Clinical Characteristics, Therapeutic Options, and Outcomes in Hyperphosphatemic Tumoral Calcinosis: A Systematic Review.

This systematic review was performed to understand better the myriad presentations, various therapeutic options, response to therapy, and its clinical outcomes in hyperphosphatemic tumoral calcinosis (HTC). Full texts were selected according to strict inclusion criteria. All case reports of HTC wherein baseline phosphate was measured, treatment offered was mentioned, and information on follow-up and response to therapy that were available were included. A total of 43 of 188 eligible studies (N = 63 patients) met the inclusion criteria. A list of desired data was extracted and graded for methodological quality. A total of 63 individuals (Males = 33) were included from the 43 eligible case studies. The median age of the patients was 18 (IQR 8-32) years. The most frequently involved sites were the hip/gluteal region (34/63; 53.9%) followed by the elbow/forearm (26/63; 41.2%), and the shoulder (18/63; 28.5%). Three patients had conjunctival calcific deposits. The mean (SD) phosphate was 6.9 (1.1) mg/dL. Among the subjects, 36/63 (57.1%) underwent surgical excision with some form of medical therapy. Two patients underwent only surgical excision (2.1%). One patient was maintained on follow-up (1.6%) and 24/63 (38.1%) patients were treated with medical measures. The median (IQR) follow-up duration was 3 (1-9) years. Regression or reduction in lesion size was reported in 19/63 (30.2%) subjects; 20/63 (31.7%) showed progression, 24/63 (38.1%) had features of stable disease, and mortality was reported in 3 patients (4.7%). We report for the first time a detailed description of the clinical and therapeutic response of HTC. A combination of medical measures aimed at lowering serum phosphate appears to be the cornerstone of treatment, although clinical responses may vary.

Acetazolamide therapy in patients with acute heart failure: a systematic review and meta-analysis of randomized controlled trials.

Acute heart failure (AHF) often leads to unfavorable outcomes due to fluid overload. While diuretics are the cornerstone treatment, acetazolamide may enhance diuretic efficiency by reducing sodium reabsorption. We performed a systematic review and meta-analysis on the effects of acetazolamide as an add-on therapy in patients with AHF compared to diuretic therapy. PubMed, Embase, and Cochrane databases were searched for randomized controlled trials (RCT). A random-effects model was employed to compute mean differences and risk ratios. Statistical analysis was performed using R software. The GRADE approach was used to rate the certainty of the evidence. We included 4 RCTs with 634 patients aged 68 to 81 years. Over a mean follow-up of 3 days to 34 months, acetazolamide significantly increased diuresis (MD 899.2 mL; 95% CI 249.5 to 1549; p < 0.01) and natriuresis (MD 72.44 mmol/L; 95% CI 39.4 to 105.4; p < 0.01) after 48 h of its administration. No association was found between acetazolamide use and WRF (RR 2.4; 95% CI 0.4 to 14.2; p = 0.3) or all-cause mortality (RR 1.2; 95% CI 0.8 to 1.9; p = 0.3). Clinical decongestion was significantly higher in the intervention group (RR 1.35; 95% CI 1.09 to 1.68; p = 0.01). Acetazolamide is an effective add-on therapy in patients with AHF, increasing diuresis, natriuresis, and clinical decongestion, but it was not associated with differences in mortality.

A case of middle-aged central sleep apnea due to Joubert syndrome with different treatment effects of oxygen and acetazolamide.

We report a case of severe central sleep apnea incidentally diagnosed during polysomnography for suspected obstructive sleep apnea. Characteristic clinical features included episodic hyperventilation followed by apnea from hypocapnia, which did not follow a Cheyne-Stokes pattern. Combined with the identification of cerebellar and brainstem malformations known as the "molar tooth sign" on a brain MRI, developmental delay, and motor coordination problems, Joubert syndrome (a congenital disease) was first diagnosed at the age of 50 years. Central apneas were also observed during wakefulness, although not continuously. During sleep, continuous positive airway pressure and adaptive servo-ventilation were ineffective at the referring clinic and at our hospital. Supplemental oxygen decreased the frequency of central apneas and significantly shortened the duration of each central sleep apnea compared with room air. In contrast, the opposite response was observed with acetazolamide administration.

Acetazolamide Tolerance in Acute Decompensated Heart Failure: An Observational Study.

Objectives: This real-life study aimed to evaluate the safety of acetazolamide (ACZ), a carbonic anhydrase inhibitor with diuretic effects. ACZ has recently been proven to improve decongestion in the context of patients hospitalized for acute heart failure (HF). However, data in terms of safety are lacking. Methods: We conducted a monocentric observational prospective study from November 2023 to February 2024 in a 12-bed cardiology department, recording adverse events (hypotension, severe metabolic acidosis, severe hypokalemia and renal events) during in-hospital HF treatment. All patients hospitalized for acute HF during the study period treated with ACZ (500 mg IV daily for 3 days) on top of IV furosemide (n = 28, 48.3%) were compared with patients who have been treated with IV furosemide alone (n = 30, 51.7%). Results: The patients treated with ACZ were younger than those without (median age 78 (range 67-86) vs. 85 (79-90) years, respectively, p = 0.01) and had less frequent chronic kidney disease (median estimated glomerular fraction rate (60 (35-65) vs. 38 (26-63) mL/min, p = 0.02). As concerned adverse events during HF treatment, there were no differences in the occurrences of hypotension (three patients [10.7%] in the ACZ group vs. four [13.3%], p = 0.8), renal events (four patients [14.3%] in the ACZ group vs. five [16.7%], p = 1) and severe hypokalemia (two [7.1%] in the ACZ group vs. three [10%], p = 1). No severe metabolic acidosis occurred in either group. Conclusions: Although the clinical characteristics differed at baseline, with younger age and better renal function in patients receiving ACZ, the tolerance profile did not significantly differ from patients receiving furosemide alone. Additional observational data are needed to further assess the safety of ACZ-furosemide combination in the in-hospital management of HF, especially in older, frail populations.

Management of Neisseria gonorrhoeae infection: from drug resistance to drug repurposing.

INTRODUCTION: Neisseria gonorrhoeae 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.

Fabrication of acetazolamide loaded leciplex for intraocular delivery: Optimization by 32 full factorial design, in vitro, ex vivo and in vivo pharmacodynamics.

The complex structure of the eye poses challenges in delivering drugs effectively, which can be circumvented by employing nanotechnologies. The present study aimed to prepareacetazolamide-loadedleciplex (ACZ - LP) using a simple one-step fabrication approach followed byoptimization employing a 32 Full Factorial Design. The ACZ - LP demonstrated high entrapment efficiency (93.25 ± 2.32 %), average diameter was recorded around 171.03 ± 3.32 with monodisperse size distribution and zeta potential of 41.33 ± 2.10 mV. Invitro release and ex vivo permeation studies of prepared formulation demonstrated an initial burst release in 1 h followed by sustained release pattern as compared to plain acetazolamide solution. Moreover, an ex vivo corneal drug retention (27.05 ± 1.20 %) and in vitro mucoadhesive studies with different concentration of mucin indicated strong electrostatic bonding confirming the mucoadhesive characteristics of the formulation. Additionally, the histopathological studies ensured that the formulation was non-irritant and nontoxic while and HET-CAM ensured substantial tolerability of the formulation. The in vivo pharmacodynamic investigation carried out on a rabbit model demonstrated that treatment with ACZ - LP resulted in a significant and prolonged reduction in intraocular pressure as compared to plain acetazolamide solution, acetazolamide oral tablet, and Brinzox®. In summary, the ACZ - LP is anefficient and versatile drug delivery approach which demonstrates significant potential in controlling glaucoma.

Peri-operative management of endoscopic endonasal cerebrospinal fluid leak repair: an international survey.

PURPOSE: Peri-operative management of nasal cerebrospinal fluid (CSF) leaks is not consensual due to limited evidence. The main aim of this study was to identify key factors in peri-operative management of endoscopic endonasal CSF leak repair among international experts. METHODS: A 60-item survey questionnaire collected opinions of members of international learned societies of ENT surgeons and neurosurgeons on nasal packing, post-operative instructions, antibiotic prophylaxis, and CSF volume depletion. RESULTS: The survey had 153 respondents (124 otorhinolaryngologists and 29 neurosurgeons). A resting position was recommended by 85% (130/151) of respondents for extended CSF leak of the anterior skull base, mainly in Fowler's position (72% (110/153)). Nasal packing was used by 85% (130/153) of respondents; 33.3% (51/153) used it to stabilize the reconstruction, and 22.2% (34/153) to prevent bleeding. It was usually removed after 48 h in 44.4% of cases (68/153). CSF depletion was considered by 47.1% (72/153) of respondents in case of CSF leak recurrence and by 34.6% (53/153) in cases of increased intracranial pressure. All respondents gave specific postoperative instructions to patients including driving, running, swimming, diving restrictions and flighting restrictions. In subgroup analysis, ENT surgeons more often recommended a resting position than neurosurgeons (71% vs. 37.9% ; p = 0.0008) and prescribed more antibiotics (82.3% vs. 21.4% ; p < 0.0001). CONCLUSION: Although postoperative management after CSF closure remains challenging and not codified, this international survey revealed some points of consensus concerning resting position and restriction of post-operative activities. Prospective clinical studies must be undertaken to evaluate their efficiency.

Morning Glory Anomaly With Serous Macular Detachment.

The morning glory (MG) disc anomaly is a congenital excavation of the posterior globe involving the optic disc, with a distinct appearance reminiscent of the MG flower. Various intracranial and ocular associations with MG have been documented. Conditions such as trans-sphenoidal encephalocele and hypoplasia of the intracranial vasculature have been observed in association with this anomaly. In this report, we present a case of MG optic disc anomaly accompanied by serous macular detachment.

Acetazolamide As A Valuable Addition to Acute Heart Failure?

Consider IV Acetazolamide in addition to standard IV loop diuretic therapy in patients hospitalized for acute decompensated heart failure.1.

Acetazolamide-induced pulmonary oedema: A disproportionality analysis from the EudraVigilance database.

To our knowledge, no prior study has analysed a possible association between acetazolamide and pulmonary oedema. The aim of this study was to use data from the EudraVigilance to detect a safety signal for acetazolamide-induced pulmonary oedema. We performed a disproportionality analysis (case-noncase method), calculating reporting odds ratios (RORs) up to 22 February 2024. Among 11 684 208 spontaneous cases of adverse reactions registered in EudraVigilance, 38 275 were pulmonary oedemas. Acetazolamide was involved in 31 cases. In more than half of those cases, the patients received a single dose of acetazolamide after undergoing cataract surgery: latency was 10-90 min. Remarkably, there were five cases of positive rechallenge and six cases resulted in death. The ROR for acetazolamide was 3.63 (95% CI 2.55-5.17). Disproportionality was also observed in VigiBase®: ROR 4.44 (95% CI 3.34-5.90). Our study confirms a signal that suggests a risk of serious pulmonary oedema associated with acetazolamide.

Diuresis Efficacy in Ambulatory Congested Heart Failure Patients: Intrapatient Comparison of 3 Diuretic Regimens (DEA-HF).

BACKGROUND: Limited evidence exists regarding efficacy and safety of diuretic regimens in ambulatory, congestion-refractory, chronic heart failure (CHF) patients. OBJECTIVES: The authors sought to compare the potency and safety of commonly used diuretic regimens in CHF patients. METHODS: A prospective, randomized, open-label, crossover study conducted in NYHA functional class II to IV CHF patients, treated in an ambulatory day-care unit. Each patient received 3 different diuretic regimens: intravenous (IV) furosemide 250 mg; IV furosemide 250 mg plus oral metolazone 5 mg; and IV furosemide 250 mg plus IV acetazolamide 500 mg. Treatments were administered once a week, in 1 of 6 randomized sequences. The primary endpoint was total sodium excretion, and the secondary was total urinary volume excreted, both measured for 6 hours post-treatment initiation. RESULTS: A total of 42 patients were recruited. Administration of furosemide plus metolazone resulted in the highest weight of sodium excreted, 4,691 mg (95% CI: 4,153-5,229 mg) compared with furosemide alone, 3,835 mg (95% CI: 3,279-4,392 mg; P = 0.015) and to furosemide plus acetazolamide 3,584 mg (95% CI: 3,020-4,148 mg; P = 0.001). Furosemide plus metolazone resulted in 1.84 L of urine (95% CI: 1.63-2.05 L), compared with 1.58 L (95% CI: 1.37-1.8); P = 0.039 collected following administration of furosemide plus acetazolamide and 1.71 L (95% CI: 1.49-1.93 L) following furosemide alone. The incidence of worsening renal function was significantly higher when adding metolazone (39%) to furosemide compared with furosemide alone (16%) and to furosemide plus acetazolamide (2.6%) (P < 0.001). CONCLUSIONS: In ambulatory CHF patients, furosemide plus metolazone resulted in a significantly higher natriuresis compared with IV furosemide alone or furosemide plus acetazolamide.

Using modified Fenn diagrams to assess ventilatory acclimatization during ascent to high altitude: Effect of acetazolamide.

High altitude (HA) ascent imposes systemic hypoxia and associated risk of acute mountain sickness. Acute hypoxia elicits a hypoxic ventilatory response (HVR), which is augmented with chronic HA exposure (i.e., ventilatory acclimatization; VA). However, laboratory-based HVR tests lack portability and feasibility in field studies. As an alternative, we aimed to characterize area under the curve (AUC) calculations on Fenn diagrams, modified by plotting portable measurements of end-tidal carbon dioxide ( P ETC O 2 ${P_{{\mathrm{ETC}}{{\mathrm{O}}_{\mathrm{2}}}}}$ ) against peripheral oxygen saturation ( S p O 2 ${S_{{\mathrm{p}}{{\mathrm{O}}_{\mathrm{2}}}}}$ ) to characterize and quantify VA during incremental ascent to HA (n = 46). Secondarily, these participants were compared with a separate group following the identical ascent profile whilst self-administering a prophylactic oral dose of acetazolamide (Az; 125 mg BID; n = 20) during ascent. First, morning P ETC O 2 ${P_{{\mathrm{ETC}}{{\mathrm{O}}_{\mathrm{2}}}}}$ and S p O 2 ${S_{{\mathrm{p}}{{\mathrm{O}}_{\mathrm{2}}}}}$ measurements were collected on 46 acetazolamide-free (NAz) lowland participants during an incremental ascent over 10 days to 5160 m in the Nepal Himalaya. AUC was calculated from individually constructed Fenn diagrams, with a trichotomized split on ranked values characterizing the smallest, medium, and largest magnitudes of AUC, representing high (n = 15), moderate (n = 16), and low (n = 15) degrees of acclimatization. After characterizing the range of response magnitudes, we further demonstrated that AUC magnitudes were significantly smaller in the Az group compared to the NAz group (P = 0.0021), suggesting improved VA. These results suggest that calculating AUC on modified Fenn diagrams has utility in assessing VA in large groups of trekkers during incremental ascent to HA, due to the associated portability and congruency with known physiology, although this novel analytical method requires further validation in controlled experiments. HIGHLIGHTS: What is the central question of this study? What are the characteristics of a novel methodological approach to assess ventilatory acclimatization (VA) with incremental ascent to high altitude (HA)? What is the main finding and its importance? Area under the curve (AUC) magnitudes calculated from modified Fenn diagrams were significantly smaller in trekkers taking an oral prophylactic dose of acetazolamide compared to an acetazolamide-free group, suggesting improved VA. During incremental HA ascent, quantifying AUC using modified Fenn diagrams is feasible to assess VA in large groups of trekkers with ascent, although this novel analytical method requires further validation in controlled experiments.

Inappropriate Acetazolamide Use for a Hiker Who Developed Acute Kidney Injury.

Prophylactic use of acetazolamide (ACZ) to prevent acute mountain sickness (AMS) is a common practice among high altitude travelers and mountaineers. With its use comes a possible risk of acute kidney injury (AKI). We present a case in which a 56-year-old male hiker in Grand Canyon National Park developed acute exertional rhabdomyolysis and subsequent AKI while taking prophylactic ACZ to prevent AMS. This medication was prescribed despite the hiker encountering only moderate altitude at Grand Canyon with a planned descent within <24 h. The resulting AKI was determined to be the combined result of acute exertional rhabdomyolysis and dehydration/hypovolemia, with the ACZ, a diuretic, as a contributing factor. Medical providers need to recognize the risks/benefits with ACZ use for AMS prophylaxis and avoid prescribing it to individuals whose altitude exposure and activity fall outside the clinical practice guidelines recommended for use.

Sterile Cerebrospinal Fluid Ascites With High Serum Ascites Albumin Gradient Treated With Acetazolamide.

Cerebrospinal fluid (CSF) ascites is a rare cause of ascites that presents in patients with ventriculoperitoneal (VP) shunts, treated by conversion to a ventriculoatrial shunt. Our case describes a patient presenting with CSF ascites almost 40 years after VP shunt placement, with fluid analysis showing elevated serum ascites albumin gradient, and response to acetazolamide therapy. As shown in this case, CSF ascites can present with elevated serum ascites albumin gradient and should be kept a differential diagnosis. Acetazolamide can be considered as a potential alternative treatment in patients who are not candidates for a VP to ventriculoatrial shunt conversion.

Case for supporting astrocyte energetics in glucose transporter 1 deficiency syndrome.

In glucose transporter 1 deficiency syndrome (Glut1DS), glucose transport into brain is reduced due to impaired Glut1 function in endothelial cells at the blood-brain barrier. This can lead to shortages of glucose in brain and is thought to contribute to seizures. Ketogenic diets are the first-line treatment and, among many beneficial effects, provide auxiliary fuel in the form of ketone bodies that are largely metabolized by neurons. However, Glut1 is also the main glucose transporter in astrocytes. Here, we review data indicating that glucose shortage may also impact astrocytes in addition to neurons and discuss the expected negative biochemical consequences of compromised astrocytic glucose transport for neurons. Based on these effects, auxiliary fuels are needed for both cell types and adding medium chain triglycerides (MCTs) to ketogenic diets is a biochemically superior treatment for Glut1DS compared to classical ketogenic diets. MCTs provide medium chain fatty acids (MCFAs), which are largely metabolized by astrocytes and not neurons. MCFAs supply energy and contribute carbons for glutamine and γ-aminobutyric acid synthesis, and decanoic acid can also block α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptors. MCTs do not compete with metabolism of ketone bodies mostly occurring in neurons. Triheptanoin, an anaplerotic but also gluconeogenic uneven MCT, may be another potential addition to ketogenic diets, although maintenance of "ketosis" can be difficult. Gene therapy has also targeted both endothelial cells and astrocytes. Other approaches to increase fuel delivery to the brain currently investigated include exchange of Glut1DS erythrocytes with healthy cells, infusion of lactate, and pharmacological improvement of glucose transport. In conclusion, although it remains difficult to assess impaired astrocytic energy metabolism in vivo, astrocytic energy needs are most likely not met by ketogenic diets in Glut1DS. Thus, we propose prospective studies including monitoring of blood MCFA levels to find optimal doses for add-on MCT to ketogenic diets and assessing of short- and long-term outcomes.

Ibuprofen Compared to Acetazolamide for the Prevention of Acute Mountain Sickness: A Randomized Placebo-Controlled Trial.

INTRODUCTION: Acetazolamide is recommended for the prevention of acute mountain sickness (AMS); however, its use is limited in some areas because of side effects. Previous studies report ibuprofen to be similar to or slightly inferior to acetazolamide. This randomized, triple-blinded, parallel-group, placebo-controlled trial was designed to compare ibuprofen with acetazolamide for the prevention of AMS. METHODS: Four hundred forty-three healthy Asian Indian men with a mean age of 29 (range: 20-49) years were randomized into three groups A, B, and P at 350m (SL). Acetazolamide (A): 85 mg; ibuprofen (B): 600 mg; or placebo (P): calcium carbonate was administered thrice daily, starting one day prior and continuing for three days after arrival at 3500m (HA). Participants were evaluated for AMS using the Lake Louise Questionnaire and for pulse, BP, SpO2, and respiratory rate twice daily for the first two days during rest and once a day for days three to six at HA. RESULTS: Of the 443 participants recruited at SL, 139 could not be airlifted due to logistical limitations, and 304 were available for follow-up at HA. Among these, 254 had ascended as per protocol. By intent to treat (IT) (N = 304; A = 99, B = 102, P = 103), the incidence of AMS (LLQS>/=3) was 12%, 5%, and 13%, and the incidence of severe AMS was 1%, 2%, and 6%, in groups A, B, and P, respectively. Using per protocol analysis (PP) (N = 254; A = 83, B = 87, P = 84), the incidence of AMS was 12%, 6%, and 13% in groups A, B, and P, respectively. The relative risk for developing AMS vs. placebo was A-0.96 (CI:0.46-2.0, p=0.91), B-0.39 (CI:0.14-1.04, p=0.06), A-0.94 (CI:0.42-2.1, p=0.88), and B-0.45 (0.16-1.24, p=0.12) by IT and PP, respectively. CONCLUSION: Ibuprofen is effective in males for the prevention of AMS with rapid ascent to 3500 m-rest for the first two days. Acetazolamide was superior to ibuprofen in the prevention of moderate-to-severe AMS.

Acetazolamide and Hydrochlorothiazide in Patients With Acute Decompensated Heart Failure: Insights From Recent Trials.

Acetazolamide and thiazide diuretics have been combined with loop diuretics to overcome diuretic resistance in heart failure patients. However, recent studies have assessed the upfront combination of acetazolamide and hydrochlorothiazide with loop diuretics in hospitalized patients with acute decompensated heart failure without loop diuretic resistance. We reviewed two recent randomized controlled trials on the upfront use of acetazolamide and thiazide diuretics in acute decompensated heart failure, respectively. When the two trials on acetazolamide are considered together, adding oral or intravenous acetazolamide to loop diuretics in decompensated heart failure patients resulted in increased diuresis and natriuresis. However, the effects were significantly higher in patients with serum bicarbonate ≥ 27 mmol/L and those with higher baseline glomerular filtration rate (GFR). Similarly, when the two trials on thiazide diuretics are considered together, adding hydrochlorothiazide to loop diuretics in decompensated heart failure patients resulted in increased diuresis and weight loss. However, it increases the risk of impaired renal function. When all the trials are considered together, the upfront use of acetazolamide may be helpful in carefully selected patients, including patients with underlying elevated bicarbonate levels (≥ 27 mmol/L) and those with good renal function (GFR > 50). Conversely, though the upfront use of thiazide diuretic added to intravenous furosemide improved diuretic response in acute decompensated heart failure, it causes an increased risk of worsening renal function and lack of clear evidence of reducing hospital length of stay.

Combinational Diuretics in Heart Failure.

PURPOSE OF REVIEW: Diuretics are the cornerstone therapy for acute heart failure (HF) and congestion. Patients chronically exposed to loop diuretics may develop diuretic resistance as a consequence of nephron remodelling, and the combination of diuretics will be necessary to improve diuretic response and achieve decongestion. This review integrates data from recent research and offers a practical approach to current pharmacologic therapies to manage congestion in HF with a focus on combinational therapy. RECENT FINDINGS: Until recently, combined diuretic treatment was based on observational studies and expert opinion. Recent evidence from clinical trials has shown that combined diuretic treatment can be started earlier without escalating the doses of loop diuretics with an adequate safety profile. Diuretic combination is a promising strategy for overcoming diuretic resistance in HF. Further studies aiming to get more insights into the pathophysiology of diuretic resistance and large clinical trials confirming the safety and efficacy over standard diuretics regimens are warranted.

A mathematical model for temporal cerebral blood flow response to acetazolamide evaluated in patients with Moyamoya disease.

BACKGROUND: Paired cerebral blood flow (CBF) measurement is usually acquired before and after vasoactive stimulus to estimate cerebrovascular reserve (CVR). However, CVR may be confounded because of variations in time-to-maximum CBF response (tmax) following acetazolamide injection. With a mathematical model, CVR can be calculated insensitive to variations in tmax, and a model offers the possibility to calculate additional model-derived parameters. A model that describes the temporal CBF response following a vasodilating acetazolamide injection is proposed and evaluated. METHODS: A bi-exponential model was adopted and fitted to four CBF measurements acquired using arterial spin labelling before and initialised at 5, 15 and 25 min after acetazolamide injection in a total of fifteen patients with Moyamoya disease. Curve fitting was performed using a non-linear least squares method with a priori constraints based on simulations. RESULTS: Goodness of fit (mean absolute error) varied between 0.30 and 0.62 ml·100 g-1·min-1. Model-derived CVR was significantly higher compared to static CVR measures. Maximum CBF increase occurred earlier in healthy- compared to diseased vascular regions. CONCLUSIONS: The proposed mathematical model offers the possibility to calculate CVR insensitive to variations in time to maximum CBF response which gives a more detailed characterisation of CVR compared to static CVR measures. Although the mathematical model adapts generally well to this dataset of patients with MMD it should be considered as experimental; hence, further studies in healthy populations and other patient cohorts are warranted.

Exposure to topiramate and acetazolamide causes endocrine disrupting effects in female rats during estrus.

BACKGROUND: Idiopathic intracranial hypertension (IIH) is a disease characterized by elevated intracranial pressure (ICP) and is a disease of young females. The first line pharmacological treatments include acetazolamide and topiramate and given the nature of IIH patients and the dosing regimen of these drugs, their effect on the endocrine system is important to evaluate. We aimed to assess the effects of acetazolamide and topiramate on steroid profiles in relevant endocrine tissues. METHODS: Female Sprague Dawley rats received chronic clinically equivalent doses of acetazolamide or topiramate by oral gavage and were sacrificed in estrus. Tissue specific steroid profiles of lateral ventricle CP, 4th ventricle CP, CSF, serum, uterine horn and fundus, ovaries, adrenal glands and pituitary glands were assessed by quantitative targeted LC-MS/MS. We determined luteinizing hormone (LH) and follicle stimulating hormones (FSH) levels in paired serum by ELISA. RESULTS: Topiramate increased the concentration of estradiol and decreased the concentration of DHEA in lateral choroid plexus. Moreover, it decreased the concentration of androstenediol in the pituitary gland. Topiramate increased serum LH. Acetazolamide decreased progesterone levels in serum and uterine fundus and increased corticosteroid levels in the adrenal glands. CONCLUSION: These results demonstrate that both acetazolamide and topiramate have endocrine disrupting effects in rats. Topiramate primarily targeted the choroid plexus and the pituitary gland while acetazolamide had broader systemic effects. Furthermore, topiramate predominantly targeted sex hormones, whereas acetazolamide widely affected all classes of hormones. A similar effect in humans has not yet been documented but these concerning findings warrants further investigations.