Subsequent Titration Research Articles

#346 Oxylanthanum carbonate for hyperphosphatemia in ESKD: tolerability trial in progress

Abstract Background and Aims Despite current therapies, more than 43% of patients undergoing dialysis in the USA have hyperphosphatemia, defined as serum phosphate values >5.5 mg/dL and is commonly associated with an increased risk of death. Most currently available phosphate binders are known to cause gastrointestinal (GI) adverse events (AEs) that can negatively impact the patient experience. Common GI AEs include abdominal pain, nausea, and bloating. Phosphate binders are usually formulated as large tablets, and some must be chewed before ingestion. Commonly a high number of pills are needed per day to achieve goal serum phosphate levels. Oxylanthanum carbonate (OLC) is a new lanthanum-based nanotechnology product in development with a high in vitro binding capacity as compared to other phosphate binders. OLC is formulated as a small pill that is swallowed whole instead of being chewed before swallowing as is the case for lanthanum carbonate. The safety of OLC has been studied in >100 healthy subjects. The most common treatment-related AE (>5%) in an OLC bioequivalence (BE) study was nausea. This study aims to evaluate the tolerability of clinically effective (serum phosphate ≤5.5 mg/dL) doses of OLC in patients on hemodialysis. Method This open-label, single-arm, multicenter, multidose study will enroll up to 90 patients on hemodialysis who require phosphate binder therapy and have mean historical serum phosphate levels between ≥4.0 and ≤7.0 mg/dL for ≥8 weeks. The primary endpoint of the study is tolerability as assessed by the incidence of discontinuations due to treatment-related AEs. Additionally, the incidence of AEs related to OLC will be collected. Participants will undergo up to 3 weeks of phosphate binder washout until their serum phosphate levels reach >5.5 and ≤10.0 mg/dL (Fig. 1). During the 6-week Titration Period, all patients will receive 1500 mg/day OLC (500 mg TID with meals/snacks) for the initial 2 weeks, with subsequent titration every 2 weeks until achieving a target serum phosphate level (≤5.5 mg/dL) or to a maximum OLC dose of 3000 mg/day. After titration, patients will enter a 4-week Maintenance Period at the effective OLC dose. Results We intend to present results elucidating tolerability of clinically effective doses of OLC in patients on dialysis. Conclusion The tolerability of OLC at doses effective in achieving a serum phosphate ≤5.5 mg/dL in patients on hemodialysis will be evaluated in this study.

Effectiveness and optimization of low-sodium oxybate in participants with narcolepsy switching from a high-sodium oxybate: data from the Substitution of Equal Grams of Uninterrupted Xyrem to Xywav study.

Low-sodium oxybate (LXB; calcium, magnesium, potassium, and sodium oxybates; Xywav) contains the same active moiety as high-sodium oxybates (SXBs; SXB [Xyrem] and fixed-dose SXB [Lumryz]), with 92% less sodium, and is approved in the United States for treatment of cataplexy or excessive daytime sleepiness in patients 7 years of age and older with narcolepsy, and idiopathic hypersomnia in adults. Patients with narcolepsy have increased cardiovascular risk relative to people without narcolepsy. LXB's lower sodium content is recognized by the United States Food and Drug Administration in the narcolepsy population as clinically meaningful in reducing cardiovascular morbidity compared with SXBs. The Substitution of Equal Grams of Uninterrupted Xyrem to Xywav study (NCT04794491) examined the transition experience of patients with narcolepsy switching from SXB to LXB. Eligible participants were aged 18-80 years with narcolepsy type 1 or 2 on a stable SXB dose/regimen. After 2 weeks, participants transitioned gram-per-gram to LXB for 6 weeks, with opportunity for subsequent titration. Assessments included the Epworth Sleepiness Scale, Patient Global Impression of change, Ease of Switching Medication Scale, and Forced Preference Questionnaire. The study enrolled 62 participants at baseline; 60 transitioned to LXB and 54 completed the study. At baseline and end of the LXB intervention/early discontinuation, respectively, mean total doses were 8.0 and 8.0 g/night; mean Epworth Sleepiness Scale scores were 9.4 and 8.8. Most participants reported improvement (45%) or no change (48%) in narcolepsy symptoms on the Patient Global Impression of change, reported the transition to LXB was "easy" (easy, extremely easy, not difficult at all; 93%) on the Ease of Switching Medication Scale, and preferred LXB compared with SXB (79%) on the Forced Preference Questionnaire, most commonly due to the lower sodium content. Most participants switched from SXB to LXB with minimal modifications of dose/regimen and reported the transition process was easy. Effectiveness of oxybate treatment was maintained on LXB, and most participants preferred LXB to SXB. No new safety or tolerability issues were identified. Registry: ClinicalTrials.gov; Name: An Interventional Safety Switch Study (Segue Study) of XYWAV in Narcolepsy; URL: https://classic.clinicaltrials.gov/ct2/show/NCT04794491; Identifier: NCT04794491. Macfadden W, Leary EB, Fuller DS, Kirby MT, Roy A. Effectiveness and optimization of low-sodium oxybate in participants with narcolepsy switching from a high-sodium oxybate: data from the Substitution of Equal Grams of Uninterrupted Xyrem to Xywav study. J Clin Sleep Med. 2024;20(9):1467-1477.

Sertraline for anxiety in adults with a diagnosis of autism (STRATA): study protocol for a pragmatic, multicentre, double-blind, placebo-controlled randomised controlled trial

BackgroundSelective serotonin reuptake inhibitors (SSRIs) are commonly prescribed to manage anxiety in adults with an autism diagnosis. However, their effectiveness and adverse effect profile in the autistic population are not well known. This trial aims to determine the effectiveness and cost-effectiveness of the SSRI sertraline in reducing symptoms of anxiety and improving quality of life in adults with a diagnosis of autism compared with placebo and to quantify any adverse effects.MethodsSTRATA is a two-parallel group, multi-centre, pragmatic, double-blind, randomised placebo-controlled trial with allocation at the level of the individual. It will be delivered through recruiting sites with autism services in 4 regional centres in the United Kingdom (UK) and 1 in Australia. Adults with an autism diagnosis and a Generalised Anxiety Disorder Assessment (GAD-7) score ≥ 10 at screening will be randomised 1:1 to either 25 mg sertraline or placebo, with subsequent flexible dose titration up to 200 mg. The primary outcome is GAD-7 scores at 16 weeks post-randomisation. Secondary outcomes include adverse effects, proportionate change in GAD-7 scores including 50% reduction, social anxiety, obsessive-compulsive symptoms, panic attacks, repetitive behaviours, meltdowns, depressive symptoms, composite depression and anxiety, functioning and disability and quality of life. Carer burden will be assessed in a linked carer sub-study. Outcome data will be collected using online/paper methods via video call, face-to-face or telephone according to participant preference at 16, 24 and 52 weeks post-randomisation, with brief safety checks and data collection at 1–2, 4, 8, 12 and 36 weeks. An economic evaluation to study the cost-effectiveness of sertraline vs placebo and a QuinteT Recruitment Intervention (QRI) to optimise recruitment and informed consent are embedded within the trial. Qualitative interviews at various times during the study will explore experiences of participating and taking the trial medication.DiscussionResults from this study should help autistic adults and their clinicians make evidence-based decisions on the use of sertraline for managing anxiety in this population.Trial registrationISRCTN, ISRCTN15984604. Registered on 08 February 2021. EudraCT 2019-004312-66. ANZCTR ACTRN12621000801819. Registered on 07 April 2021.

Bexarotene-induced hypothyroidism and dyslipidemia; a nation-wide study.

Central hypothyroidism and dyslipidemia are well-known adverse events (AEs) of bexarotene therapy. Although hypothyroidism is known to cause dyslipidemia, no study has examined the association between hypothyroidism and dyslipidemia in patients undergoing bexarotene therapy. The aim of this study is to examine this association. A retrospective observational study was performed among 294 patients who initiated bexarotene therapy in Japan (nation-wide postmarketing complete surveillance). Jonckheere-Terpstra (one sided) test was performed to evaluate the effect of the bexarotene dose on lipid metabolisms, and regression analyses were performed to evaluate associations of bexarotene dose, free thyroxine (FT4), body mass index (BMI), and lipid metabolisms. Most patients developed hypothyroidism. Two-third of patients showed FT4 values below the lower limit at 1 week. Triglycerides (TG) increased in a bexarotene dose-dependent manner, and grade ≥3 AEs on hypertriglyceridemia was observed in 39% of the patients. Additionally, one-third of grade ≥3 AEs on hypertriglyceridemia occurred within 1 week. The delta_FT4 (difference in FT4 from baseline) negatively correlated with TG increase at 1 week (p = 0.012) but not with low density lipoprotein cholesterol (LDL-C) increase at any week. Bexarotene-induced hypothyroidism is almost inevitable and occurred quickly. Bexarotene-induced hypertriglyceridemia showed positive bexarotene dose dependency and negative delta_FT4 dependency. Prophylactic and appropriate thyroid hormone compensation therapy and starting bexarotene at low doses with subsequent titration while managing dyslipidemia may have a beneficial effect for the successful continuation of bexarotene therapy without severe endocrine and metabolic AEs.

FRI232 Importance Of Rapid Treatment Initiation In Ectopic Cushing Syndrome: Abstract

Abstract Disclosure: D. Mendez: None. M.G. Fernandez: None. D.J. Selen: None. Background: Endogenous Cushing syndrome may result from an ectopic non-pituitary tumor. Severe hypercortisolism has high mortality, so prompt medical management to acutely decrease cortisol levels is necessary when no surgical options are available. Clinical Case: A 67-year-old male presented to the hospital with four weeks of fatigue and was found to have a right hilar mass with unsuppressed cortisol levels for which an ectopic tumor was suspected. On initial evaluation, the patient presented with hypokalemia, acute kidney injury, and metabolic alkalosis. In addition, a CT of the chest and abdomen with contrast revealed a right hilar mass with multiple liver lesions concerning for metastasis. These findings prompted workup for hypercortisolism, including 1mg and 8 mg dexamethasone suppression tests. Both tests demonstrated unsuppressed cortisol levels above 150 (reference range [RR] 5.5-20 ug/dl and assay maximum>150) and elevated 24-hour urinary cortisol of 8125 (RR <60 ug/dl), suspicious for an ACTH-secreting tumor. Subsequently, he underwent a liver biopsy to characterize the tumor further and was started on Bactrim for Pneumocystis pneumonia prophylaxis. Metyrapone and osilodrostat were considered for treatment but not available at our facility such that treatment was initiated with ketoconazole 200 mg orally twice daily with subsequent dose titration. He had a mild elevation of AST 52 (RR 7-42 IU/L) and ALT 52 (RR 10-45); therefore, his liver profile was monitored daily due to his elevated risk for hepatotoxicity. With the initiation of ketoconazole, cortisol serum levels decreased to 145 ug/dl after two days of treatment. The pathology report revealed small lung cell carcinoma as the etiology for ectopic Cushing’s syndrome, for which the oncology team-initiated etoposide and carboplatin. Unfortunately, on day 6 of the initiation of treatment, the patient rapidly deteriorated and passed away from pneumonia and septic shock. Conclusion: Severe hypercortisolism leads to an immunosuppressed state resulting in high mortality. Therapeutic options depend significantly on the accessibility of first-line treatment options and prompt initiation of medical treatment. When no other agents are available, ketoconazole should be started at high doses despite the mild elevation of liver enzymes with close monitoring of LFTs. While it is unclear if the patient’s deterioration was due to his cancer burden, chemotherapy, severe hypercortisolism, or a combination, given that osilodrostat and metyrapone are first-line treatment options, standardized systems should be reviewed in hospitals for faster acquisition of these medications to avoid delays in treatment initiation. In addition, the decision to transfer patients to the intensive care unit for etomidate infusion while awaiting the acquisition of the above medications should be considered promptly. Presentation: Friday, June 16, 2023

SAT165 A Novel Mutation In The HNF4α Gene (C.691C>T, P.arg231trp) Likely To Be Pathogenic For Maturity Onset Diabetes Of The Young Type 1 Presenting With Hyperinsulinemic Hypoglycemia In An Infant

Abstract Disclosure: A. Rodriguez: None. S. Sastry: None. W. Chemaitilly: None. N. Gurtunca: None. Background: Maturity Onset Diabetes of the Young type 1 (MODY 1) is a monogenic form of diabetes mellitus caused by a defective HNF4α gene, resulting in reduced insulin secretion and diabetes in early adolescence and young adulthood. MODY 1 is also known to be associated with increased insulin secretion during fetal, neonatal and childhood periods with consequences that range from fetal macrosomia to persistent hyperinsulinism. Traditionally, HNF4α gene mutations represents 5% of all cases of diazoxide-responsive hyperinsulinism. Clinical Case: A 1 month old male born full term and large for gestational age (birth weight of 4920g) following an uncomplicated pregnancy and delivery developed hypoglycemia soon after birth and required hospital admission on day of life 2 with a serum glucose of 30 mg/dL and an insulin level of 5 uIU/mL. A fasting challenge showed hypoglycemia at 9 hours with a serum glucose of 47 mg/dL and an insulin level of 10.3 uIU/mL confirming hyperinsulinemic hypoglycemia. He was started on diazoxide to which he responded well and was placed on a continuous glucose monitor (CGM). He was originally started on diazoxide 8mg/kg/day that later was decreased to 6.6mg/kg/day due to blood glucoses in the 200’s. He passed the fasting study 5 days after starting diazoxide and went home with the CGM with subsequent dose titration made with guidance from remote data sharing. A neonatal hypoglycemia panel was sent and showed a novel mutation, c.691C>T, p.ARG231Trp in the HNF4α gene classified as a variant of uncertain significance. Computer modeling software suggested that this gene might disrupts the gene structure and function. This variant is present in population databases at a 0.0009% frequency and this missense change has been observed in individuals with clinical features of maturity onset diabetes of the young. Patient’s father carries the same mutation and paternal grandmother carries a diagnosis of type 2 diabetes mellitus. Conclusion: This is a novel mutation that should be considered pathogenic based on this patient’s neonatal presentation and previous literature. This case also presents possible uses of CGM in infants with diazoxide responsive congenital hyperinsulinism in order to decrease burden from monitoring and streamline communication with the medical team Presentation: Saturday, June 17, 2023

Development of methods for controlling the quality of hypochlorous acid solution obtained by electrochemical synthesis

The article presents materials on developing quality control methods for hypochlorite acid obtained by electrochemical synthesis. Electrochemical synthesis of hypochlorous acid was carried out using a combined electrochemical-pyrolytic method. The electrocatalytic activity of the obtained materials in the hypochlorite acid synthesis reaction was evaluated under the electrolysis of 0.05 M NaCl solutions in a duct cell with a Ti cathode at 25 ºС. The cathode area was varied, so the cathode current density was 40 mA/cm2. The pH of the solutions was monitored with a pX-150MI universal ionometer. The volumetric current density in the channel cell was 2.4 A/dm3, and the volumetric rate of solution supply was 9.5 l/h. The authors developed an original method of iodometric titration, which is based on the sequential determination of the content of hypochlorite ions, their total content with chlorite ions, and the total content simultaneously with chlorite and chlorate ions. The content of individual components of the mixture is determined as the difference between the total content of ions and the content of hypochlorite ions. The iodometric method of titration of oxidants is based on the reaction of replacing oxygen-containing compounds of chlorine with elemental iodine with its subsequent titration with standard solutions of sodium thiosulfate. It is proposed to fix the endpoint of the titration potentiometrically, which allows you to speed up the analysis, and it is also relatively easy to automate it using an automatic titrator. The content of oxygen-containing compounds in the solutions depends on the oxidation conditions and the specified operating modes of the electrochemical catalyst. The solution's acidity determines the presence of hypochlorous acid and can be calculated based on the equilibrium constant of its dissociation. The developed analysis methods will allow the control of the quality of veterinary drugs based on hypochlorous acid obtained by electrochemical synthesis.

Heat inactivation by high temperature as an approach to combat infections caused by airborne pathogens

The current pandemic of SARS-CoV-2 coronavirus infection has highlighted the importance of control measures to combat infections caused by airborne pathogens. Non-specific actions include various means of microorganism inactivation by chemical or physical methods targeting structural components of a given pathogen. Exposure of viruses and bacteria to elevated temperatures is one of the effective methods for discharging their harmful potential. Using a model of the Human Adenovirus 5 exposed to elevated temperatures with subsequent titration of the virus in vitro in A549 cells, we showed a dramatic decrease of the virus titer after heat treatment for 5 s at temperatures over 100°C. To verify the potential of the heat inactivation in a closed environment, the prototype of a high-capacity pathogen-cleaning device was constructed and tested. Application of the device for 2 h at an airflow rate of 900 m3/h in a room of 226 m3 reduced the total number of microorganisms in the air by more than 50% at all collection sites in the room.

0980 A Child with Achondroplasia, Cervicomedullary Junction Compression, Severe Obstructive Sleep Apnea and Pulmonary Hypertension

Abstract Introduction Achondroplasia is a short stature autosomal dominant skeletal dysplasia. Children with Achondroplasia are at risk for multiple medical comorbidities including sleep disordered breathing due to midface hypoplasia and craniocervical junction compression. Recent guidelines from American Academy of Pediatrics on health supervision of children with achondroplasia recommend routine clinical screening for symptoms of obstructive sleep apnea (OSA) and craniocervical junction compression in which case a polysomnogram should be considered. Report of case(s) The patient is a now 15 month old male who was initially seen in sleep medicine clinic at age 4 months for snoring and respiratory distress while awake. Polysomnogram 2 days later demonstrated severe OSA. The study demonstrated an oAHI of 25.1/hour, O2 nadir of 77%, and TcCO2 with evidence of significant hypoventilation with TcCO2 max of 67mmHg. This was adequately treated with supplemental oxygen. The patient subsequently presented to the emergency department at age 7 months with hypoxemic respiratory failure and signs of right heart failure and was started on CPAP. Echocardiogram demonstrated significant pulmonary hypertension. Subsequent CPAP titration study during admission demonstrated adequate treatment of OSA and his pulmonary hypertension significantly improved with the patient requiring no pulmonary hypertension treatment at discharge. At age 9 months, the patient was again admitted with hypoxemic respiratory failure and subsequent brain MRI demonstrated foramen magnum stenosis requiring subsequent surgical decompression. He was discharged on CPAP, however, was not tolerating this at home. Therefore, repeat polysomnogram was obtained that demonstrated severe OSA that was not responsive to supplemental oxygen. The patient was then started on BPAP therapy which he has since been tolerating well. Conclusion Children with achondroplasia are at increased risk for sleep disordered breathing and craniocervical junction compression. Our patient experienced significant complications from OSA at a young age. His sleep apnea worsened significantly in a short period making it unresponsive to previous treatment recommendations. There is a need for further studies to determine better screening guidelines for craniocervical junction narrowing and OSA. This case highlights the dynamic nature of sleep disordered breathing in achondroplasia and need for close follow up and monitoring of symptoms at all clinical encounters. Support (if any)

1018 Finally Awake: Treatment of Severe REM-Isolated Obstructive Sleep Apnea

Abstract Introduction Obstructive sleep apnea (OSA) is typically treated with positive airway pressure (PAP) therapy in symptomatic patients with ≥ 5 obstructive respiratory events (apneas, hypopneas or respiratory effort related arousals) per hour of sleep. In this case, we present a patient with severe OSA isolated to REM sleep who demonstrated significant symptomatic improvement on PAP therapy, despite an overall apnea-hypopnea index (AHI) of less than 5 events/hour. Report of case(s) A 73-year-old obese male with history of SVT, hypertension, and diabetes presented with symptoms of snoring, witnessed apneas, non-restorative sleep, restless sleep, excessive daytime sleepiness, and fatigue. A baseline polysomnogram (PSG) demonstrated severe OSA exclusively in REM sleep (overall AHI 2.9, REM AHI of 37.3, minimum SpO2 of 84%). A subsequent PAP titration study tested CPAP 5-17 and BPAP 19/15 cm of water but was unable to identify an effective pressure during REM sleep. Pressures as low as CPAP 5 cm of water appeared effective in NREM sleep. Ultimately, as the patient was unwilling to undergo a re-titration study, empiric treatment with auto-BPAP (min EPAP 5, max IPAP 25, PS 4) was initiated. With excellent adherence to BPAP therapy, the patient experienced profound symptomatic benefit, with resolution of daytime symptoms, less restlessness during sleep, and more restorative sleep. Conclusion This case highlights a gap, and potential pitfall, in current practice. Our patient 1) did not meet the overall AHI criteria for diagnosis of OSA yet had typical symptoms and high pretest probability for OSA; 2) had a PSG which showed severe OSA exclusively during REM sleep; and 3) experienced resolution of symptoms with PAP therapy. Presently, there is no consensus on whether REM-dependent OSA should be treated if the overall AHI is < 5 events/hour. In fact, there is no standardized definition for REM-dependent OSA. This patient with cardiovascular risk factors was able to receive PAP therapy through the Veterans’ Affairs, and access to PAP therapy changed the Veteran’s quality of life dramatically. Obtaining a PAP device for this patient through private payors would have been nearly impossible. More research is needed to understand the clinical implications of this condition. Support (if any)

Temporal analysis of products (TAP) reactor study of the dynamics of CO2 interaction with a Ru/γ-Al2O3 supported catalyst

As part of a comprehensive study on the reduction of COx on supported Ru catalysts we systematically investigated the dynamic interaction of CO2 with a Ru/γ-Al2O3 catalyst in a temporal analysis of products (TAP) reactor, focusing on the redox properties of the catalyst, specifically on the deposition of active oxygen (Oact) from CO2. This was investigated by exposing the pre-reduced catalyst to CO2 pulses and subsequent titration of the deposited Oact by CO pulses. CO2 is much less active for Oact deposition than O2. Reductive co-reactants reduce (CO) or increase (H2) the activity of CO2 for Oact deposition. 18O-marked CO2 pulses show facile oxygen exchange of CO2 with the catalyst, despite the inertness of the support. Based on excess effluent CO2 we conclude that surface carbonates can both build up on the surface upon interaction with CO or CO2 and also decompose upon O2 or CO2 pulsing, releasing additional CO2.

Vancomycin use for haemodialysis patients-Development of a new dosing protocol.

To develop a dosing and monitoring protocol to achieve therapeutic vancomycin levels on intermittent haemodialysis. We identified 15 vancomycin treatment courses received by patients on intermittent haemodialysis at a district health board in Auckland, New Zealand. Demographic, biochemical and clinical parameters were gathered from their health records. We subsequently devised and implemented a new vancomycin protocol consisting of weight-based loading dose, and subsequent dose titration according to same-day measured pre-dialysis levels. We then re-audited 16 vancomycin treatment courses to assess the performance of the protocol. A significantly higher proportion of vancomycin levels were within the target range (15-20 mg/L) following the implementation of protocol, from 23% to 46% (p< .005). Additionally, a greater proportion of treatment courses had >50% of pre-dialysis levels within the target range, rising from 13% to 56% (p< .01). In the pre-protocol group, 19 out of 117 doses of vancomycin were withheld during treatment, compared to 1 out of 118 doses in the post-protocol group. A total of 62% of total maintenance doses were administered in adherence to protocol. Length of hospital stay and number of positive blood cultures while on treatment were reduced. Our initial audit revealed deficiencies in our clinical practice in the absence of a local vancomycin protocol for patients receiving intermittent haemodialysis. Following the implementation of our novel protocol, there was an improvement in therapeutic levels and fewer doses were withheld. Our sample size was too small to allow for interpretation of clinical outcome data.

Arterial blood gas tensions during recovery in horses anesthetized with apneustic anesthesia ventilation compared with conventional mechanical ventilation

ObjectiveTo compare PaO2 and PaCO2 in horses recovering from general anesthesia maintained with either apneustic anesthesia ventilation (AAV) or conventional mechanical ventilation (CMV). Study designRandomized, crossover design. AnimalsA total of 10 healthy adult horses from a university-owned herd. MethodsDorsally recumbent horses were anesthetized with isoflurane in oxygen [inspired oxygen fraction = 0.3 initially, with subsequent titration to maintain PaO2 ≥ 85 mmHg (11.3 kPa)] and ventilated with AAV or CMV according to predefined criteria [10 mL kg–1 tidal volume, PaCO2 40–45 mmHg (5.3–6.0 kPa) during CMV and < 60 mmHg (8.0 kPa) during AAV]. Horses were weaned from ventilation using a predefined protocol and transferred to a stall for unassisted recovery. Arterial blood samples were collected and analyzed at predefined time points. Tracheal oxygen insufflation at 15 L minute–1 was provided if PaO2 < 60 mmHg (8.0 kPa) on any analysis. Time to oxygen insufflation, first movement, sternal recumbency and standing were recorded. Data were analyzed using repeated measures anova, paired t tests and Fisher’s exact test with significance defined as p < 0.05. ResultsData from 10 horses were analyzed. Between modes, PaO2 was significantly higher immediately after weaning from ventilation and lower at sternal recumbency for AAV than for CMV. No PaCO2 differences were noted between ventilation modes. All horses ventilated with CMV required supplemental oxygen, whereas three horses ventilated with AAV did not. Time to first movement was shorter with AAV. Time to oxygen insufflation was not different between ventilation modes. ConclusionsAlthough horses ventilated with AAV entered the recovery period with higher PaO2, this advantage was not sustained during recovery. Whereas fewer horses required supplemental oxygen after AAV, the use of AAV does not preclude the need for routine supplemental oxygen administration in horses recovering from general anesthesia.

Определение содержания йода, йодидов и йодатов в пищевых продуктах

Currently iodine deficiency diseases are one of the most important medical and social problems. In this regard, the purpose of the study is to determine the content of iodine, iodides, iodates in iodized salt, drinking and mineral water, seaweed, to determine the stability of the iodine content in salt. For the qualitative determination of iodides and iodates ions in salts and molecular iodine in seaweed, an iodine starch reaction has been carried out. The presence of iodide ions in iodized water has been determined by reaction with silver nitrate and chlorine water, the iodine released has been extracted with chloroform. Quantitative determination of iodine in salt has been carried out by the titrimetric method, in water – by colorimetric method, in seaweed – by gravimetric method with subsequent titration. The study has found that iodized salt contains iodine in the form of potassium iodate, in an amount of 18.65 μg / g of elemental iodine, kelp contains molecular iodine in the amount of 8.12 μg / g of elemental iodine, and iodized water contains potassium iodide in the amount of 0.327 μg / ml of elemental iodine. The study has proved that over time, the amount of iodine in the salt iodized with potassium iodate decreases after a month by 5.6 times. In order to comply with the daily rate of iodine intake, it is necessary to include in your diet about 9.7 g of iodized salt, which exceeds the daily norm of its consumption in 5 g. In this regard, it is recommended to use iodized salt (not more than 5 g) or iodized water (0.7 L of water) or kelp (18.47 g) as a prevention of iodine deficiency.

Relationship between the dose titration and adherence of mirogabalin in patients with peripheral neuropathic pain depending on renal function: a nationwide electronic medical record database study

ABSTRACT Background Mirogabalin has been attracting attention for treating peripheral neuropathic pain. The package insert recommends that mirogabalin should be titrated depending on renal function. Here, we investigated the relationship between dose titration patterns and adherence, and persistence of mirogabalin treatment. Research design and methods Peripheral neuropathic pain patients who initiated mirogabalin between March 2020 and May 2021 were identified using an electronic medical record database. The dose titration pattern was described according to degrees of renal function. Regression analyses were performed to compare adherence and persistence between the patients with and without titration. Results Of the 4,138 identified patients, 1,696 (41.0%) titrated the dose within 45 days and were more adherent than those without titration (Adjusted odds ratio: 1.75, 95% CI 1.21, 2.54). Of the total 952 patients with renal function parameters, 229 (24.1%) titrated to the effective dose within 45 days and were less likely to discontinue than those without titration (Adjusted hazard ratio: 0.57, 95% CI 0.40, 0.81). Conclusion Mirogabalin dose titration was associated with better adherence and persistence. It is important for mirogabalin treatment to determine the initial prescription dose based on renal function and subsequent dose titration according to the package insert. Trial registration UMIN000047313

ODP173 Control of Alpelisib-Induced Hyperglycemia With DPP4- Inhibitors as add on to Metformin and Insulin

Abstract Context Alpelisib is an oral phosphatidylinositol-3-kinase alpha (PI3Ka) inhibitor approved in 2019 for treatment of ER/PR+, HER2-negative advanced breast cancer. The main side effect of PI3Ka inhibition is hyperglycemia. Case A 38 year-old woman was started on alpelisib and fulvestrant therapy for Stage IV bilateral breast carcinoma (ER+, PR+, HER2-negative) with multiple distant metastases. She had previously received multiple courses of systemic therapy with palbociclib, letrozole, and everolimus, in combination with fulvestrant. She was lean (BMI 20.6 kg/m 2), had a prior history of GDM only requiring diet control, and pre-existing pre-diabetes, with a baseline FPG of 5.6 mmol/L and HbA1c of 5.9%. She developed hyperglycemia after 2 months of Alpelisib 200 mg OD (FPG 138.6 mg/dL; HbA1c 5.8%) and was started on metformin 500 mg BD. Glucose levels remained under control (fasting BG of 108-126 mg/dL) until alpelisib dose was increased to 300 mg OD. Within 6 weeks of dose increment, her fasting BG markedly increased to 324 mg/dL and HbA1c to 10%. Metformin dose was increased to 1000 mg BD, linagliptin 5 mg OD and isophane insulin at 8 units once daily, was introduced in addition to lifestyle modifications. Due to the side effects resulting in diarrhea, alpelisib was discontinued temporarily for 3 weeks before subsequent reintroduction and titration to a maximum tolerable dose of 200 mg OD. Glycemic control subsequently improved with metformin, linagliptin and titration of insulin to 14units daily, with HbA1c reduction to 6. 0% and fasting BG of 84.6 mg/dL, without any hypoglycemia. Oncological assessment showed disease response, with smaller primary tumour and stable metastatic lesions. Discussion The PI3K/AKT pathway plays a central role in cellular growth and glucose metabolism. This pathway is a potent target of anticancer therapy. In physiological glucose homeostasis, postprandial insulin secretion activates the PI3Ka pathway, subsequently upregulating glucose transporters for cellular uptake and utilization of glucose. In the phase III clinical trial (SOLAR-1), the incidence of alpelisib-induced hyperglycemia was 63.7%, and was treated with insulin sensitizers such as metformin and pioglitazone. Subsequent case series have reported effective glycemic control using very low calorie diet (VLCD), SGLT2-inhibitors and insulin therapy 1 . In our patient, linagliptin, was chosen as an adjunct therapy in addition to metformin due to its mechanism of action that address insulin resistance and favourable safety profile. We also note that the severity of alpelisib side effects appeared to be dose-dependent, as seen in the clinical trial. Conclusion We demonstrated effective control of alpelisib-induced hyperglycemia using DPP4-inhibitors as an option, in combination with metformin and insulin.

Effects of guideline directed medical therapy on secondary mitral regurgitation

Abstract Background Guideline directed medical therapy (GDMT) is the recommended initial treatment for secondary mitral regurgitation (SMR), however supported by only little comprehensive evidence. This study therefore sought to assess the effect of GDMT titration on SMR and to identify specific substance combinations able to reduce SMR severity. Methods We included 261 patients who completed two visits with an echocardiographic exam available within one month at each visit. After comprehensively defining GDMT titration as well as SMR reduction, logistic regression analysis was applied in order to assess the effects of overall GDMT titration and specific substance combinations on SMR severity. Results SMR severity improved by at least one degree in 39.3% of patients with subsequent titration of GDMT and was accompanied by reverse remodelling and clinical improvement. The effects of GDMT titration were significantly associated with SMR reduction (adj. OR 0.31, 95% CI 0.13–0.71, P=0.006). Moreover, ARNI as well as the combined dosage effects of (i) renin angiotensin system inhibitors (RASi) and mineralocorticoid-receptor antagonists (MRA), (ii) betablockers (BB) and MRA, as well as (iii) RASi, BB, and MRA were all significantly associated with SMR improvement (P&amp;lt;0.001 for all). Conclusions The present study provides comprehensive evidence for the effectiveness of contemporary GDMT to specifically improve SMR. Our data indicates that GDMT titration conveys a threefold increased chance of reducing SMR severity. Moreover, the dosage effects of ARNI, as well as the combination of RASi and MRA, BB and MRA, and all three substances in aggregate are able to significantly improve SMR. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): FWF - Austrian Science Fund

Determination of Metoclopramide Hydrochloride in Pharmaceutical Formulations using N-Oxidation Caroate.

To develop two (titrimetric and spectrophotometric) simple, rapid, sensitive and cost-effective methods for the determination of metoclopramide (MCP) in pharmaceutical dosage forms. The titrimetric method (A) was based on the N-oxidation reaction involving the use of potassium hydrogen peroxymonosulfate and subsequent iodometric back titration of a known residual reagent. The spectrophotometric method (B) was based on derivatization of MCP with potassium hydrogen peroxymonosulfate in the presence of iodide to produce a chromogen (triiodide) with a wavelength of maximum absorption at 350 nm. Method "A" was applicable over the concentration range of 0.25-3.5 mg to end volume 10 mL. In method "B", Beer's law was obeyed over the concentration range of 0.3-3.5 μg/mL with molar absorptivity of 24600 L/mol cm. The limits of quantification were calculated to be 0.25 mg/10 mL (A) and 0.2 μg/mL (B), respectively. The proposed methods were suitable for determination of MCP as a pure substance in tablets and injection.

Preferential Recognition of Human Telomeric G-Quadruplex DNA by a Red-Emissive Molecular Rotor.

The development of new fluorescent molecules for the recognition of specific G-quadruplex DNA structures has attracted wide attention due to their diverse roles in drug design, sensing, and cellular probing. In this work, we report the discovery of a red-emissive styryl quinolinium-based molecular rotor (compound 1), which recognizes human telomeric G-quadruplex with a distinct preference over DNA duplexes. Optical spectroscopy (UV-vis and circular dichroism)-based experiments indicated discernible interaction of compound 1 with the human telomeric DNA G-quadruplex with features of stacking interactions. Fluorescence-based Job's plot revealed a 1:1 binding stoichiometry between compound 1 and the human telomeric DNA G-quadruplex, and subsequent titration experiments showed micromolar affinities (Ka = 0.51 × 106 M-1). Molecular docking experiments showed interactions of compound 1 in the grooves of the quadruplex. Finally, we provide the application of compound 1 as a reporter molecule in the fluorescence displacement experiments, which showed its ability to act as a fluorescent probe compatible with ligands having aromatic cores.

Mapping of the sGC Stimulator BAY 41-2272 Binding Site on H-NOX Domain and Its Regulation by the Redox State of the Heme.

Soluble guanylate cyclase (sGC) is the main receptor of nitric oxide (NO) and by converting GTP to cGMP regulates numerous biological processes. The β1 subunit of the most abundant, α1β1 heterodimer, harbors an N-terminal domain called H-NOX, responsible for heme and NO binding and thus sGC activation. Dysfunction of the NO/sGC/cGMP axis is causally associated with pathological states such as heart failure and pulmonary hypertension. Enhancement of sGC enzymatic function can be effected by a class of drugs called sGC “stimulators,” which depend on reduced heme and synergize with low NO concentrations. Until recently, our knowledge about the binding mode of stimulators relied on low resolution cryo-EM structures of human sGC in complex with known stimulators, while information about the mode of synergy with NO is still limited. Herein, we couple NMR spectroscopy using the H-NOX domain of the Nostoc sp. cyanobacterium with cGMP determinations in aortic smooth muscle cells (A7r5) to study the impact of the redox state of the heme on the binding of the sGC stimulator BAY 41-2272 to the Ns H-NOX domain and on the catalytic function of the sGC. BAY 41-2272 binds on the surface of H-NOX with low affinity and this binding is enhanced by low NO concentrations. Subsequent titration of the heme oxidant ODQ, fails to modify the conformation of H-NOX or elicit loss of the heme, despite its oxidation. Treatment of A7r5 cells with ODQ following the addition of BAY 41-2272 and an NO donor can still inhibit cGMP synthesis. Overall, we describe an analysis in real time of the interaction of the sGC stimulator, BAY 41-2272, with the Ns H-NOX, map the amino acids that mediate this interaction and provide evidence to explain the characteristic synergy of BAY 41-2272 with NO. We also propose that ODQ can still oxidize the heme in the H-NOX/NO complex and inhibit sGC activity, even though the heme remains associated with H-NOX. These data provide a more-in-depth understanding of the molecular mode of action of sGC stimulators and can lead to an optimized design and development of novel sGC agonists.