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AUTHOR CONTRIBUTIONS | PMC10632612 |
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CONFLICT OF INTEREST STATEMENT | Andrew H. Talal has received honoraria and funds to his institution from Gilead Sciences and Abbvie Inc. The other authors declare no conflict of interest. | PMC10632612 |
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ETHICS STATEMENT | This study was approved by the University at Buffalo Institutional Review Board (IRB) and by IRBs at each of the sites where the study was conducted. All participants provided written informed consent before study participation. | PMC10632612 |
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ACKNOWLEDGEMENTS | The authors thank the study participants for their participation and the staff at each of the study sites. The authors also acknowledge Darlene Meyer for interviewing assistance, Ravi Krishnan, and Harrison He for assistance with transcript verification. This work was supported by a Patient‐Centred Outcomes Research Institute (PCORI) Award (IHS‐1507‐31640) and partially supported by the Troup Fund of the Kaleida Health Foundation. The statements in this work are solely the responsibility of the authors and do not necessarily represent the views of PCORI, its Board of Governors or Methodology Committee. | PMC10632612 |
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DATA AVAILABILITY STATEMENT | The data that support the findings of this study are available from the corresponding author upon reasonable request. | PMC10632612 |
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REFERENCES | PMC10632612 |
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Background | PONV, Postoperative nausea and vomiting | SIDE EFFECT | Postoperative nausea and vomiting (PONV) is a common side effect associated with general anesthesia. Both ondansetron and aprepitant been effectively used to prevent PONV. However, there is a disagreement of opinions regarding the superiority of these two drugs. This study aims to compare the efficacy of aprepitant with ondansetron in preventing PONV following orthognathic surgeries. | PMC10717277 |
Methods | PONV | In this double-blinded clinical trial, 80 patients scheduled for orthognathic surgery at Imam Hossein Hospital, Tehran, Iran, were randomly assigned to two groups. A standardized anesthesia protocol was used for all patients. The first group received a placebo capsule administered one hour before the surgical procedure along with 4 mg (2 ml) of ondansetron intravenously after anesthesia induction. The second group was given 80 mg aprepitant capsules one hour before the surgery, followed by an injection of 2 ml intravenous distilled water after anesthesia induction.The occurrence and severity of PONV, the amount of rescue medication required, and the complete response of patients assessed within 24 h after the surgery. | PMC10717277 |
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Results | nausea, vomiting | There were no significant differences in demographic data between the two groups. Patients in the aprepitant group had a significantly lower incidence and severity of nausea (2.5% versus 27.5%), vomiting (5% versus 25%), and required fewer rescue medications (7.5% versus 62.5%) compared to the ondansetron group. Additionally, the aprepitant group showed a higher complete response rate (90% versus 67.5%) in the 0-2 and 12-24 postoperative hours. | PMC10717277 |
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Conclusion | PONV | According to the findings of this study, aprepitant has demonstrated a greater efficacy in preventing PONV following orthognathic surgery, when compared to ondansetron. | PMC10717277 |
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Trial registration | Iranian Registry of Clinical Trials (IRCT code: IRCT20211205053279N3), date of registration: 16/12/2022. | PMC10717277 |
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Keywords | PMC10717277 |
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Introduction | PONV, emesis, nausea and vomiting, postoperative pain | SIDE EFFECT | Post-operative nausea and vomiting (PONV) is a common side effect of general anesthesia that can significantly decrease patient satisfaction. In fact, many patients find PONV more distressing than postoperative pain [Aprepitant is a highly selective neurokinin-1 (NK1) receptor and substance P antagonist. It is commonly used to prevent nausea and vomiting in patients undergoing chemotherapy, as well as to prevent opioid-induced emesis [ | PMC10717277 |
Methods | PMC10717277 |
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Study design ethics, and patient population | PONV, hypersensitivity, abnormal liver or renal function | MOTION SICKNESS, HYPERSENSITIVITY | This study was a double-blinded, randomized clinical trial that was carried out in the oral and maxillofacial surgery department of Imam Hossein Hospital (Tehran-Iran). This study was approved by the Research Ethics Committees of the research institute of Dental sciences-Shahid Beheshti University of medical sciences and registered at the Iranian Registry of Clinical Trials (IRCT code: IRCT20211205053279N3) and conducted following the Declaration of Helsinki. All patients provided written informed consent to participate in the study.All patients between the ages of 15-50 years with an American Society of Anesthesiologists (ASA) physical status of I–II scheduled to undergo orthognathic surgery under general anesthesia were enrolled in this study between April 31, 2022, and March 8, 2023. Exclusion criteria were as follows: abnormal liver or renal function, patients with known hypersensitivity to ondansetron or aprepitant, and pregnant or nursing mothers. Patient information, including gender, history of PONV and motion sickness, and smoking status was recorded. Computer-generated random numbers divided the patients into two groups. Randomization was forwarded directly to a nurse who was not involved with the patients’ management and assessment. | PMC10717277 |
Intervention | The first group received a placebo capsule administered one hour before the surgical procedure along with 4 mg (2 ml) of ondansetron intravenously after anesthesia induction. The second group was given 80 mg aprepitant capsules one hour before the surgery, followed by an injection of 2 ml intravenous distilled water after anesthesia induction.All patients undergo Lefort I maxillary advancement osteotomy and Bilateral Sagittal Split Osteotomy mandibular setback surgery with the Dalpont method. Fixation of the maxilla was done by 4 L-shaped plates with 4 holes and fixation of the mandible by 3 screws.The anesthesia method of all patients was similar. Firstly, initial standard monitoring including non-invasive blood pressure (NIBP), heart rate (HR), electrocardiogram (ECG), end-tidal-CO | PMC10717277 |
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Assessment of outcomes | PONV, nausea, vomiting | The duration of surgery and the total amount of administered narcotics were recorded. All patients were kept in PACU for two hours and while assessing their vital signs (BP, HR, and SPO2), the occurrence and severity of PONV were evaluated and recorded as the primary outcome. In addition, the feeling of nausea, the frequency of vomiting, and the amount of receiving antiemetics rescue medicine after transferring to ward in time period intervals up to 24 h after the surgery were evaluated by an investigator who was unaware of the patients group. The 11-point verbal rating scale (VRS) index was used to record nausea. In this index, patients were asked to assign a number from 0 to 10 to assess their feeling of nausea, where the number zero means the absence of nausea and the number ten most intense feelings of nausea. The investigator also recorded the number of vomiting. A single dose intravenous 20 mg metoclopramide used as the rescue therapy of nausea, which allowed it to be administered by the investigator in case of vomiting; nausea with a score higher than seven did that lasted for more than 15 min and at the patient's own request. | PMC10717277 |
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Statics | nausea, vomiting | Based on Gan et al. [The data was analyzed using Statistical Package for Social Sciences (SPSS) software (version 21, SPSS INC., Chicago, IL, USA). Demographic and other patient characteristics were expressed as means ± standard deviations. Values < 0.05 were considered statistically significant. For analyzing patient demographics, the cumulative incidence of vomiting at each time point, the incidence of nausea, rescue antiemetic use, and complete response (no vomiting and no rescue) in periods of 0–2, 2–6, 6–12, and 12-24 h after surgery t-test and | PMC10717277 |
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Discussion | nausea, postoperative pain, anxiety, cancer, nausea and vomiting, vomiting, pain, hypoxemia, Nausea, PONV, depression, Diemensch | CANCER, ELECTROLYTE DISTURBANCE, COMPLICATIONS, COMPLICATION | Advancements in surgical techniques and the development of new anesthesia drugs have significantly reduced the occurrence of severe, life-threatening side effects. However, despite these improvements, the issue of PONV remains a persistent concern and none of the current antiemetic drugs has been able to resolve this simple but important problem.Apipan et al. consider that PONV is the most common complication after orthognathic surgery under general anesthesia. This complication causes a decaying and undesirable feeling, and the occurrence of serious but albeit complications such as aspiration, postoperative hypoxemia, water and electrolyte disturbances, opening of the surgical incision, and delay in the discharge of patients [In a double-blind clinical trial conducted by Salome Jeyabalan et al., the researchers aimed to compare the efficacy of two different treatment regimens in preventing PONV. They divided 120 patients who underwent abdominal or thyroid surgery into two groups. One group received ondansetron along with aprepitant, while the other group received ondansetron with a placebo. The primary outcomes measured were the incidence of nausea and vomiting, as well as the time required for rescue drugs to be administered. They concluded that a single dose of 40 mg of aprepitant had a comparable effect to 8 mg of intravenous ondansetron every 8 h in preventing PONV, the severity of nausea, the number of times rescue medication was requested, and the time of the first nausea attack in 24 h after surgery. The findings of this study about the effectiveness of aprepitant on PONV are similar to our study. However, the design of their study is different from our study because they injected ondansetron in both groups at the end of the operation and then every 8 h, while in our study only one group of patients received ondansetron and the patients in the aprepitant group received distilled water instead of ondansetron [In a randomized double-blind study, Diemensch P et al. compared the effect of two single doses of aprepitant (40 mg and 125 mg) with 4 mg of intravenous ondansetron on the prevention of PONV in 922 patients who underwent general anesthesia for open abdominal surgery. They recorded episodes of vomiting, the use of rescue medication, and the severity of nausea for 48 h. The primary outcome was a complete response (no vomiting and no use of rescue therapy) within 0-24 h of surgery. They concluded that both doses of aprepitant were non-inferior to ondansetron in achieving a complete response in the first 24 h. Aprepitant was significantly more effective than ondansetron in preventing vomiting and reducing nausea in both 24 and 48 h. The findings of our study are consistent with the mentioned study [In a randomized double-blind study, Bergese et al. compared the three drugs of aprepitant, dexamethasone, and promethazine with ondansetron, dexamethasone, and promethazine on declining the incidence of PONV in 176 patients who underwent craniotomy under general anesthesia. The researchers concluded that both triple-drug regimens have a similar effect on the prevention of PONV. The results of this study regarding the superiority of ondansetron over aprepitant are different from our study. The explanation for the discrepancy in the results between our study and the study conducted by Bergese et al. is not entirely clear. However, the differences in patient populations between the two studies, variations in the dosages or administration of two additional drugs (dexamethasone, and promethazine), and differences in study design (sample size, randomization methods, blinding techniques, and outcome measures), may contribute to discrepancies between two studies [Gan TJ et al. in a multicenter study compared the effect of two different doses of oral aprepitant for the prevention of PONV on patients who underwent open abdominal surgery under general anesthesia. In their study, patients divided into three groups. The first and second groups received 40 and 125 mg of oral aprepitant, respectively, and the third group received 4 mg of intravenous ondansetron. The researchers concluded that for the prevention of vomiting in the first 48 h after the operation, aprepitant is superior to ondansetron, but there is no significant difference between aprepitant and ondansetron in controlling nausea, using rescue drugs, and complete response. The results of our study regarding the occurrence of vomiting are consistent with the results of the above study. However, regarding the use of rescue drugs and control of nausea and complete response, the results of this study are inconsistent with our study, which be attributed to the difference in kind of surgery in the patients of the two studies and the possibility of lower chance of complete response and reduction of nausea in open abdominal surgeries [In a randomized double-blind clinical trial, Hassan AME et al. divided 150 patients who underwent laparoscopic bariatric surgery into three groups (50 patients in the ondansetron group (A), 50 patients in the aprepitant group (B), and 50 patients in the ondansetron group + aprepitant [Safarnejad F et al. compared the effect of aprepitant and ondansetron on PONV following laparoscopic cholecystectomy separately and in combination in their study. They divided patients into three groups. The first group received 80 mg of oral aprepitant, the second group received 4 mg of intravenous ondansetron, and the third group received 4 mg of intravenous ondansetron and 80 mg of oral aprepitant. Nausea and vomiting in the third group were less than the other two groups. In addition, the occurrence of vomiting in the first group was significantly lower than in the second group. Results of the mentioned study were consistent with our findings [In a systematic review, Liu et al. reviewed 14 clinical trials about the effects of two doses of 40- and 80-mg of aprepitant on PNOV. According to their systematic review, both doses of aprepitant are more effective than 4 mg of ondansetron in preventing PONV. According to the results of the mentioned studies and the current study, in the first 24 h after the surgery, aprepitant compared to ondansetron significantly reduces the incidence and severity of nausea and vomiting, use of rescue medication, and increases complete response [Kakuta and colleagues in a study investigated the effectiveness of aprepitant on nausea and vomiting, and post-operative pain. They concluded that aprepitant not only reduces nausea and vomiting but also increases pain tolerance. Investigation about postoperative pain was not among our study goals [Aprepitant is traditionally used in the treatment of nausea and vomiting caused by cancer chemotherapy. Recently, it has been observed that aprepitant is effective not only in the treatment of PONV but also in reducing postoperative pain. Substance P is one of the neurotransmitters that is found in both central and peripheral nerves. It has been found that after binding to neurokinin 1 receptors, substance P regulates many biological functions of the central nervous system, such as emotions, negative behaviors, stress, depression, pain, and anxiety. Neurokinin 1 receptor antagonists specifically inhibit some biological functions that mediated by the binding of substance P to neurokinin 1 receptors [ | PMC10717277 |
Limitation | The current study had several limitations. First, the aprepitant was administered 60 min before the induction of anesthesia. Considering that it takes approximately 3 h for the oral aprepitant to reach the maximum blood concentration [ | PMC10717277 |
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Conclusion | postoperative nausea and vomiting | According to the findings of this study, aprepitant has demonstrated a greater efficacy in preventing postoperative nausea and vomiting following orthognathic surgery, when compared to ondansetron. | PMC10717277 |
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Acknowledgements | This article derived from Sadaf Nasseri dental doctoral thesis. The authors would like to thank the Research Center of Shahid Beheshti University of Medical Sciences for providing support, and resources to succeed this study. We would like to thank Imam Hossein hospital operative room staffs for their collaboration and supports too. | PMC10717277 |
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Authors’ contributions | MA: substantial contributions to the conception and design of the work; interpretation of data; have drafted the work. AK: substantial contributions to the conception and design of the work; interpretation of data; have drafted the work. AS: the design of the work; analysis, interpretation of data; have drafted the work. SN: conception and design of the work; the acquisition, interpretation of data; drafted the work or substantively. KN: conception and design of the work; the acquisition, interpretation of data; drafted the work or substantively. | PMC10717277 |
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Funding | No funding was received in any forms. | PMC10717277 |
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Availability of data and materials | The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. | PMC10717277 |
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Declarations | PMC10717277 |
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Ethics approval and consent to participate | https://irct.ir/16/12/2022 | This study was by the Ethics Committee of the research institute 0f Dental sciences-Shahid Beheshti University of medical sciences approved this study. The study registered at the Iranian Registry of Clinical Trials ( https://irct.ir/16/12/2022, IRCT20211205053279N3). All patients signed the informed consent form, and all methods were carried out in accordance with the Declaration of Helsinki. | PMC10717277 |
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Consent for publication | Not applicable. | PMC10717277 |
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Competing interests | The authors declare no competing interests. | PMC10717277 |
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References | PMC10717277 |
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Key words | PE, diabetes mellitus, Preeclampsia | SECONDARY, DIABETES MELLITUS, PREECLAMPSIA | Preeclampsia (PE) affects up to five times more women with pre-existing diabetes mellitus (PDM) than women without it. The present study aimed to identify the effect of the DASH diet on PE incidence (primary outcome) and blood pressure, glycated haemoglobin (GH), serum lipids, glutathione peroxidase (GP), C-reactive protein (CRP – secondary outcomes) in pregnant with PDM. This randomised, controlled, single-blind trial studied sixty-eight pregnant women with PDM throughout prenatal care until delivery (18 weeks) at a public maternity hospital, Brazil. The standard diet group (SDG) received a diet containing 45–65 % carbohydrates, 15–20 % protein and 25–30 % lipids. The DASH diet group (DDG) received the adapted DASH diet with a similar macronutrient distribution, but with a higher concentration of fibres, unsaturated fats, calcium, magnesium and potassium as well as lower saturated fat. Student's | PMC10345782 |
Abbreviation | PMC10345782 |
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Introduction | diabetes mellitus, GHS, hypertensive, Diabetes, weight loss | DIABETES MELLITUS, DIABETES MELLITUS (DM), SECONDARY, SYNDROMES, DIABETES | Gestational hypertensive syndromes (GHS) affect about 14 % of pregnancies worldwide. In Latin America and the Caribbean, they are responsible for 22 % of maternal deathsWomen with pre-existing diabetes mellitus (PDM), either type 1 or type 2, are considered to be at a higher risk of developing PE. With the increased prevalence of diabetes mellitus (DM) observed in recent years, the proportion of pregnant women with PE is also on the riseThe American Diabetes AssociationIn addition, the DASH diet seems to help reduce the blood pressure, body weight loss and lipid profile of women of reproductive age, besides having a protective effect against the development of gestational DMGiven the scientific evidence of the protective effect of the DASH diet on inflammatory markers, blood pressure and lipid levels in adult populations, the primary aim of this study was to evaluate the effect of the DASH diet adapted to Brazilian women with PDM on the PE incidence, and its secondary aim was to assess its effect on maternal metabolic outcomes (blood pressure, glycated haemoglobin, serum lipids, glutathione peroxidase, CRP). | PMC10345782 |
Experimental methods | PMC10345782 |
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Design | The study was a randomised, controlled, single-blind, two-arm treatment trial. The women were not told which treatment group they were allotted to. The study protocol was registered on the Brazilian Clinical Trials Registration Platform (Rebec – RBR-4tbgv6).The study was conducted between November 2016 and March 2020 at the maternity teaching hospital of the Federal University of Rio de Janeiro (MT/UFRJ), Brazil. MT/UFRJ is a reference in Rio de Janeiro for the prenatal care of women with PDM. Pregnant women diagnosed with DM are referred to it from primary care centres through an online system (SISREG).Eighty-seven pregnant women with PDM were recruited to participate in the study, and those who accepted and met the inclusion criteria were randomly allocated to the study groups: standard diet group (SDG) or adapted DASH diet (DDG) (Summary of patient enrolment and follow-up. | PMC10345782 |
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Participants | The study population consisted of pregnant women diagnosed with PDM before referral, whose diagnosis was confirmed by an endocrinologist at the study site according to the criteria of the Brazilian Society of DiabetesAll the women received prenatal care throughout pregnancy from a multidisciplinary team at MT/UFRJ. Data were collected from the pregnancy, postpartum and newborn medical records and in face-to-face interviews with a nutritionist. All data were collected by a trained and supervised research team.Insulin doses for both study groups were set by the endocrinologist based on the patients’ gestational weight. In addition, the women were instructed to self-monitor their blood glucose by measuring capillary blood glucose at least six times a day, before and after meals. Finally, all the women who began prenatal care before 16 weeks of gestation were prescribed a daily dose of 100 mg aspirin. All three practices are part of the routine prenatal care offered at the study site. | PMC10345782 |
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Randomisation | Upon enrolment, the women were randomly allocated to either the SDG or the DDG using a random number from a list prepared using Excel® 2007. The women who received an odd number were put in the SDG and the women with an even number were put in the DDG by the nutritionist. The pregnant women did not know which study group they belonged to; only the researcher responsible for providing the nutritional guidance had this information. | PMC10345782 |
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Nutritional intervention | fat-free milk, weight gain | COMPLICATIONS | The nutritional intervention for both groups occurred from enrolment to the end of pregnancy and included a minimum of six individual appointments with the nutritionist when individualised guidance was given according to the occurrence of maternal complications. To improve dietary adherence, the women from the DDG were given a portion of seeds (200 g), nuts (150 g) and fat-free milk (280 g) at each visit, while the women from the SDG received a portion of oats (250 g) and low-fat milk (1–2 %, 300 g). All the women were also given a 500 ml bottle of extra-virgin olive oil at their first appointment.In the preparation of the dietary plans, two methods of dietary guidance were used – the traditional method and the carbohydrate counting method – which the women themselves selected according to their preferenceThe total energy value of each diet was calculated individually to promote adequate gestational weight gain. The proportion of macronutrients was similar for the two groups, ranging from 45 to 55 % carbohydrates, 15 to 20 % proteins and 25 to 30 % lipidsAll the women with low calcium intake (<900 mg/d) were prescribed 500 mg calcium carbonate supplementation per day from the 20th gestational week onwards | PMC10345782 |
Standard diet | Diabetes | DIABETES | The standard diet was the diet already recommended in routine prenatal nutritional care at the study site, which is consistent with American Diabetes Association guidelines | PMC10345782 |
Adapted DASH diet | The DASH diet used in the study was the version translated into Portuguese and adapted to the Brazilian population by Saunders A comparison of the constituents of the standard and DASH diets applied in the present research was published in the study of Fagherazzi | PMC10345782 |
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Anthropometric assessment | Weight measurements (kg) were taken at all the appointments using an electronic platform scale, and height (m) was measured using a stadiometer attached to the scale. Measurements were taken according to standard nursing practice at the study site | PMC10345782 |
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Assessment of food consumption and dietary adherence | weight gain | Food intake was assessed in two 24 h recalls administered during the 3rd (between the 22nd and 24th gestational week) and 5th (between the 29th and 34th gestational week) nutritional appointments. Foods in the 24 h recalls were expressed in household measurements, which were then quantified in grams or millilitres per day using a conversion tableAdherence to the diets was assessed by reported food intake and weekly weight gain | PMC10345782 |
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Biochemical assessment | Venous blood samples (10 ml) were collected after 8–12 h fasting at baseline and after 12 weeks of intervention at a specialised laboratory. Serum glycated haemoglobin concentration (%) was determined by turbidimetry, and total cholesterol (mg/dl), triglycerides (mg/dl), high-density lipoprotein cholesterol (HDL-c, mg/dl) and low-density lipoprotein cholesterol (LDL-c, mg/dl) were determined by an enzymatic colorimetric method. Glutathione peroxidase (μmol/l) was quantified by an enzymatic method and CRP (mg/dl) was evaluated by turbidimetry. All exams were performed using commercials kits. | PMC10345782 |
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Diagnosis of PE | hypertension, proteinuria | HYPERTENSION | PE was diagnosed by the medical team based on: the gradual development of hypertension (after the 20th gestational week) and the presence of proteinuria (>0⋅3 g protein excretion in 24 h urine), or chronic hypertension associated with proteinuriaThe risk of developing early PE, up to the 34th gestational week, was estimated using the algorithm created and published by the Fetal Medicine Foundation | PMC10345782 |
Sociodemographic, biological and obstetric assessment | THYROID DISORDERS, HYPERTENSION, CHRONIC DISEASES | The characteristics evaluated were: partnership status (partnered/unpartnered), maternal age (years) skin colour (by self-classification – white/black or brown), household income (in multiples of the minimum wage, based on its 2019 value) and educational level (high school non-graduate/high school graduate or higher education). As for the patients’ obstetric history, parity (0/≥1) and personal history of GHS (yes/no) were obtained.The biological characteristics collected were: type of DM, duration of DM and presence of chronic diseases (hypertension and/or thyroid disorders). In addition, prenatal care variables were observed: gestational age at the first prenatal appointment and the first prenatal nutritional appointment (weeks), the total number of prenatal appointments and prenatal nutritional appointments calcium supplements use (yes/no) and basal insulin use. | PMC10345782 |
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Outcomes | SECONDARY | The primary outcome was the PE incidence (%). The secondary outcomes included systolic and diastolic blood pressure levels (mmHg), changes in glycated haemoglobin (%), total cholesterol (mg/dl), LDL-c (mg/dl), HDL-c (mg/dl), triglycerides (mg/dl), CRP (mg/dl) and glutathione peroxidase (μmol/l). All secondary outcomes were compared between study groups (inter-group analysis) and were also compared within each group (intra-group analysis) and considered the means or medians variations between baseline and post-intervention. | PMC10345782 |
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Sample size | HYPERTENSIVE DISORDER | The sample size was calculated based on the primary outcome (prevalence of hypertensive disorders of pregnancy) using G*Power | PMC10345782 |
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Statistical analysis | Data distribution was evaluated by the Shapiro–Wilk test and visual inspection. The sample was described using mean and standard deviation, median and interquartile range, or relative and absolute frequencies. To identify differences in the general characteristics and dietary intake of the groups, the Student's The PE incidence (primary outcome) and categorical variables were compared between the groups using the χStudent's | PMC10345782 |
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Ethical issues | All the women in the study signed an informed consent form and the project was approved by the ME/UFRJ research ethics committee on 07/31/15 (CAAE 47335515.0.0000.5275). The study was registered in the Brazilian Clinical Trials Registration Platform (Rebec – RBR-4tbgv6) and was conducted according to the guidelines laid down in the Declaration of Helsinki. | PMC10345782 |
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Discussion | T1DM, cardiovascular disease, TohdiniThe, GDM, Diabetes, diabetes | HIGH-RISK PREGNANCIES, CARDIOVASCULAR DISEASE, GDM, DIABETES, HYPERTENSIVE DISORDER, OXIDATIVE STRESS, HYPERTENSION, DIABETES | No differences between the group that received the standard diet and the group that received the adapted DASH diet were observed for the incidence of PE during the intervention. DDG showed an increase in serum concentrations of glutathione peroxidase and both diets contributed to a reduction of glycated haemoglobin. As the authors are unaware of any previous research evaluating the effect of the DASH diet on pregnant women with PDM, the discussion draws on the findings of studies with pregnant women with some other risk factors for PE.The incidence of total PE in this study was 17⋅7 %. According to Persson In the present study, the adapted DASH diet was not associated with any improvement in blood pressure or incidence of PE, which corroborates the findings of Fulay Studies have found that women with DM and PE have higher serum glycated haemoglobin concentrations during pregnancyThe adapted DASH diet in this study had no effect on serum lipid concentrations, unlike in the women with GDM studied by Asemi Regarding the oxidative stress marker, the DDG group had increased glutathione peroxidase and a tendency to reduce levels of the inflammatory marker CRP, which suggests improved control of oxidative stress. According to Taravati and TohdiniThe nutritional intake of the women on the DASH diet described by Asemi Interestingly, the food intake of the research participants from both groups met the Brazilian Diabetes Society recommendationsThe modest findings of this research could be attributable to the difference between the metabolic conditions of the population under study and pregnant women with GDM or hypertensive disorders and the variations in dietary adherence observed in both groups throughout the study, resulting in a similar nutritional intake, not to mention the influence of Brazilian dietary habits. Further, both groups received prenatal care at a referral hospital for mid- to high-risk pregnancies from a multidisciplinary team which involved regular medical appointments and a minimum of six prenatal appointments with a nutritionist, meaning that both study groups were given guidance in line with the dietary recommendations of the Brazilian Society of Diabetes.To date, no studies have verified the effect of the DASH diet on the prevention of PE in pregnant women with PDM, making this research unique in its scope. One limitation was the sample size, which was not large enough to ascertain the effects of the DASH diet and the fact that a private laboratory outside the study site was used to collect the blood for the analysis of the biochemical parameters, constituting a difficulty in obtaining more samples for analysis. Furthermore, the study period coincided with the COVID-19 pandemic, which meant data collection had to be interrupted due to the need for social isolation. The population of pregnant women with PDM is very heterogeneous concerning the type of diabetes and the presence of comorbidities, so it was not possible to conduct separate analyses for the women with T1DM and T2DM.The adoption of the standard diet or adapted DASH diet, together with multidisciplinary prenatal care, seems to have resulted in adequate glycaemic control, with no difference in the incidence of PE, considering partial adherence to diets. Nonetheless, the adapted DASH diet seems to favour biochemical markers related to oxidative stress, which are associated with the development of PE. This finding suggests that the adapted DASH diet may be an option for pregnant women with PDM who have other risk factors for cardiovascular disease in addition to chronic hypertension. However, further studies are needed with larger sample sizes to confirm these results. | PMC10345782 |
Acknowledgements | P., preeclampsia | PREECLAMPSIA | Lenita Zajdenverg and Marcus Miranda for their collaboration in the interpretation of the preeclampsia cases, and Joffre Amin Jr and Jorge Rezende Filho for their support throughout the development of the study.This research received financial assistance from the National Council for Scientific and Technological Development (CNPq – grant number: 409032/2016-6) and the Research Support Foundation of the State of Rio de Janeiro (FAPERJ – grant number: E-26/202.972/2016-6), and members of the research team had individual grants from CAPES and CNPq.The authors’ contributions were as follows: C. S. was responsible for the research design; C. S., P. C. P. and G. P. B. planned the study. G. P. B., K. S., L. B. G. S., T. S. V. L., E. S.G., P. C. P., R. B. G. B. and K. C. B. R. conducted the research; G. P. B. and D. R. F. performed the statistical analyses. All the authors wrote the paper and contributed to this work.None of the authors has any conflicts of interest to declare. | PMC10345782 |
References | PMC10345782 |
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Background | CHOLINE DEFICIENCY, CYSTIC FIBROSIS | Choline deficiency leads to pathologies particularly of the liver, brain and lung. Adequate supply is important for preterm infants and patients with cystic fibrosis. We analysed the assimilation of four different enterally administered deuterium-labelled (D9-) choline supplements in adults. | PMC10195734 |
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Methods | Prospective randomised cross-over study (11/2020–1/2022) in six healthy men, receiving four single doses of 2.7 mg/kg D9-choline equivalent each in the form of D9-choline chloride, D9-phosphorylcholine, D9-alpha-glycerophosphocholine (D9-GPC) or D9-1-palmitoyl-2-oleoyl-glycero-3-phosphoryl-choline (D9-POPC), in randomised order 6 weeks apart. Plasma was obtained at baseline ( | PMC10195734 |
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Results | Maximum D9-choline and D9-betaine concentrations were reached latest after D9-POPC administration versus other components. D9-POPC and D9-phosphorylcholine resulted in lower D9-trimethylamine (D9-TMAO) formation. The AUCs (0-7d) of plasma D9-PC concentration showed highest values after administration of D9-POPC. D9-POPC appeared in plasma after fatty acid remodelling, predominantly as D9-1-palmitoyl-2-linoleyl-PC (D9-PLPC), confirming cleavage to 1-palmitoyl-lyso-D9-PC and re-acylation with linoleic acid as the most prominent alimentary unsaturated fatty acid. | PMC10195734 |
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Conclusion | There was a delayed increase in plasma D9-choline and D9-betaine after D9-POPC administration, with no differences in AUC over time. D9-POPC resulted in a higher AUC of D9-PC and virtually absent D9-TMAO levels. D9-POPC is remodelled according to enterocytic fatty acid availability. D9-POPC seems best suited as choline supplement to increase plasma PC concentrations, with PC as a carrier of choline and targeted fatty acid supply as required by organs. This study was registered at Deutsches Register Klinischer Studien (DRKS) (German Register for Clinical Studies), DRKS00020498, 22.01.2020. | PMC10195734 |
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Study registration | This study was registered at Deutsches Register Klinischer Studien (DRKS) (German Register for Clinical Studies), DRKS00020498. | PMC10195734 |
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Supplementary Information | The online version contains supplementary material available at 10.1007/s00394-023-03121-z. | PMC10195734 |
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Keywords | Open Access funding enabled and organized by Projekt DEAL. | PMC10195734 |
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Introduction | breast milk | CYSTIC FIBROSIS, CHOLINE DEFICIENCY | Nutritional supply of choline as an essential nutrient is often not sufficient [In preterm infants, plasma levels of choline rapidly fall by 50% after birth, leading to an unphysiological decrease during a time of exponential growth and choline requirements [The liver’s choline homeostasis is important to secrete bile PC for triglyceride emulsification and to synthesise lipoprotein PC for the assembly and secretion of very low-density lipoproteins (VLDL). Notably, choline can be mobilised from the lung as high-density lipoprotein PC, which may become ‘choline-exhausted’ as it comprises only ¼ of the hepatic choline pool, to compensate for the liver’s choline deficiency [Choline requirement is not covered by endogenous synthesis. Choline was, therefore, defined as an essential nutrient by the US-Food and Drug Administration (FDA) and National Academy of Medicine of the USA (NAM) in 1998 and European Food Safety Authority (EFSA) by 2016. NAM defined the adequate intake (AI) for male adults as 550 mg/d (= ~ 7–8 mg/kg/d) [In contrast to choline salts (like choline chloride) as common components in choline supplements, nutritional choline is physiologically provided as organic esters, with phosphorylcholine and GPC dominating in breast milk and PC dominating in regular food after weaning. We aimed to analyse differences in the metabolism and kinetics of these different choline supplements to define their differences in assimilation and effects on plasma concentration of choline and its metabolites and on TMAO formation. Aim was finding an effective and safe supplement resulting in low levels of TMAO in plasma after administration. This will be important for patient groups with typically low levels of choline like preterm infants or patients with cystic fibrosis. Beyond this, we found that PC as a choline supplement, other than water-soluble compounds, substantially affected the metabolism of polyunsaturated fatty acids (LC-PUFA), therefore possibly being a tool in concert with LC-PUFA supplementation. We used D9-choline chloride, D9-phosphorylcholine, D9-GPC and D9-POPC as stable-isotope-labelled analogues of the respective natural choline supplements. | PMC10195734 |
Methods | This is a randomised cross-over study, carried out at the Department of Neonatology, Tübingen University Hospital, Germany. Six healthy adult men were recruited and studied between November 2020 and January 2022. The Institutional Review Board (project number 322/2019BO1) approved the protocol, and written informed consent was obtained prior to enrolment. | PMC10195734 |
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Inclusion criteria | chronic diseases, acute illness, thyroid diseases, alcohol abuse, diabetes | PANCREAS INSUFFICIENCY, CHRONIC DISEASES, THYROID DISEASES, METABOLIC SYNDROME, DIABETES | Test persons had to be male and at least 18 years old.Exclusion criteria were alcohol abuse, acute illness, chronic diseases (like diabetes, metabolic syndrome, thyroid diseases, pancreas insufficiency), intake of choline containing nutritional supplements or missing consent. | PMC10195734 |
Supplements | D9-phosphorylcholine chloride | The deuterium-labelled (D9) analogues choline-d9 chloride [N,N,N-trimethyl-d9] (D9-choline chloride), D9-phosphorylcholine chloride, calcium salt (D9-phosphorylcholine), D9-alpha-glycerophosphorylcholine (D9-GPC) and D9-1-palmitoyl-2-oleoyl-glycero-3-phosphorylcholine (D9-POPC) were from EQ Laboratories GmbH (Augsburg, Germany). Pure substances were aliquoted into screw capped opaque glass vials by Rainfarn-Apotheke (RAINFARN Gesundheit, Munich, Germany). Substances were delivered as dry substance for oral application in suitable quantity for a single administration of 350 mg D9-choline chloride, 620 mg D9-phosphorylcholine, 620 mg D9-GPC and 1.8 g D9-POPC to achieve a single dose of 2.7 mg/kg D9-choline equivalent. | PMC10195734 |
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Study schedule | STERILE, BLOOD | Directly prior to use, substances were dissolved/emulsified in 10 ml sterile water and topped up with 250 ml apple spritzer. Test subjects had to ingest in a randomised sequence at least 6 weeks (w) apart D9-choline metabolite for wash out.D9-choline chloride (3.6 mg/kg),D9-phosphorylcholine chloride (6.4 mg/kg),D9-alpha GPC (6.4 mg/kg) orD9-POPC (18.6 mg/kg)Experiments started in the morning after overnight fasting, and the supplement was served in 250 mL apple spritzer together with a butter pretzel (102 g) containing 16.9 mg total choline and 10.3 mg betaine as well as 12 g fat. Detailed composition of the study meal fatty acids is shown in Table s1 of the online supplement.Blood (2.7 ml EDTA) was taken before intake (− 0.1 h) and at 0.5 h, 1 h, 1.5 h, 2 h, 3 h, 4 h, 5 h, 6 h, 9 h, 24 h, 33 h and 48 h, 3d, 4d and 7d after D9-choline intake. Test persons fasted until the 6 h-blood sample was collected. Collected blood was immediately centrifuged at 1000x | PMC10195734 |
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Chemical analysis | The analyses of deuterium-labelled choline and its metabolites were performed with electrospray ionisation tandem mass spectrometry (ESI–MS/MS) as previously described [ | PMC10195734 |
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D9-choline and its water-soluble downstream metabolites | Figure Plasma kinetics of D9-choline (By contrast, ingestion of D9-POPC resulted in delayed (Similarly, the kinetics and maximum concentrations of D9-betaine were different in response to D9-POPC compared to water-soluble compounds (Fig. Finally, the concentrations of D6-dimethylglycine (D6-DMG), the demethylation product of D9-betaine used for (D3-)methionine synthesis from homocysteine, was lower after D9-POPC ingestion compared to the other deuterium-labelled compounds (Fig. Plasma kinetics of D6-DMG (Panel A) and D9-TMAO (Panel B) in response to deuterium-labelled (D9-) choline supplements. Inserts also show concentrations over time, focussing on a shorter time period (9 h). Data are shown as medians and interquartile ranges. | PMC10195734 |
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D9-TMAO | D9-TMAO was absent in response to both D9-POPC and D9-phosphocholine ingestion, but was detected after D9-choline chloride and D9-GPC, with a tendency to a later increase after D9-GPC (Fig. | PMC10195734 |
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D9-choline-labelled phospholipids in response to different D9-choline compounds | As demonstrated in Fig. Plasma kinetics of the sum of D9-labelled phosphatidylcholine (D9-PC) ( | PMC10195734 |
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Differential D9-PC metabolism in response to D9-POPC compared to water-soluble D9-choline supplements | To differentially address the metabolism of fatty acids of PC in response to supplements, D9-PC was differentiated into sub-groups containing different unsaturated fatty acid residues [Plasma concentrations of D9-PC sub-groups in response to deuterium-labelled (D9-) choline supplements. D9-PC molecular species were sub-grouped into those containing an oleic (D9-C18:1-PC) (Molar fractions of D9-PC sub-groups in plasma in response to deuterium-labelled (D9-) choline supplements. D9-PC molecular species were sub-grouped into those containing an oleic (D9-C18:1-PC) (Concentration changes of D9-C18:1-PC were virtually identical for all D9-choline supplements (Fig. | PMC10195734 |
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D3-PC from the PEMT pathway | To estimate the use of different D9-choline supplements for their contribution to methyl group metabolism and PC synthesis via PE methylation to form PC via the PEMT pathway, we investigated the plasma concentrations of D3-PC in response to D9-choline supplements. In this pathway, (D9-)betaine from (D9-)choline oxidation is required to synthesise (D3-) methionine, which after activation to (D3-)-S-adenosylmethionine is used to form D3- (and D6) PC [ | PMC10195734 |
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Discussion | Choline has been defined as an essential nutrient, with daily adequate intake (AI) values for healthy adult men of 550 mg according to NAM [All water-soluble supplements rapidly and similarly increased D9-choline and D9-betaine plasma levels, with maximum concentrations achieved at 0.5–1 h. This is consistent with the results on single administration of an AI dosage of unlabeled choline supplements in adults [The increase in plasma D9-choline concentration after D9-POPC administration, however, was different in two ways. First, plasma concentrations increased later, peak concentrations were delayed from 0.5–1 h to ~ 1.5 h and the peaks were broader, indicating different mechanisms of D9-choline assimilation from lipidic D9-POPC. Such more retarded and longer lasting increase may be of benefit for achieving a balanced increase in plasma choline concentrations. After ingesting the AI value of choline (550 mg) in the form of egg-PC (4012 mg), maximum values of plasma choline were delayed to 3 h, but maximum concentrations were similar to water-soluble choline components. This discrepancy may be due to the higher dosage of ~ 7 mg/kg choline in our previous study, compared to 2.7 mg/kg D9-choline equivalent used here as a tracer, and the higher sensitivity of metabolic follow-up using deuterium-labelled compared to native compounds [Second, the maximum value and AUC of plasma D9-choline were lower after D9-POPC compared to water-soluble D9-choline components. It was suggested that lyso-PC is only partly degraded to free choline within the enterocytes, whereas ~ 50% are re-synthesised to PC, using available coenzyme A-activated fatty acids (acyl-CoA) and lyso-PC acyltransferases (LPCAT) [ | PMC10195734 |
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Plasma D9-PC and D3-PC metabolism in response to D9-choline supplements | PC is the major carrier for the plasma transport of long-chain polyunsaturated fatty acids (LC-PUFA), mainly arachidonic (ARA) and docosahexaenoic acid (DHA) to organs, via lipoproteins [In general, the formation of betaine, and its D9-enrichment correlated with the plasma concentrations of D3-PC (see supplementary Figure s5A). In this context, the lower increase in plasma D9-betaine and, subsequently, in D3-PC in response to D9-POPC, compared to its water-soluble D9-choline analogues, may be important for the homeostasis of methyl groups. In response to the ingestion of D9-POPC, compared to that of D9-choline chloride, D9-GPC and D9-phosphocholine, the generation of free D9-choline, D9-betaine and D6-dimethylglycine was decreased and, instead, (D9-PO)PC was used by the enterocytes via (D9-) lyso-PC re-acylation to PC for chylomicron formation. In line with this, D9-PC concentrations in plasma rapidly increase and maximal concentrations are highest after (D9-PO)PC as a choline supplement. Whilst D9-POPC resulted in lower plasma concentrations of free D9-choline, D9-betaine and D6-dimethylglycine (D6-DMG), it should be noticed that the administration of any water-soluble components not only normalises plasma choline concentrations, but may increase plasma betaine above physiological values [ | PMC10195734 |
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Differential kinetics of plasma D9-PC in response to D9-choline supplements | Administration of water-soluble D9-choline compounds resulted in an increase of plasma D9-PC that showed uniform peak concentrations at 24-33 h, and a plasma half-life of 2-3d as previously demonstrated after both enteral and parenteral D9-choline chloride administration [Such fatty acid specificity is consistent with the PC synthesis de novo by adult liver, and contrasts to the preferential synthesis of C22:6-PC and C20:4-PC synthesis by the PEMT pathway using betaine as a methyl donor [Importantly, assimilation of D9-POPC resulted in an earlier (9 h) and twofold higher peak concentration of D9-PC without plateau and an increased AUC. This indicates that (D9-)choline assimilation from (D9-PO)PC is faster with respect to plasma (D9-)PC increase, suggesting preferential use of ingested (D9-PO)PC for the (D9-)PC moiety of chylomicrons (see above). The similarly rapid decrease of D9-PC after D9-POPC and other compounds, reaching similarly low levels at 72 h (see Fig. | PMC10195734 |
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Impact of different choline supplements on endogenous PC synthesis by PEMT | Our data show that, in response to (D9-PO)PC, the plasma concentrations of free (D9-)choline and (D9-)betaine are decreased but their hepatic use for the synthesis of (D3-)methionine as a methyl donor and (D3-)PC synthesis from PE via the PEMT pathway is not decreased. Hence, hepatic secretion of VLDL, where both PC synthesis de novo and via the PEMT pathway are essential [ | PMC10195734 |
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Potential consequences of choline supplementation via PC instead of water-soluble components | MINOR | The assimilation of D9-POPC, via cleavage to D9-lyso-PC, preferential small intestinal re-acylation to D9-PC and chylomicron assembly (see above), contrasted the hepatic D9-choline, -betaine, -PC and -VLDL metabolism as represented by the other D9-choline supplements. Although D9-POPC belongs to the D9-C18:1-PC subgroup, D9-C18:1-PC concentration was not increased here, but contrary to the other D9-choline supplements, remained a minor fraction of plasma D9-PC (see Figs. | PMC10195734 |
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Formation of (D9-)TMAO in response to (D9-)choline supplements | In addition to the efficacy of a choline supplement, safety is paramount. Therefore, we also investigated the concentration of D9-TMAO, the hepatic oxidation product of D9-TMA that is a bacterial D9-choline degradation product. TMAO has been described as a cardiovascular risk factor [Differences in absorption may also apply to (D9-) choline chloride and (D9-)GPC, where the latter showed a later increase of TMAO (> 6 h) that was not detected in a previous study at 0–6 h [ | PMC10195734 |
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Conclusion | There was a retarded increase in plasma D9-choline and D9-betaine as well as higher peak concentrations and AUCs of D9-PC and virtually absent D9-TMAO formation after D9-POPC and D9-phosphocholine administration. The use of (D9-PO)PC as a choline supplement for preferential enterocytic synthesis of polyunsaturated (D9-)PC implies the option of optimising DHA, and ARA supply for preterm infants [ | PMC10195734 |
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Supplementary Information | Below is the link to the electronic supplementary material.Supplementary file1 (PPTX 195 KB) | PMC10195734 |
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Abbreviations | Adequate intakeCystic fibrosisEthylenediaminetetraacetateEuropean Food Safety AuthorityUS-Food and Drug AdministrationAlpha-glycerophosphocholineGenerally recognised as safeNational Academy of Medicine of the USAPhosphatidylcholine(D9-)1-palmitoyl-2-oleoyl-PC(D9-choline labelled)PC containing an oleic acid residue(D9-choline labelled)PC containing a linoleic acid residue(D9-choline labelled)PC containing an arachidonic acid residue(D9-choline labelled)PC containing an eicosapentaenoic acid residue(D9-choline labelled)PC containing a docosahexaenoic acid residueD9-labelled sphingomyelinD9-labelled trimethylamine oxide | PMC10195734 |
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Authors’ contributions | MM, ARF | ARF | WB and AF conceptualised the study. KB, WB and AF drafted the manuscript. MM and KB coordinated and supervised the study, contributed to sample collection and assessment of clinical data and approved the final manuscript as submitted. WB developed the analytical techniques, supervised the analyses, contributed to sample collection, drafted and reviewed the manuscript, and approved the final manuscript as submitted. AS prepared the samples, and carried out the mass spectrometry analyses. CW critically revised the manuscript making important contributions, and approved the final manuscript as submitted. CFP supervised the project as the head of department, revised the manuscript for important intellectual input and approved the final manuscript as submitted. ARF, the co-coordinator of the project, was responsible for concept and design, contributed to sample collection and the assessment of clinical data, revised the manuscript and approved the final manuscript as submitted. | PMC10195734 |
Funding | Open Access funding enabled and organized by Projekt DEAL. This investigator-initiated trial was partly funded by a research grant from HiPP-Werk Georg Hipp OHG, a manufacturer of infant formula and partly funded by a research grant from the Ministry of Economy of the State of Baden-Württemberg (AsphyxDx, Az. 35-4223.10/17). The funding entities had no influence on trial design, data acquisition or analysis. | PMC10195734 |
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Declarations | PMC10195734 |
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Conflict of interest | The authors declare that they have no conflict of interest to disclose. Trial Registration: This trial was registered at | PMC10195734 |
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Ethical standards | The study has been approved by the institutional ethics committee and performed in accordance with the ethical standards laid down in the 64th WMA General Assembly, Fortalezza, Brazil, October 2013. Test persons gave their written informed consent prior to inclusion in the study. | PMC10195734 |
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References | PMC10195734 |
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ABSTRACT | headaches, mild/moderate, hypoparathyroidism, PaTHway, hypocalcemia | HYPOCALCEMIA, SECONDARY, HYPOPARATHYROIDISM, ADVERSE EVENTS | Conventional therapy for hypoparathyroidism consisting of active vitamin D and calcium aims to alleviate hypocalcemia but fails to restore normal parathyroid hormone (PTH) physiology. PTH replacement therapy is the ideal physiologic treatment for hypoparathyroidism. The double‐blind, placebo‐controlled, 26‐week, phase 3 PaTHway trial assessed the efficacy and safety of PTH replacement therapy for hypoparathyroidism individuals with the investigational drug TransCon PTH (palopegteriparatide). Participants (TransCon PTH is an investigational once‐daily prodrug providing sustained release of active PTH designed to maintain stable PTH levels in the physiological range for 24 hours/day. The PaTHway trial met all primary and key secondary endpoints with statistically significant differences from placebo. Most adverse events (AEs) were mild/moderate. Injection‐site reactions and headaches were the most common treatment‐related AEs. | PMC10099823 |
Introduction | hypoparathyroidism, endocrine disease, Hypoparathyroidism | HYPOCALCEMIA, HYPOPARATHYROIDISM, ENDOCRINE DISEASE, HYPOPARATHYROIDISM | Hypoparathyroidism is an endocrine disease caused by insufficient or absent production of parathyroid hormone (PTH) with multiorgan involvement. Under normal physiological conditions, PTH and its downstream hormone calcitriol are the primary regulators of calcium and phosphate and act on the bone, kidney, and intestine.Current consensus guidelines for the long‐term management of chronic hypoparathyroidism have identified six therapeutic goals: (i) prevent signs and symptoms of hypocalcemia; (ii) maintain the serum calcium concentration within or slightly below the normal range; (iii) maintain the calcium × phosphate product below 55 mgPTH replacement therapy is the ideal physiologic treatment for hypoparathyroidism.TransCon PTH (palopegteriparatide) is an investigational once‐daily prodrug with sustained release of active PTH in development as a treatment for adults with hypoparathyroidism. | PMC10099823 |
Materials and Methods | PMC10099823 |
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Trial design | PaTHway | HYPOPARATHYROIDISM | PaTHway is a phase 3, multicenter (North America and Europe), randomized, double‐blind, placebo‐controlled, parallel‐group, 26‐week trial with an open‐label extension of 156 weeks that evaluated the efficacy, safety, and tolerability of once‐daily TransCon PTH as PTH replacement therapy in individuals with hypoparathyroidism. Screening for the trial began on February 15, 2021. The last participant completed the blinded portion of the trial on January 12, 2022, and the open‐label extension is ongoing. The trial consisted of an approximately 4‐week screening period followed by a 26‐week blinded treatment period. All participants who completed the 26‐week blinded treatment period were allowed to enroll in the 156‐week open‐label extension period. Data through week 26 of the PaTHway trial are reported herein. The protocol was reviewed by the appropriate institutional review boards and independent ethics committees (ClinicalTrials.gov identifier: NCT04701203; EudraCT no: 2020‐003380‐26). The trial was designed by the sponsor and authors and conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice guidelines as described in the International Conference on Harmonization Guideline E6. | PMC10099823 |
Participants | μg/d, hypoparathyroidism, idiopathic etiologies | HYPOPARATHYROIDISM | Eligible participants included men and nonpregnant women (≥18 years of age) with chronic hypoparathyroidism of postsurgical, autoimmune, genetic, or idiopathic etiologies for a duration of at least 26 weeks. Participants must have been treated with calcitriol ≥0.5 μg/d or alfacalcidol ≥1.0 μg/d in addition to elemental calcium ≥800 mg/d for at least 12 weeks before screening. Stable doses of conventional therapy (ie, active vitamin D and calcium) were required for at least 5 weeks before screening, not precluding occasional (≤2/week) pro re nata (PRN, as needed) doses of calcium and/or active vitamin D. To ensure safety for those who might be randomized to the placebo arm, participants were required to achieve an albumin‐adjusted or ionized serum calcium within the normal range or slightly below the normal range (albumin‐adjusted serum calcium 7.8–10.6 mg/dL [1.95–2.64 mmol/L] or ionized serum calcium 4.40–5.29 mg/dL [1.10–1.32 mmol/L]), 25(OH) vitamin D levels 20–80 ng/mL (49–200 nmol/L), and magnesium levels ≥1.3 mg/dL (0.53 mmol/L), as is currently the goal of conventional treatment. | PMC10099823 |
Trial protocol | hypoparathyroidism | HYPOPARATHYROIDISM | Once enrolled, participants were randomized 3:1 into two treatment groups: TransCon PTH 18 μg PTH(1‐34)/d or placebo (excipient solution) mimicking 18 μg/d, both co‐administered with conventional therapy (active vitamin D and elemental calcium). Randomization was stratified by etiology of hypoparathyroidism (postsurgical versus nonsurgical). In addition to frequent laboratory visits to measure serum calcium levels, the blinded treatment period included 10 clinic visits over 26 weeks. Once‐daily treatment with TransCon PTH or placebo was delivered by a modified Ypsomed (Burgdorf, Switzerland) UnoPen Fix pen injector using 31‐gauge, 5‐mm pen needles to deliver doses of 6–30 μg/injection in a volume of ≤100 μL to either abdomen or anterior thigh, rotating injection sites. All participants were initially prescribed TransCon PTH 18 μg PTH(1‐34)/d or a corresponding volume of placebo and were individually and progressively titrated to an optimal dose (allowable range 6–60 μg/d) in increments of 3 μg/d. Titration of study drug and conventional therapy was performed according to a protocol‐specified algorithm guided by serum calcium values (Supplemental Fig. | PMC10099823 |
Efficacy assessments | The composite primary efficacy outcome of the PaTHway trial was the proportion of participants at week 26 who achieved albumin‐adjusted serum calcium in the normal range (8.3–10.6 mg/dL [2.07–2.64 mmol/L]), independence from active vitamin D, and independence from therapeutic doses of elemental calcium (>600 mg/d) with no increase in the prescribed study drug over the 4 weeks before week 26. Independence from active vitamin D was defined as a daily standing dose equal to zero on all days and use of any PRN active vitamin D on no more than 7 days during the 4 weeks before the week 26 visit. Independence from therapeutic calcium was defined as an average daily standing dose of ≤600 mg and use of PRN doses on no more than 7 days during the 4 weeks before the week 26 visit. Secondary efficacy outcomes included active vitamin D and elemental calcium doses, daily “pill burden” of active vitamin D and calcium (as oral tablets, powder, liquid solutions, liquid suspensions, or transdermal patches), albumin‐adjusted serum calcium, serum phosphate, and serum calcium × phosphate product. | PMC10099823 |
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Patient‐reported outcomes | pain, disability, Hypoparathyroidism | HYPOPARATHYROIDISM | At baseline and weeks 10, 20, and 26, participants completed the Hypoparathyroidism Patient Experience Scale (HPES), a psychometrically validated, disease‐specific questionnaire that includes both symptom and impact measures.Participants also completed the 36‐Item Short‐Form Health Survey (SF‐36, version 2), a 36‐item health questionnaire that assesses eight dimensions of health: physical functioning, role physical (ie, role limitations due to physical health problems), bodily pain, general health, vitality, social functioning, role emotional (ie, role limitations due to emotional problems), and mental health. The SF‐36 also includes two summary scores for physical and mental health. All scores are expressed relative to the mean of the general US population, with higher scores corresponding to less disability. | PMC10099823 |
Safety assessments | TEAEs, hypercalcemia | ADVERSE EVENTS, EVENTS, HYPERCALCEMIA | At prespecified intervals throughout the trial, information on the use of concomitant medications was collected. Serum chemistries, hematology, and 25‐hydroxyvitamin D levels, as well as antibodies against PTH, TransCon PTH, and polyethylene glycol (PEG) were measured. Twenty‐four‐hour urine calcium excretion was also assessed. Clinical events of symptomatic hypo‐ or hypercalcemia were also monitored. Treatment‐emergent adverse events (TEAEs), adverse events of special interest (AESI), and treatment‐emergent serious adverse events (SAEs) were documented by site staff at clinic visits and upon review of participant diaries. The seriousness, severity, and causality of all recorded TEAEs were assessed by the trial investigators. Vasodilatory signs and symptoms were prespecified as AESIs. | PMC10099823 |
Statistical analysis | hypoparathyroidism | SECONDARY, HYPOPARATHYROIDISM | Sample size calculations assuming a 70% response rate for TransCon PTH and 15% for placebo for the primary composite endpoint indicated that 68 participants randomized 3:1 to active TransCon PTH versus placebo would have 99% statistical power at Data from clinical assessments were summarized using descriptive statistics. Categorical data were presented using counts and percentages of participants, whereas continuous variables were summarized by mean and standard deviation (SD). All statistical tests were 2‐sided and tested at the statistically significant level of For the primary efficacy endpoint, the Cochran–Mantel Haenszel test stratified by etiology of hypoparathyroidism (postsurgical or other) was used to compare the proportion of participants meeting the composite primary endpoint in the TransCon PTH versus placebo groups. A prespecified sensitivity analysis of the primary composite endpoint permitting no PRN doses of active vitamin D or calcium for 4 weeks before the week 26 visit was also performed. Participants without week 26 albumin‐adjusted serum calcium or with >25% (ie, >7 days) missing diary data of active vitamin D or elemental calcium during the 4 weeks before week 26 were considered non‐responders.Continuous secondary endpoints were analyzed using an analysis of covariance (ANCOVA) model with unequal variance, which included change from baseline for the endpoint of interest as a response variable, treatment assignment and etiology of hypoparathyroidism as fixed factors, and baseline variable of the endpoint as a covariate. For key secondary patient‐reported outcomes (PROs), the ANCOVA model described above was used to test the change from baseline to week 26 between participants treated with TransCon PTH versus placebo in a prespecified sequence. The prespecified sequential testing procedure was applied to control the family‐wise, type 1 error rate for the primary and key secondary endpoints. All statistical analyses were conducted using SAS version 9.4 (SAS Institute, Cary, NC, USA). | PMC10099823 |
Results | PMC10099823 |
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Participant disposition and baseline demographics | cardiac arrest | DISEASE, CARDIAC ARREST, BREAST CANCER | A total of 106 participants were screened for eligibility, and 84 were randomized to treatment (Patient disposition. A total of 106 participants were screened, and 84 met eligibility criteria, were enrolled in the trial, and randomized to treatment. Two participants randomized to TransCon PTH discontinued the trial before receiving treatment: one withdrew consent, and one withdrew due to thyroid cancer recurrence. Sixty‐one participants in the TransCon PTH and 21 participants in the placebo group received ≥1 blinded treatment and comprised the intent‐to‐treat population. During the trial, one participant in the TransCon PTH group experienced a fatal cardiac arrest (unrelated to the study drug), and 2 withdrew from the placebo group: one withdrew consent, and one withdrew due to breast cancer. A total of 79 participants completed the blinded treatment through week 26.Baseline Demographics, Disease Characteristics, and SupplementationAbbreviations: PTH = parathyroid hormone; SD = standard deviation. | PMC10099823 |
Efficacy | hypoparathyroidism, normocalcemia | HYPOPARATHYROIDISM | After 26 weeks of blinded treatment, 79% (48/61) of participants receiving TransCon PTH versus 5% (1/21) receiving placebo achieved the primary composite endpoint of independence from conventional therapy, with maintenance of normocalcemia without an increase in study drug dose in the final 4 weeks of the blinded period (Percentage of Participants Meeting the Composite Primary Endpoint at Week 26
Abbreviations: CI, confidence interval; PTH, parathyroid hormone.Cochran–Mantel–Haenszel test controlling for etiology of hypoparathyroidism (postsurgical versus nonsurgical).The normal range for albumin‐adjusted serum calcium is 8.3–10.6 mg/dL (2.07–2.64 mmol/L).Elemental calcium supplement dose with TransCon PTH treatment. Treatment with TransCon PTH resulted in a greater reduction in mean daily calcium dose than placebo as early as 4 weeks (Active vitamin D supplement dose with TransCon PTH treatment. Per trial protocol, all participants decreased their active vitamin D dose by 33% to 50% (eg, by skipping the second dose of the day if taking 2 times daily (BID), skipping the final dose of the day if taking 3 times daily (TID), or reducing a once‐daily dose of alfacalcidol ≥1.0 μg by 50% (≥0.5 μg) at the start of the blinded treatment period. Subsequent dose decreases or discontinuations were done according to a predefined protocol. Within 4 weeks, the majority of participants treated with TransCon PTH discontinued active vitamin D. Mean doses of active vitamin D supplements were calculated from actual micrograms prescribed and are not adjusted for relative potency of calcitriol versus alfacalcidol. The difference in least squares (LS) means between TransCon PTH and placebo groups was statistically significant at all time points (Albumin‐adjusted serum calcium with TransCon PTH treatment. In the TransCon PTH group, mean serum calcium values remained within the normal range at all study visits through week 26. Baseline mean serum calcium was 8.8 mg/dL (2.2 mmol/L) and 8.6 mg/dL (2.15 mmol/L) for TransCon PTH and placebo, respectively, and 8.9 mg/dL (2.22 mmol/L) and 8.2 mg/dL (2.05 mmol/L), respectively, at week 26. Normal range for serum calcium = 8.3–10.6 mg/dL (2.07–2.64 mmol/L).Baseline and Week 26 Serum Biochemistries in Participants Treated With TransCon PTH and PlaceboAbbreviation: eGFR, estimated glomerular filtration rate.Albumin‐adjusted serum calcium.
eGFR adjusted for body surface area. | PMC10099823 |
Patient‐reported outcomes | hypoparathyroidism | HYPOPARATHYROID, SECONDARY, HYPOPARATHYROIDISM | Both HPES and SF‐36 scores improved through week 26 in the TransCon PTH group. The disease‐specific HPES showed improvements in hypoparathyroidism‐related symptoms, functioning, and well‐being for participants treated with TransCon PTH. Treatment with TransCon PTH demonstrated a statistically significant improvement compared with placebo in all key secondary endpoints at week 26: HPES‐Symptom physical (Week 26 Improvement From Baseline in Hypoparathyroid Patient Experience Scale (HPES) Impact and Symptom ScoresAbbreviations: HPES, hypoparathyroid patient experience scale; PTH, parathyroid hormone; SD, standard deviation.Lower scores reflect improvement in hypoparathyroidism‐related symptoms, functioning, and well‐being.Treatment effect of TransCon PTH on the hypoparathyroidism patient experience scale (HPES).Treatment effect of TransCon PTH on general health, 36‐Item Short Form Survey (SF‐36). | PMC10099823 |
Safety | toxicity, cardiac arrest | ADVERSE EVENT, ADVERSE EVENT, CARDIAC ARREST | Mean 24‐hour urine calcium levels decreased from 392 mg/24 h at baseline to 220 mg/24 h in participants treated with TransCon PTH compared with 329 mg/24 h at baseline to 292 mg/24 h with placebo (Fig. Twenty four‐hour urine calcium with TransCon PTH treatment. Box plot of 24‐hour urine calcium. Within each box, horizontal lines denote median values and the square (TransCon PTH), and circle (placebo) denote mean values; boxes extend from the 25th to the 75th percentile of each treatment group's distribution of values; vertical extending lines denote adjacent values within 1.5 interquartile range of the 25th and 75th percentile of each group; dots outside the box denote data points outside the range of adjacent values. Mean 24‐hour urine calcium values decreased from 390 mg/24 h at baseline to 220 mg/24 h at week 26 in participants treated with TransCon PTH, and from 329 to 292 mg/24 h in participants who received placebo. The mean change from baseline was statistically significant in the TransCon PTH group (Albumin‐Adjusted Serum Calcium Excursions by Time Period
Abbreviations: EBT, end of blinded treatment; PTH, parathyroid hormone.Treatment‐emergent AEs were reported in 50/61 (82%) participants treated with TransCon PTH and in 21/21 (100%) participants treated with placebo (Tables Summary: Overall Treatment‐Emergent Adverse EventsAbbreviatiions: ER, emergency room; PTH, parathyroid hormone; TEAE, treatment‐emergent adverse event.Percentages are calculated based on the number of participants in the safety analysis population. In the severity categories, participants are displayed for the highest severity only. TEAEs occurring before the first dose of open‐label treatment are included.AE severity is assessed by the World Health Organization toxicity grading scale.One participant experienced a fatal cardiac arrest (grade 4 TEAE), which subsequently led to discontinuation of the study drug and trial.Treatment‐Emergent Adverse Events in ≥5% of ParticipantsAbbreviations: PTH, parathyroid hormone; TEAE, treatment‐emergent adverse event.Percentages are calculated based on the number of participants in the safety analysis population. | PMC10099823 |
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