RESUMO
OBJECTIVE: Recombinant human parathyroid hormone (1-84) (rhPTH[1-84]) is efficacious in patients with hypoparathyroidism but additional data supporting its prolonged use are needed. We evaluated whether efficacy, safety, and tolerability are maintained during long-term rhPTH(1-84) treatment of patients with chronic hypoparathyroidism. METHODS: This was a phase 4, single-center, open-label, single-arm, 3-year extension (NCT02910466) of the phase 3 Hypo Extended (HEXT) study (NCT01199614). Patients self-administered rhPTH(1-84) once daily by subcutaneous injection, with doses individualized based on clinical parameters. Albumin-adjusted serum calcium levels (primary outcome measure), other disease biomarkers, health-related quality of life, and safety of rhPTH(1-84) were assessed using descriptive statistics. RESULTS: All patients (n = 39) had been exposed to rhPTH(1-84) (mean exposure [SD] 8.5 [3.5] years) before the start of the study, resulting in a mean exposure of 10.8 years including the present study. Mean patient age was 51.9 years, 79.5% were female, and 97.4% were White. Mean albumin-adjusted serum calcium concentrations were within the target range, and mean serum phosphate, serum calcium-phosphate product, and 24-hour urinary calcium excretion levels were within reference ranges at end of treatment. Mean doses of supplemental calcium and active vitamin D were maintained throughout the study. Bone turnover marker levels were maintained from baseline to end of treatment. No clinically relevant changes in bone mineral density were observed. Patient-reported health-related quality-of-life scores were generally maintained throughout the study. Four adverse events were considered treatment related and no new safety signals were identified. CONCLUSION: The effects of rhPTH(1-84) on biochemical, skeletal, and health-related quality-of-life parameters did not wane with extended use.
Assuntos
Cálcio , Hipoparatireoidismo , Adulto , Humanos , Feminino , Pessoa de Meia-Idade , Masculino , Cálcio/uso terapêutico , Qualidade de Vida , Hormônio Paratireóideo/uso terapêutico , Hipoparatireoidismo/tratamento farmacológico , Proteínas Recombinantes/efeitos adversos , Fosfatos/uso terapêutico , Albuminas/uso terapêuticoRESUMO
OBJECTIVE: A significant problem that compels clinicians in the conventional treatment of hypoparathyroidism is patients' non-adherence to treatment. This study aimed to evaluate the effects of adequate Ca intake with dietary recommendations among hypoparathyroidism patients who persistently use Ca supplementation irregularly on plasma Ca and phosphate levels. METHODS: This prospective, randomized, controlled study was conducted on patients diagnosed with chronic hypoparathyroidism who persistently interrupt Ca supplementation therapy and therefore have a hypocalcemic course. Patients with a total daily Ca intake below 800 mg were randomized. All patients were advised to keep the doses of active vitamin D and Ca supplements they were currently using. The patients in the study group (n=32) were advised to consume 1,000-1,200 mg of Ca daily, and the patients in the control group (n=35) were advised to continue their diet according to their daily habits. After 12 weeks of follow-up, the patients' laboratory values were compared between groups to assess treatment goals. RESULTS: The mean of the total Ca level was 8.56±0.36 mg/dL in the study group and was found to be significantly higher than that in the control group, which was 7.67±0.48 mg/dL (p<0.001). The mean serum phosphate and serum Ca-P product levels were significantly higher in the study group (p<0.001) but did not exceed the safe upper limits in any patient. CONCLUSION: A suitable increase in dietary Ca intake could effectively control hypocalcemia in patients with hypoparathyroidism who persistently interrupt the recommended calcium supplementation.
Assuntos
Hipocalcemia , Hipoparatireoidismo , Humanos , Cálcio da Dieta/uso terapêutico , Cálcio , Estudos Prospectivos , Hipoparatireoidismo/tratamento farmacológico , Vitamina D/uso terapêutico , Hipocalcemia/tratamento farmacológico , Fosfatos/uso terapêutico , Hormônio Paratireóideo/uso terapêuticoRESUMO
This study aimed to evaluate the cost-effectiveness of Chaiyin Granules compared with Oseltamivir Phosphate Capsules in the treatment of influenza(exogenous wind-heat syndrome). Based on a randomized, double-blind, positive drug parallel control clinical trial, this study evaluated the pharmacoeconomics of Chaiyin Granules with cost-effectiveness analysis method. A total of 116 patients with influenza from eight hospitals(grade â ¡ level A above) in 6 cities were selected in this study, including 78 cases in the experimental group with Chaiyin Granules and Oseltamivir Phosphate Capsules placebo, and 38 cases in the control group with Oseltamivir Phosphate Capsules and Chaiyin Granules placebo. The total cost of this study included direct medical cost, direct non-medical cost, and indirect cost. The remission time of clinical symptoms, cure time/cure rate, antipyretic onset time/complete antipyretic time, viral nucleic acid negative rate, and traditional Chinese medicine(TCM) syndrome curative effect were selected as the effect indicators for cost-effectiveness analysis. Four-quadrant diagram was used to estimate the incremental cost-effectiveness ratio. The results showed that Chaiyin Granules were not inferior to Oseltamivir Phosphate Capsules in the remission time of clinical symptoms of influenza(3.1 d vs 2.9 d, P=0.360, non-inferiority margin was 0.5 d). Compared with Oseltamivir Phosphate Capsules, Chaiyin Granules would delay the remission time of clinic symptoms of influenza for 1 d, but could save 213.9 yuan. 1 d delay in cure time could save 149.3 yuan; 1% reduction in the cure rate could save 8.2 yuan; 1 d delay in antipyretic onset time could save 295.4 yuan; 1 d delay in complete antipyretic time could save 114.3 yuan; 1% reduction in the 5-day cure rate of TCM syndrome could save 19.2 yuan. Different from other indicators, there was no statistically significant difference between two groups in the effect of negative conversion rate of viral nucleic acid, but the cost was lower and the effect was superior, and the pharmacoeconomics was not different from that of Oseltamivir Phosphate Capsules in the field of influenza treatment.
Assuntos
Antipiréticos , Influenza Humana , Ácidos Nucleicos , Humanos , Antipiréticos/uso terapêutico , Antivirais/uso terapêutico , Análise de Custo-Efetividade , Influenza Humana/tratamento farmacológico , Ácidos Nucleicos/uso terapêutico , Oseltamivir/uso terapêutico , Fosfatos/uso terapêutico , Resultado do Tratamento , Método Duplo-CegoRESUMO
X-linked hypophosphatemia (XLH) associated with short stature during childhood are mostly referred to the hospital and diagnosed as vitamin D deficiency rickets and received vitamin D before adulthood. A case is presented with clinical features of hypophosphatemia from childhood who did not seek medical care for diagnosis and treatment, nor did his mother or two brothers, who have short statures, bone pain, and fractures. The patient was assessed for sociodemographic, hematological, and biochemical parameters together with a genetic assessment. A DEXA scan and X-ray were done to determine the abnormalities and deformities of joints and bones despite clinical examination by an expert physician. All imaging, laboratory parameters, and the genetic study confirmed the diagnosis of XLH. A detailed follow-up of his condition was performed after the use of phosphate tablets and other treatments. X-linked hypophosphatemia needs a good assessment, care, and follow up through a complementary medical team including several specialties. Phosphate tablets in adulthood significantly affects clinical and physical improvement and prevention of further skeletal abnormality and burden on daily activity. The patients should be maintained with an adequate dose of phosphate for better patient compliance. More awareness is needed in society and for health professionals when conducting medical checkups during the presence of stress fractures, frequent dental and gum problems, rickets, short stature, or abnormality in the skeleton or walking to think of secondary causes such as hypophosphatemia. Further investigations including a visit to a specialist is imperative to check for the primary cause of these disturbances.
Assuntos
Raquitismo Hipofosfatêmico Familiar , Hipofosfatemia , Adulto , Humanos , Masculino , Osso e Ossos , Raquitismo Hipofosfatêmico Familiar/diagnóstico , Raquitismo Hipofosfatêmico Familiar/genética , Raquitismo Hipofosfatêmico Familiar/tratamento farmacológico , Hipofosfatemia/complicações , Hipofosfatemia/tratamento farmacológico , Hipofosfatemia/genética , Fosfatos/uso terapêutico , Vitamina D/uso terapêuticoRESUMO
Patients with non-muscle invasive bladder cancer (NMIBC) that are unresponsive to Bacillus Calmette-Guérin (BCG) have historically had limited treatment options. A new perspective is represented by OncoTherad® (MRB-CFI-1) immunotherapy, a nanostructured inorganic phosphate complex associated with glycosidic protein, developed by the University of Campinas in Brazil. Previous studies have shown that Platelet-Rich Plasma (PRP) also acts on immune activation and exerts antitumor effects. This study characterized the effects of the OncoTherad® associated with PRP in the treatment of NMIBC chemically induced in mice. When treated intravesically with PRP only, mice showed 28.6% of tumor progression inhibition rate; with OncoTherad® 85.7%; and with OncoTherad®+PRP 71.4%. Intravesical treatments led to distinct activation of Toll-like Receptors (TLRs) 2 and 4-mediated innate immune system in the interleukins (canonical) and interferons (non-canonical) signaling pathways. OncoTherad® isolated or associated with PRP upregulated TLR4 and its downstream cascade mediators as well as increased interleukins 6 (IL-6) and 1ß (IL-1ß), and interferon-γ (IFN-γ). In this way, the NMIBC microenvironment was modulated to a cytotoxic profile correlated with the IL-1ß increase by stimulating immune pathways for IFN-γ production and consequent cytotoxic T lymphocytes (as CD8+ T-cells) activation and regulatory T-cells (Tregs) reduction. In addition, PRP did not trigger carcinogenic effects through the biomarkers evaluated. Considering the possibility of personalizing the treatment with the PRP use as well as the antitumor properties of OncoTherad®, we highlight this association as a potential new therapeutic strategy for NMIBC, mainly in cases of relapse and/or resistance to BCG.
Assuntos
Neoplasias não Músculo Invasivas da Bexiga , Plasma Rico em Plaquetas , Neoplasias da Bexiga Urinária , Humanos , Camundongos , Animais , Vacina BCG , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Fosfatos/uso terapêutico , Imunoterapia , Adjuvantes Imunológicos/uso terapêutico , Microambiente TumoralRESUMO
BACKGROUND: The morbidity of influenza in children increased rapidly in decade. Reduning injection (RDN), a small but fine Chinese herbal formula, has antipyretic, antiviral, anti-inflammatory effects. We intend to evaluate the efficacy and safety of RDN for the influenza in children versus Oseltamivir, explore the possible antiviral mechanism of RDN and provide evidence-based medical evidence for rational clinical drug usage. METHOD: We design a randomized, double-blind, double-dummy, parallel control of positive drug, multi-centre clinical study. According to the formula of mean superiority test, a total of 240 patients with influenza in children will be randomized 1:1 into the experimental group and control group. The experimental group will take RDN and Oseltamivir phosphate granule simulants and the control group will take Oseltamivir phosphate granule and RDN simulants. Each group will be treated for 5 days. The primary outcome measure is temperature recovery time, and the secondary outcome measures include time when the fever begins to subside, time and degree of disease to alleviate, disappearance rate of individual symptoms and so on. We will measure before enrollment and each 24 h after treatment for comparison. DISCUSSION: The study is launched to evaluate the efficacy and safety of RDN for the treatment of influenza in children and to provide an alternative option for influenza in children. TRIAL REGISTRATION: This study is registered in ClinicalTrials.gov as NCT04183725, registered on 3 December, 2019.
Assuntos
Influenza Humana , Humanos , Criança , Influenza Humana/tratamento farmacológico , Oseltamivir/uso terapêutico , Antivirais/uso terapêutico , Método Duplo-Cego , Fosfatos/uso terapêuticoRESUMO
The treatment and interdisciplinary management of patients with chronic kidney disease (CKD) continue to improve long-term outcomes. The medical nutrition intervention's role is to establish a healthy diet plan for kidney protection, reach blood pressure and blood glucose goals, and prevent or delay health problems caused by kidney disease. Our study aims to report the effects of medical nutrition therapy-substituting foods rich in phosphorus-containing additives with ones low in phosphates content on phosphatemia and phosphate binders drug prescription in stage 5 CKD patients with hemodialysis. Thus, 18 adults with high phosphatemia levels (over 5.5 mg/dL) were monitored at a single center. Everyone received standard personalized diets to replace processed foods with phosphorus additives according to their comorbidities and treatment with prosphate binder drugs. Clinical laboratory data, including dialysis protocol, calcemia, and phosphatemia, were evaluated at the beginning of the study, after 30 and 60 days. A food survey was assessed at baseline and after 60 days. The results did not show significant differences between serum phosphate levels between the first and second measurements; thus, the phosphate binders' initial doses did not change. After 2 months, phosphate levels decreased considerably (from 7.322 mg/dL to 5.368 mg/dL); therefore, phosphate binder doses were diminished. In conclusion, medical nutrition intervention in patients with hemodialysis significantly reduced serum phosphate concentrations after 60 days. Restricting the intake of processed foods containing phosphorus additives-in particularized diets adapted to each patient's comorbidities-and receiving phosphate binders represented substantial steps to decrease phosphatemia levels. The best results were significantly associated with life expectancy; at the same time, they showed a negative correlation with the dialysis period and participants' age.
Assuntos
Hiperfosfatemia , Falência Renal Crônica , Insuficiência Renal Crônica , Adulto , Humanos , Hiperfosfatemia/etiologia , Hiperfosfatemia/prevenção & controle , Falência Renal Crônica/terapia , Diálise Renal/efeitos adversos , Fosfatos/uso terapêutico , Fósforo , Insuficiência Renal Crônica/complicaçõesRESUMO
The development of drug resistance is one of the most severe concerns of malaria control because it increases the risk of malaria morbidity and death. A new candidate drug with antiplasmodial activity is urgently needed. This study evaluated the efficacy of different dosages of aqueous extract of Strychnos ligustrina combined with dihydroartemisinin and piperaquine phosphate (DHP) against murine Plasmodium berghei infection. The BALB/c mice aged 6-8 weeks were divided into 6 groups, each consisting of 10 mice. The growth inhibition of compounds against P. berghei was monitored by calculating the percentage of parasitemia. The results showed that the mice receiving aqueous extract and combination treatment showed growth inhibition of P. berghei in 74% and 94%, respectively. S. ligustrina extract, which consisted of brucine and strychnine, effectively inhibited the multiplication of P. berghei. The treated mice showed improved hematology profiles, body weight, and temperature, as compared to control mice. Co-treatment with S. ligustrina extract and DHP revealed significant antimalarial and antipyretic effects. Our results provide prospects for further discovery of antimalarial drugs that may show more successful chemotherapeutic treatment.
Assuntos
Antimaláricos , Artemisininas , Malária , Strychnos , Camundongos , Animais , Plasmodium berghei , Extratos Vegetais/farmacologia , Artemisininas/farmacologia , Camundongos Endogâmicos BALB C , Fosfatos/farmacologia , Fosfatos/uso terapêuticoRESUMO
OBJECTIVE: Secondary hyperparathyroidism commonly occurs in the setting of mid-to low-normal serum calcium levels, often in the setting of chronic kidney disease, phosphate loading, vitamin D deficiency, or insufficient calcium intake or absorption. In this article, we report 9 patients who had adequate kidney function (estimated glomerular filtration rate >60 mL/min/1.73 m2) and normal 25-hydroxy vitamin D level (≥30 ng/dL) and whose secondary hyperparathyroidism resolved after starting adequate oral calcium intake. METHODS: Our retrospective case series included 8 women and 1 man; the mean age was 69.0 ± 12.2 years (mean ± standard deviation). The initial intact parathyroid hormone (iPTH) level was 80.6 ± 13.4 pg/mL (reference range [ref], 10-65 pg/mL), corrected serum calcium level was 9.2 ± 0.2 mg/dL (ref, 8.5-10.5 mg/dL), serum phosphate level was 3.6 ± 0.4 mg/dL (ref, 2.5-4.9 mg/dL), 25-hydroxy vitamin D level was 42.2 ± 10.5 mg/dL (ref, 20-50 ng/mL), and estimated glomerular filtration rate was 72.6 ± 14.4 mL/min/1.73 m2. Patients were treated clinically with oral calcium 600 mg twice a day. RESULTS: iPTH was retested after a mean duration of 17.6 ± 12.7 days of calcium supplementation; the iPTH level decreased to 51.0 ± 10.6 pg/mL, with all patients achieving iPTH in the normal range with normocalcemia, consistent with hyperparathyroidism being because of insufficient calcium intake or absorption. All patients were normocalcemic after supplementation. CONCLUSION: Secondary hyperparathyroidism can result from insufficient oral calcium intake. Calcium challenge is an efficacious and cost-effective tool for confirming and treating secondary hyperparathyroidism in the setting of normal vitamin D levels and kidney function.
Assuntos
Cálcio , Hiperparatireoidismo Secundário , Idoso , Idoso de 80 Anos ou mais , Calcifediol , Cálcio da Dieta/uso terapêutico , Feminino , Humanos , Hiperparatireoidismo Secundário/tratamento farmacológico , Hiperparatireoidismo Secundário/etiologia , Masculino , Pessoa de Meia-Idade , Hormônio Paratireóideo , Fosfatos/uso terapêutico , Estudos Retrospectivos , Vitamina D/uso terapêuticoRESUMO
OBJECTIVE: Hypophosphatemia might cause respiratory and heart failure and even death. We aimed to evaluate risk factors for hypophosphatemia and refeeding-related hypophosphatemia in patients requiring parental nutrition (PN). METHODS: This was a single-center, retrospective study. Clinical parameters were obtained from medical records. Serum phosphate (inorganic phosphorus) was measured by photometric analysis. Hypophosphatemia was confirmed when serum phosphate level was less than 0.8 mmol/L (≈2.5 mg/dl). Refeeding related hypophosphatemia was confirmed if serum phosphate level had a decrease of 0.16 mmol/L or more from baseline and if the final assessment was below 0.65 mmol/L. RESULTS: A total number of 655 (426 men and 229 women, aged 62.8 ± 14.8 years) hospitalized patients requiring PN were included in the study, and 60.6% of them were patients with cancer. The average body mass index (BMI) was 21.1 ± 4.1 kg/m2 and the median of serum phosphate was 0.9 mmol/L (quartile range: 0.68 mmol/L, 1.11 mmol/L). The prevalence of hypophosphatemia was 37.6% (246/655). Older age (≥ 65 years vs. < 65 years), lower serum level of pre-albumin (< 160 mg/L vs. ≥ 160 mg/L), calcium (< 2.11 mmol/L vs. ≥ 2.11 mmol/L), and magnesium (< 0.75 mmol/L vs. ≥ 0.75 mmol/L) were associated with high risk of hypophosphatemia by multivariate logistic regression (OR ranged from 1.43 to 3.06, all p < 0.05). Refeeding related hypophosphatemia was 9.5% (16/168). Serum level of calcium at baseline was significantly lower in participants with refeeding related hypophosphatemia than those without it. Total calorie and nitrogen delivered during first week of PN period showed no obvious difference between patients with and without refeeding related hypophosphatemia. CONCLUSIONS: Hypophosphatemia is common (37.6%) in hospitalized patients requiring PN. Monitoring of serum level of phosphorus is necessary to facilitate early treatment of hypophosphatemia.
Assuntos
Cálcio , Hipofosfatemia , Cálcio/uso terapêutico , Feminino , Humanos , Hipofosfatemia/epidemiologia , Hipofosfatemia/etiologia , Masculino , Pais , Fosfatos/uso terapêutico , Fósforo/uso terapêutico , Prevalência , Estudos RetrospectivosRESUMO
Background: Abnormal sphingolipid metabolism is closely related to the occurrence and development of Alzheimer's disease (AD). With heat-clearing and detoxifying effects, Huanglian Jiedu decoction (HLJDD) has been used to treat dementia and improve learning and memory impairments. Purpose: To study the therapeutic effect of HLJDD on AD as it relates to sphingolipid metabolism. Methods: The level of sphingolipids in the brains of APP/PS1 mice and in the supernatant of ß-amyloid (Aß)25-35-induced BV2 microglia was detected by HPLC-QTOF-MS and HPLC-QTRAP-MS techniques, respectively. The co-expression of ionized calcium-binding adapter molecule 1 (Iba1) and Aß as well as four enzymes related to sphingolipid metabolism, including serine palmitoyltransferase 2 (SPTLC2), cer synthase 2 (CERS2), sphingomyelin phosphodiesterase 1 (SMPD1), and sphingomyelin synthase 1 (SGMS1), in the brains of APP/PS1 mice were evaluated by immunofluorescence double labelling. In addition, real-time quantitative reverse transcription-polymerase chain reaction was conducted to determine the mRNA expression of SPTLC2, CERS2, SMPD1, SGMS1, galactosylceramidase (GALC), and sphingosine kinase 2 (SPHK2) in Aß25-35-stimulated BV2 microglia. Results: Abnormal sphingolipid metabolism was observed both in APP/PS1 mouse brain tissues and Aß25-35-stimulated BV2 cells. The levels of sphingosine, sphinganine, sphingosine-1-phosphate, sphinganine-1-phosphate and sphingomyelin were significantly reduced, while the levels of ceramide-1-phosphate, ceramide, lactosylceramide and hexosylceramide significantly increased in Aß25-35-stimulated BV2 cells. In AD mice, more microglia were clustered in the Aß-positive region. The decreased level of SGMS1 and increased levels of CERS2, SPTLC and SMPD1 were also found. In addition, the expressions of SPTLC2, CERS2, and SMPD1 in Aß25-35-stimulated BV2 cells were increased significantly, while the expressions of GALC, SPHK2, and SGMS1 were decreased. These changes all showed a significant correction after HLJDD treatment. Conclusion: HLJDD is a good candidate for treating AD. This study provides a novel perspective on the potential roles of the sphingolipid metabolism in AD.
Assuntos
Doença de Alzheimer , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Ceramidas/metabolismo , Ceramidas/uso terapêutico , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas , Camundongos , Camundongos Transgênicos , Microglia/metabolismo , Fosfatos/uso terapêutico , EsfingolipídeosRESUMO
PURPOSE: The main purpose of this study was to investigate the effects of 12 months of rhPTH (1-84) (Natpar®) treatment in a cohort of patients selected according to the indications of hypoparathyroidism guidelines. The use of recombinant human PTH (1-84) [rhPTH (1-84)] is approved as hormonal replacement therapy in patients with hypoparathyroidism not adequately controlled with conventional therapy. METHODS: It is a multicenter, observational, retro-prospective, open label study. Eleven Italian Endocrinological centers, members of Hypoparathyroidism Working Group of the Italian Society of Endocrinology (HypoparaNET) were involved. Main outcome measures were serum and urinary calcium and phosphate concentration, calcium-phosphate product, renal function, oral calcium and vitamin D doses, and clinical manifestations. RESULTS: Fourteen adult subjects, affected by chronic hypoparathyroidism, were treated with rhPTH (1-84) for 12 months. At 12 months of rhPTH (1-84) treatment, 61.5% of patients discontinued calcium supplement and 69.2% calcitriol. Mean albumin-adjusted total serum calcium levels quickly normalized after initiation of rhPTH (1-84) treatment compared to baseline (p = 0.009), remaining in the normal range until 12 months. Rare hypo-hypercalcemia episodes were reported. Renal function was maintained normal and no renal complications were reported. Serum and urinary phosphate and urinary calcium were maintained in the normal range. Mean phosphatemia levels linearly decreased from 3 months up to 12 months compared to baseline (p = 0.014). No severe adverse events were described. CONCLUSIONS: Biochemical and clinical results confirm the efficacy and safety of rhPTH (1-84) therapy, which represents an important option for hypoparathyroid patients unresponsive to conventional therapy.
Assuntos
Cálcio , Hipoparatireoidismo , Adulto , Humanos , Hormônio Paratireóideo , Fosfatos/uso terapêutico , Estudos Prospectivos , Resultado do TratamentoRESUMO
AIM: To investigate the short-term efficacy and safety of high-dose pyridoxine and pyridoxal 5-phosphate (P5P) in the treatment of inherited glycosylphosphatidylinositol (GPI) deficiency-associated epilepsy. METHOD: Participants with genetically confirmed GPI deficiency were treated with oral pyridoxine or P5P as compassionate use in an agreed-upon clinical regimen. Pyridoxine (20-30 mg/kg/day) was used for 3 months. Baseline evaluation included 4 weeks of prospective seizure data and one video electroencephalogram (EEG). Seizure frequency was captured daily. The EEG was repeated after reaching maximum dosage of pyridoxine. Pyridoxine was switched to P5P (20-30 mg/kg/day) if seizure burden was unchanged after 3 months' treatment. Another EEG was done after 3 months of P5P treatment. Primary outcome measures were reduction of seizure frequency and EEG improvements. RESULTS: Seven participants (one female, six males; age range 5-23 year; mean age 11 years 10 months, SD 5 year 2 months) were included. The genetic causes of inherited GPI deficiency were phosphatidylinositol N-acetylglucosaminyltransferase subunit A/T/V deficiency. All had drug-resistant epilepsy and neurodevelopmental impairment. We observed more than 50% seizure frequency reduction in 2 out of 7 and less than 50% reduction in another 3 out of 7 participants. No participants reached seizure freedom. No remarkable changes in electrophysiological findings were observed in 6 out of 7 participants treated with pyridoxine or P5P when comparing the baseline and follow-up EEGs. INTERPRETATION: We observed no long-lasting electrophysiological improvements during treatment but pyridoxine may reduce seizure frequency or burden in inherited GPI deficiency. WHAT THIS PAPER ADDS: Inherited glycosylphosphatidylinositol (GPI) deficiency often causes early-onset and drug-resistant epilepsy. Vitamin B6 is a potential disease-specific treatment; however, efficacy and safety are ill-defined. Pyridoxine may reduce seizure frequency or burden in inherited GPI deficiency. Pyridoxine and P5P could prove to be a useful treatment in some individuals with inherited GPI deficiency and epilepsy.
Assuntos
Epilepsia Resistente a Medicamentos , Epilepsia , Estudos de Coortes , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Epilepsia/complicações , Epilepsia/tratamento farmacológico , Epilepsia/genética , Feminino , Glicosilfosfatidilinositóis/deficiência , Glicosilfosfatidilinositóis/uso terapêutico , Humanos , Lactente , Masculino , Fosfatos/uso terapêutico , Estudos Prospectivos , Fosfato de Piridoxal/uso terapêutico , Piridoxina/uso terapêutico , Convulsões/tratamento farmacológico , Convulsões/etiologiaRESUMO
BACKGROUND: Obsessive-compulsive disorder (OCD) is often challenging to treat and resistant to psychological interventions and prescribed medications. The adjunctive use of nutraceuticals with potential neuromodulatory effects on underpinning pathways such as the glutamatergic and serotonergic systems is one novel approach. OBJECTIVE: To assess the effectiveness and safety of a purpose-formulated combination of nutraceuticals in treating OCD: N-acetyl cysteine, L-theanine, zinc, magnesium, pyridoxal-5' phosphate, and selenium. METHODS: A 20-week open label proof-of-concept study was undertaken involving 28 participants with treatment-resistant DSM-5-diagnosed OCD, during 2017 to 2020. The primary outcome measure was the Yale-Brown Obsessive-Compulsive Scale (YBOCS), administered every 4 weeks. RESULTS: An intention-to-treat analysis revealed an estimated mean reduction across time (baseline to week-20) on the YBOCS total score of -7.13 (95% confidence interval = -9.24, -5.01), with a mean reduction of -1.21 points per post-baseline visit (P ≤ .001). At 20-weeks, 23% of the participants were considered "responders" (YBOCS ≥35% reduction and "very much" or "much improved" on the Clinical Global Impression-Improvement scale). Statistically significant improvements were also revealed on all secondary outcomes (eg, mood, anxiety, and quality of life). Notably, treatment response on OCD outcome scales (eg, YBOCS) was greatest in those with lower baseline symptom levels, while response was limited in those with relatively more severe OCD. CONCLUSIONS: While this pilot study lacks placebo-control, the significant time effect in this treatment-resistant OCD population is encouraging and suggests potential utility especially for those with lower symptom levels. Our findings need to be confirmed or refuted via a follow-up placebo-controlled study.
Assuntos
Transtorno Obsessivo-Compulsivo , Selênio , Humanos , Projetos Piloto , Escalas de Graduação Psiquiátrica , Qualidade de Vida , Magnésio/uso terapêutico , Selênio/uso terapêutico , Cisteína/uso terapêutico , Resultado do Tratamento , Transtorno Obsessivo-Compulsivo/tratamento farmacológico , Transtorno Obsessivo-Compulsivo/diagnóstico , Suplementos Nutricionais , Zinco/uso terapêutico , Fosfatos/uso terapêutico , Piridoxal/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
X-linked hypophosphatemic rickets (XLH) is primarily characterized by renal phosphate wasting with hypophosphatemia, short stature, and bone deformity of the leg. Here we present a male case of XLH with relatively mild bone deformity caused by a mosaic mutation of the phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX). Polymerase chain reaction (PCR) direct sequencing revealed a novel in-frame deletion, NM-000444.6:c.671-685del p.Gln224-Ser228del, at exon 6 in PHEX as a mosaic pattern. This mutation was not found in any database and may result in a significant change in higher-order protein structure and function. TA cloning of the PCR product and clone sequencing estimated the mutation allele frequency at 21%. Literature review of the previously reported three cases with novel mosaic mutations in PHEX, together with the present case, suggests that the rates of the mutation allele correlate with phenotype severity to some extent. We initially treated him with nutritional vitamin D supplements and phosphate salts. However, to avoid the development of secondary/tertiary hyperparathyroidism, we had switched nutritional to active vitamin D supplementation with reduced phosphorus salts. The present report contributes to understanding the relationship between the mosaic rate, in addition to the mutation locus, of the PHEX gene, and clinical features of XLH.
Assuntos
Osso e Ossos/anormalidades , Raquitismo Hipofosfatêmico Familiar/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Endopeptidase Neutra Reguladora de Fosfato PHEX/genética , Povo Asiático/genética , Osso e Ossos/diagnóstico por imagem , Raquitismo Hipofosfatêmico Familiar/sangue , Raquitismo Hipofosfatêmico Familiar/terapia , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Mosaicismo , Hormônio Paratireóideo/sangue , Fenótipo , Fosfatos/uso terapêutico , Radiografia , Deleção de Sequência/genética , Vitamina D/sangue , Vitamina D/uso terapêuticoRESUMO
Loss of bone mineral density (BMD) is a substantial risk of mortality in addition to fracture in hemodialysis patients. However, the factors affecting BMD are not fully determined. We conducted a single-center, cross-sectional study on 321 maintenance hemodialysis patients who underwent evaluation of femoral neck BMD using dual-energy X-ray absorptiometry from August 1, 2018, to July 31, 2019. We examined factors associated with osteoporosis defined by T-score of ≤ - 2.5, using logistic regression models. Median age of patients was 66 years, and 131 patients (41%) were diagnosed with osteoporosis. Older age, female, lower body mass index, diabetes mellitus, and higher Kt/V ratios were associated with higher osteoporosis risk. The only medication associated with lower osteoporosis risk was calcium-based phosphate binders (CBPBs) [odds ratio (OR), 0.41; 95% confidence interval (CI), 0.21-0.81]. In particular, CBPB reduced the osteoporosis risk within subgroups with dialysis vintage of ≥ 10 years, albumin level of < 3.5 mg/dL, active vitamin D analog use, and no proton pump inhibitor (PPI) use. In conclusion, CBPB use was associated with lower osteoporosis risk in hemodialysis patients. This effect might be partially attributable to calcium supplementation, given its higher impact in users of active vitamin D analogs or non-users of PPI, which modulate calcium absorption.
Assuntos
Densidade Óssea/efeitos dos fármacos , Cálcio/uso terapêutico , Osteoporose/prevenção & controle , Fosfatos/uso terapêutico , Diálise Renal/métodos , Vitamina D/uso terapêutico , Idoso , Hormônios e Agentes Reguladores de Cálcio/uso terapêutico , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteoporose/etiologia , Osteoporose/patologia , Diálise Renal/efeitos adversos , Diálise Renal/instrumentação , Fatores de RiscoRESUMO
Tumor-induced osteomalacia (TIO) can cause severe, persistent hypo-phosphatemia due to high fibroblast growth factor-23 (FGF-23) levels, which lead to uri-nary phosphate wasting. TIO is frequently encountered in association with mesenchy-mal tumors and responds well to resection of the primary malignancy. Rarely, TIO may be seen as a paraneoplastic phenomenon with solid organ malignancies where correction of biochemical abnormalities requires ongoing phosphorus replacement. We report a case of TIO in a patient with metastatic breast cancer complicated by increased parathyroid hormone release secondary to denosumab-induced hypocalcemia. The patient required intensive intravenous and oral phosphate supplementation in addition to vitamin D repletion. A high index of clinical suspicion can yield the correct diagnosis where TIO arises in the setting of a solid organ tumor and help the clinician appropriately manage these challenging cases.
Assuntos
Neoplasias da Mama , Osteomalacia , Síndromes Paraneoplásicas , Fosfatos , Neoplasias da Mama/complicações , Neoplasias da Mama/patologia , Feminino , Fator de Crescimento de Fibroblastos 23 , Humanos , Hipocalcemia , Osteomalacia/etiologia , Osteomalacia/urina , Síndromes Paraneoplásicas/etiologia , Síndromes Paraneoplásicas/urina , Fosfatos/administração & dosagem , Fosfatos/uso terapêutico , Fosfatos/urinaRESUMO
X-linked hypophosphatemia (XLH) caused by PHEX mutations results in elevated serum FGF23 levels, renal phosphate wasting and low 1,25-dihydroxyvitamin D. The glycophosphoprotein osteopontin, a potent inhibitor of mineralization normally degraded by PHEX, accumulates within the bone matrix. Conventional therapy consisting of supplementation with phosphate and vitamin D analogs is burdensome and the effects on bone material poorly characterized. We analyzed transiliac bone biopsies from four adult patients, two of them severely affected due to no diagnosis and no treatment until adulthood. We used light microscopy, qBEI and FTIRI to study histology, histomorphometry, bone mineralization density distribution, properties of the organic matrix and size of hypomineralized periosteocytic lesions. Non-treatment resulted in severe osteomalacia, twice the amount of mineralized trabecular volume, multiple osteon-like perforations, continuity of lamellae from mineralized to unmineralized areas and distinctive patches of woven bone. Periosteocytic lesions were larger than in treated patients. The latter had nearly normal osteoid thicknesses, although surface was still elevated. The median calcium content of the matrix was always within normal range, although the percentage of lowly mineralized bone areas was highly increased in non-treated patients, resulting in a marked heterogeneity in mineralization. Divalent collagen cross-links were evident independently of the mineral content of the matrix. Broad osteoid seams lacked measurable pyridinoline, a mature trivalent cross-link and exhibited considerable acidic lipid content, typically found in matrix vesicles. Based on our results, we propose a model that possibly integrates the relationship between the observed mineralization disturbances, FGF23 secretion and the known osteopontin accumulation in XLH.
Assuntos
Osso e Ossos/diagnóstico por imagem , Raquitismo Hipofosfatêmico Familiar/diagnóstico por imagem , Raquitismo Hipofosfatêmico Familiar/patologia , Adulto , Densidade Óssea , Matriz Óssea/diagnóstico por imagem , Matriz Óssea/patologia , Osso e Ossos/patologia , Calcitriol/uso terapêutico , Raquitismo Hipofosfatêmico Familiar/tratamento farmacológico , Raquitismo Hipofosfatêmico Familiar/genética , Fator de Crescimento de Fibroblastos 23 , Doenças Genéticas Ligadas ao Cromossomo X/genética , Humanos , Masculino , Endopeptidase Neutra Reguladora de Fosfato PHEX/genética , Fosfatos/administração & dosagem , Fosfatos/uso terapêutico , Estudos Retrospectivos , Espectroscopia de Infravermelho com Transformada de FourierRESUMO
Conventional treatment of X-linked hypophosphataemia (XLH) consists in the oral administration of phosphate plus calcitriol supplements. Although this therapy has reduced bone deformities and even achieved adequate patient growth, overtreatment or low adherence could lead to subsequent consequences that may compromise the efficacy of the therapy. Some of the complications associated with phosphate and vitamin D treatment are abdominal discomfort, diarrhoea, hypokalaemia, hyperparathyroidism, hypercalcaemia or hypercalciuria, nephrocalcinosis or nephrolithiasis, and ectopic calcifications. Therefore, constant multidisciplinary monitoring of patients with XLH is necessary to prevent the manifestation of these complications and to deal with them as soon as they appear. The main objective of this article is to review the main complications arising from conventional treatment of XLH and how to deal with them.
Assuntos
Calcitriol/efeitos adversos , Hormônios e Agentes Reguladores de Cálcio/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Raquitismo Hipofosfatêmico Familiar/diagnóstico , Raquitismo Hipofosfatêmico Familiar/tratamento farmacológico , Fosfatos/efeitos adversos , Vitamina D/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Calcitriol/uso terapêutico , Hormônios e Agentes Reguladores de Cálcio/uso terapêutico , Feminino , Fator de Crescimento de Fibroblastos 23 , Humanos , Masculino , Pessoa de Meia-Idade , Fosfatos/uso terapêutico , Vitamina D/uso terapêuticoRESUMO
Early diagnosis, optimal therapeutic management and regular follow up of children with X-linked hypophosphatemia (XLH) determine their long term outcomes and future quality of life. Biochemical screening of potentially affected newborns in familial cases and improving physician's knowledge on clinical signs, symptoms and biochemical characteristics of XLH for de novo cases should lead to earlier diagnosis and treatment initiation. The follow-up of children with XLH includes clinical, biochemical and radiological monitoring of treatment (efficacy and complications) and screening for XLH-related dental, neurosurgical, rheumatological, cardiovascular, renal and ENT complications. In 2018, the European Union approved the use of burosumab, a humanized monoclonal anti-FGF23 antibody, as an alternative therapy to conventional therapy (active vitamin D analogues and phosphate supplements) in growing children with XLH and insufficiently controlled disease. Diagnostic criteria of XLH and the principles of disease management with conventional treatment or with burosumab are reviewed in this paper.