < 0.0001). These results indicate that [Ga]Ga-LF-4 is a novel small-molecule probe that targets CAIX and can be used to image localized and metastatic ccRCC lesions.
Topics: Animals; Carbonic Anhydrase IX; Humans; Mice; Carcinoma, Renal Cell; Gallium Radioisotopes; Kidney Neoplasms; Tissue Distribution; Cell Line, Tumor; Radiopharmaceuticals; Mice, Nude; Antigens, Neoplasm; Molecular Probes; Positron Emission Tomography Computed Tomography; Acetazolamide; Female; Mice, Inbred BALB C; Positron-Emission Tomography; Male; Xenograft Model Antitumor Assays
PubMed: 38831541
DOI: 10.1021/acs.molpharmaceut.4c00104 -
Cureus Apr 2024Benign intracranial hypertension (BIH) in children is recognized as elevated intracranial pressure without hydrocephalus or intracranial mass. It manifests differently...
Benign intracranial hypertension (BIH) in children is recognized as elevated intracranial pressure without hydrocephalus or intracranial mass. It manifests differently in adults, with no apparent predilection for sex or weight. Headache, papilledema, and possibly sixth nerve palsy with visual field defects are the typical symptoms of this syndrome. Vitamin A toxicity is a rare cause of BIH. We report the case of a previously healthy 13-year-old girl presenting with photophobia, a frontal headache, and vomiting. She had bilateral papilledema discovered by fundoscopy. Both magnetic resonance imaging and brain CT were normal. At admission, a lumbar puncture (LP) revealed an opening pressure of 26 cm HO with normal cerebrospinal fluid (CSF) analysis. The diagnosis of BIH was established, and treatment with acetazolamide was started, with good clinical results. Regular eye evaluations showed a regression of papilledema. Elevated serum vitamin A levels were the only positive findings. Within two weeks, the patient was discharged without any symptoms. This study aims to attract the attention of clinicians to the importance of evaluating vitamin A toxicity in the context of papilledema and oculomotor problems in a child who has undergone normal neuroradiological investigations.
PubMed: 38817456
DOI: 10.7759/cureus.59401