Adherence to medical treatment for Wilson's disease in children and adolescents: a cohort study from Turkey.

BACKGROUND: This study aimed to assess medication adherence and demographic, clinical, and psychopathological parameters such as quality of life, depression, and anxiety levels that can affect pediatrics with Wilson's Disease (WD). METHODS: A prospective cohort study was conducted at an outpatient clinic in Turkey among pediatric patients (2 to 18 years) with WD between November 2022 and April 2023. The Medication Adherence Report Scale (MARS-5) as a subjective and Medication Possession Ratio (MPR) as an objective assessment were scored. Physical, genetic and biochemical parameters, the Pediatric Quality of Life Inventory (PedsQL) for both parents and patients, Childhood Depression Inventory, State Trait Anxiety Inventory were also administered. RESULTS: A total of 30 pediatric outpatients who were prescribed D-penicillamine (n = 27) or trientine (n = 3) as chelators and zinc (n = 29) and pyridoxine (n = 19) as supplements were included. Proteinuria (n = 3), skin rash (n = 2), and gastrointestinal upset (n = 2) were observed. When the correlation between MARS-5 and duration of follow-up was examined, a significant negative correlation was found (p = 0.014). According to MPRs, non-adherence rates (missed doses ≥ 20%) were 29.6%, 17.2% and 5.3% for D-penicillamine, zinc and pyridoxine, respectively. PedsQL scores were higher than those of parents, with a positive correlation between them (p < 0.001). Also, there was a significant positive correlation between PedsQL and State Anxiety Inventory (p < 0.001). Comparing the change in urinary copper levels between different levels of treatment knowledge, significant differences were observed between high- and low levels (p = 0.043). CONCLUSIONS: Overall, nonadherence rates were 23.3% based on MARS-5 and 5.3-29.6% based on MPR. It is essential to consider factors such as the duration of follow-up, biochemical parameters, treatment knowledge, quality of life and anxiety as potential influencers of medication adherence.

The Management of Nausea and Vomiting in Pregnancy and Hyperemesis Gravidarum (Green-top Guideline No. 69).

An objective and validated index of nausea and vomiting such as the Pregnancy-Unique Quantification of Emesis (PUQE) and HyperEmesis Level Prediction (HELP) tools can be used to classify the severity of NVP and HG. [Grade C] Ketonuria is not an indicator of dehydration and should not be used to assess severity. [Grade A] There are safety and efficacy data for first line antiemetics such as anti (H1) histamines, phenothiazines and doxylamine/pyridoxine (Xonvea®) and they should be prescribed initially when required for NVP and HG (Appendix III). [Grade A] There is evidence that ondansetron is safe and effective. Its use as a second line antiemetic should not be discouraged if first line antiemetics are ineffective. Women can be reassured regarding a very small increase in the absolute risk of orofacial clefting with ondansetron use in the first trimester, which should be balanced with the risks of poorly managed HG. [Grade B] Metoclopramide is safe and effective and can be used alone or in combination with other antiemetics. [Grade B] Because of the risk of extrapyramidal effects metoclopramide should be used as second-line therapy. Intravenous doses should be administered by slow bolus injection over at least 3 minutes to help minimise these. [Grade C] Women should be asked about previous adverse reactions to antiemetic therapies. If adverse reactions occur, there should be prompt cessation of the medications. [GPP] Normal saline (0.9% NaCl) with additional potassium chloride in each bag, with administration guided by daily monitoring of electrolytes, is the most appropriate intravenous hydration. [Grade C] Combinations of different drugs should be used in women who do not respond to a single antiemetic. Suggested antiemetics for UK use are given in Appendix III. [GPP] Thiamine supplementation (either oral 100 mg tds or intravenous as part of vitamin B complex (Pabrinex®)) should be given to all women admitted with vomiting, or severely reduced dietary intake, especially before administration of dextrose or parenteral nutrition. [Grade D] All therapeutic measures should have been tried before considering termination of pregnancy. [Grade C].

Classical homocystinuria presenting with transient basal ganglia pathology and dystonia.

Classical homocystinuria is caused by pathogenic variants in the CBS gene leading to a deficiency of the vitamin B6-dependent enzyme cystathionine beta synthase. The disease is typically associated with high blood homocysteine concentrations. Clinical features include developmental delay/intellectual disability, psychiatric problems, thromboembolism, lens dislocation, and marfanoid habitus. We report on a child with classical homocystinuria presenting with acute episodes of dystonia and symmetrical basal ganglia abnormalities mimicking a mitochondrial disease. After starting treatment with vitamin B6, homocysteine levels rapidly normalized and dystonic episodes did not re-occur. Moreover, brain-imaging findings almost completely disappeared. The case illustrates that homocystinuria should be considered as a treatable differential diagnosis of dystonia.

Pearls & Oy-sters: Delayed Response to Pyridoxine in Pyridoxine-Dependent Epilepsy.

Inborn errors of metabolism are a diverse group of genetic disorders including many that cause neonatal-onset epilepsy such as pyridoxine-dependent epilepsy (PDE). PDE occurs secondary to biallelic pathogenic variants in ALDH7A1 and can present with refractory neonatal seizures and status epilepticus. Neonatal seizures and encephalopathy are modifiable with pyridoxine (vitamin B6) supplementation. However, the clinical response to pyridoxine supplementation can be delayed. We present the case of a full-term neonate with PDE in which seizure cessation was seen a few hours after intravenous pyridoxine load, but the improvement in EEG background and level of clinical encephalopathy occurred 5 days later. We share this case to provide an example in which clinical improvement in PDE was gradual and required continuation of treatment for several days illustrating the necessity of continuing vitamin B6 supplementation in suspected cases until confirmatory genetic testing is obtained or an alternate cause is found.

The Role of Vitamin B6 in Peripheral Neuropathy: A Systematic Review.

INTRODUCTION: Vitamin B6 is a water-soluble vitamin that is naturally present in many foods and is accessible in many dietary supplements. The three natural forms are pyridoxine, pyridoxal, and pyridoxamine. Both vitamin B6 deficiency and high B6 intake have been described as risk factors for developing peripheral neuropathy (PN). The aim of this systematic review is to characterize and comprehensively describe B6-related PN. METHOD: A systematic, computer-based search was conducted using the PubMed database. Twenty articles were included in this review. RESULTS: Higher vitamin B6 levels, which usually occur following the taking of nutritional supplements, may lead to the development of a predominantly, if not exclusively, sensory neuropathy of the axonal type. After pyridoxine discontinuation, such patients subjectively report improved symptoms. However, although low vitamin B6 levels can be seen in patients suffering from peripheral neuropathy of various etiologies, there is no firm evidence that low B6 levels have a direct causal relationship with PN. Many studies suggest subjective improvement of neuropathy symptoms in patients suffering from PN of various etiologies after receiving B6 supplementation; however, no data about B6 administration as a monotherapy exist, only as part of a combination treatment, usually with other vitamins. Therefore, the potential therapeutic role of B6 cannot be confirmed to date. Supplementation with vitamin B6, even as part of a nutritional multivitamin supplement, has not been proven harmful at permitted daily doses in patients who already suffer from PN. CONCLUSION: Current scientific evidence supports a neurotoxic role of B6 at high levels. Although some studies suggest that low B6 is also a potential risk factor, further studies in this area are needed.

B Vitamins as Adjunctive Treatment for Chronic Heart Failure.

INTRODUCTION: Vitamin B deficiency causes cardiac hypertrophy, reduced cardiac contractility, and arrhythmias.The purpose of this study is to perform a network meta-analysis of randomized controlled trials of vitamin B supplements in a group of 150 patients who meet the eligibility criteria.The study also aims to describe the effect of synthetic multivitamins (pyridoxine, folic acid, and cyanocobalamin) on the laboratory findings reflecting the severity of chronic heart failure (cholesterol, glucose, and fibrinogen). METHODS: The experiment involved a group of people (150 individuals) diagnosed with chronic heart failure with reduced left ventricular ejection fraction. The study compared serum levels of B vitamins measured after the therapy and at baseline. The second part of the study focused on the assessment of the laboratory findings reflecting the severity of cardiovascular pathology and indicating an increased risk of vascular catastrophes. RESULTS: Clinical trials among patients diagnosed with chronic heart failure showed that the intake of synthetic forms of pyridoxine, folic acid, and cyanocobalamin slightly increases systolic, diastolic and central venous pressure while decreasing the heart rate and increasing LVEF. Thiamine acts as a vasodilator. It reduces the cardiac afterload and improves heart function. CONCLUSION: The results obtained can be useful in terms of improving the comprehensive treatment strategy for chronic heart failure and further investigation of the effects produced by the intake of B vitamins.

Bioavailability of Cariban® Capsules: A Modified-Release Fixed-Dose Combination of Doxylamine and Pyridoxine to Relieve Nausea and Vomiting During Pregnancy.

BACKGROUND: Nausea and vomiting is a very prevalent condition during pregnancy. Combination of doxylamine and pyridoxine is placed as first-line pharmacological option for its treatment in most clinical guidelines. Among different release forms available, Cariban® is a fixed-dose combination of doxylamine/pyridoxine 10/10 mg, formulated as modified-release capsules. OBJECTIVES: In the present study, we aimed to characterize the bioavailability performance of Cariban® in vitro and in vivo. METHODS: An in vitro dissolution test was performed to evaluate the release profile of Cariban®, together with immediate- and delayed-release formulations available on the market. A single-center, single-dose, open-label bioavailability study following Cariban® administration in 12 healthy adult female patients was carried out to explore the drug behavior in vivo (protocol NBR-002-13; EUDRA-CT 2013-005422-35). These data were additionally used to perform a computational pharmacokinetic simulation of the posology approved for this drug. RESULTS: Cariban® capsules demonstrate a prolonged-release performance, with an early, gradual, and progressive release of both actives until reaching a complete dissolution after 4-5 h in solution. The pharmacokinetic features of these capsules show that doxylamine and pyridoxine metabolites are early absorbed, being all detectable in plasma within 1 h following oral administration. Computational pharmacokinetic simulation predicts that different posology provides distinct profiles of metabolites in plasma, with 1-1-2 (morning-midafternoon-night) being the one that concentrates higher plasma levels but lower dose dumping for 24 h. CONCLUSION: Cariban® behaves as a prolonged-release formulation, which correlates with rapid absorption and arising of the actives in the plasma, but also long-lasting and sustained bioavailability, especially when administered following the complete posology. These results would underlie its demonstrated efficacy to relieve nausea and vomiting of pregnancy (NVP) under clinical settings.

Acupuncture and Doxylamine-Pyridoxine for Nausea and Vomiting in Pregnancy : A Randomized, Controlled, 2 × 2 Factorial Trial.

BACKGROUND: An effective and safe treatment for nausea and vomiting of pregnancy (NVP) is lacking. OBJECTIVE: To assess the efficacy and safety of acupuncture, doxylamine-pyridoxine, and a combination of both in women with moderate to severe NVP. DESIGN: Multicenter, randomized, double-blind, placebo-controlled, 2 × 2 factorial trial. (ClinicalTrials.gov: NCT04401384). SETTING: 13 tertiary hospitals in mainland China from 21 June 2020 to 2 February 2022. PARTICIPANTS: 352 women in early pregnancy with moderate to severe NVP. INTERVENTION: Participants received daily active or sham acupuncture for 30 minutes and doxylamine-pyridoxine or placebo for 14 days. MEASUREMENTS: The primary outcome was the reduction in Pregnancy-Unique Quantification of Emesis (PUQE) score at the end of the intervention at day 15 relative to baseline. Secondary outcomes included quality of life, adverse events, and maternal and perinatal complications. RESULTS: No significant interaction was detected between the interventions (P = 0.69). Participants receiving acupuncture (mean difference [MD], -0.7 [95% CI, -1.3 to -0.1]), doxylamine-pyridoxine (MD, -1.0 [CI, -1.6 to -0.4]), and the combination of both (MD, -1.6 [CI, -2.2 to -0.9]) had a larger reduction in PUQE score over the treatment course than their respective control groups (sham acupuncture, placebo, and sham acupuncture plus placebo). Compared with placebo, a higher risk for births with children who were small for gestational age was observed with doxylamine-pyridoxine (odds ratio, 3.8 [CI, 1.0 to 14.1]). LIMITATION: The placebo effects of the interventions and natural regression of the disease were not evaluated. CONCLUSION: Both acupuncture and doxylamine-pyridoxine alone are efficacious for moderate and severe NVP. However, the clinical importance of this effect is uncertain because of its modest magnitude. The combination of acupuncture and doxylamine-pyridoxine may yield a potentially larger benefit than each treatment alone. PRIMARY FUNDING SOURCE: The National Key R&D Program of China and the Project of Heilongjiang Province "TouYan" Innovation Team.

Can Pyridoxine Successfully Reduce Behavioral Side Effects from Levetiracetam?: A Critically Appraised Topic.

BACKGROUND: Levetiracetam is a commonly used anti-seizure medication, with the development of neuropsychiatric symptoms being the most common side effect. Preliminary literature describes the improvement of these symptoms with pyridoxine, mostly within the pediatric population. However, randomized control trial data investigating this relationship is sparse. OBJECTIVE: The objective of this study was to critically assess evidence regarding the role of pyridoxine in the treatment of neuropsychiatric symptoms from levetiracetam. METHODS: The objective was addressed through the development of a structured, critically appraised topic. This included a clinical scenario with a clinical question, literature search strategy, critical appraisal, results, evidence summary, commentary, and bottom-line conclusions. Participants included consultant and resident neurologists, medical librarians, clinical epidemiologists, and content experts in the field of epilepsy. RESULTS: A randomized, placebo-controlled clinical trial was selected for critical appraisal. This trial compared pyridoxine versus placebo for the treatment of neuropsychiatric symptoms from levetiracetam in a pediatric population and included 105 patients (46/105 received pyridoxine, 59/105 received placebo). It found that both groups had a significant reduction in behavioral symptoms at the 2-,4-and 6-week time points ( P <0.05). However, the authors noted that the pyridoxine group had almost double the relative reduction when compared with the placebo group at all time points: 1.9 at 2 weeks, 2.0 at 4 weeks, and 1.8 at 6 weeks ( P =0.001). CONCLUSIONS: This study suggests that pyridoxine for the treatment of levetiracetam-induced behavioral side effects may result in modest improvement, although many limitations prevent conclusive results. There remains a need for a double-blinded, randomized control trial in both the adult and pediatric populations.

Vincristine-induced ptosis in a leukemia patient treated with pyridoxine and pyridostigmine.

INTRODUCTION: Blepharoptosis, commonly referred to as ptosis or eyelid sagging, is a condition where the upper eyelid droops over the eye. It can be congenital or acquired and is caused by the weakening of the eyelid muscles. CASE REPORT: We present a case of a 3-year-old boy with T-cell acute lymphoblastic leukemia who developed bilateral ptosis while on treatment with Berlin-Frankfurt Munster-98 protocol. MANAGEMENT & OUTCOME: The patient was diagnosed with bilateral ptosis due to vincristine, the primary agent in the induction phase of the protocol. The addition of the neuroregenerative agents and supportive measures led to marked improvement, followed by complete resolution within 3 weeks. DISCUSSION: Vincristine is an anticancer agent with known neurotoxicity, which has a significant role in treating hematological malignancies and sarcoma. In many studies, the addition of neuroregenerative agents such as pyridoxine and pyridostigmine has been noted to hasten recovery without any documented side effects. Similar findings were also drawn from our research due to India's higher incidence of vincristine-induced neurotoxicity. It is essential to promptly diagnose and manage symptoms at the earliest to prevent the risk of permanent nerve damage and inferior quality of life for the patient.

The spectrum of pyridoxine dependent epilepsy across the age span: A nationwide retrospective observational study.

BACKGROUND: Pyridoxine-dependent epilepsy (PDE) is a rare seizure disorder usually presenting with neonatal seizures. Most cases are caused by biallelic pathogenic ALDH7A1variants. While anti-seizure medications are ineffective, pyridoxine provides seizure control, and dietary interventions may be of benefit. As the natural history beyond adolescence is insufficiently explored, our study aimed to assess the spectrum of PDE at various ages in Norway. METHODS: Patients were ascertained by contacting all Norwegian paediatric, neurological, and neurohabilitation departments and relevant professional societies. Medical records were collected and reviewed. RESULTS: We identified 15 patients treated for PDE; 13 had ALDH7A1 variants (PDE-ALDH7A1), one had PNPO deficiency, and in one, aetiology remained obscure. Of those with PDE-ALDH7A1, 12 were alive at time of study; five were > 18 years old and six were < 4 years. Median age was 10 years (range 2 months-53 years). Estimated minimum prevalence was 6.3/million among children and 1.2/million among adults. Ten had seizure onset on the first day of life. Perinatal complications and neuroradiological abnormalities suggested additional seizure aetiologies in several patients. Pyridoxine had immediate effect in six, while six had delayed (>1 h) or uncertain effect. Median delay from first seizure to continuous treatment was 11 days (range 0-42). Nine experienced breakthrough seizures with intercurrent disease or due to pyridoxine discontinuation. Cognitive outcomes ranged from normal to severe intellectual disability. The condition appeared to remain stable in adult life. SIGNIFICANCE: We found a much higher prevalence of PDE-ALDH7A1 in children relative to adults, suggesting previous underdiagnosis and early mortality. Perinatal complications are common and can delay diagnosis and initiation of pyridoxine treatment. Lifelong and continuous treatment with pyridoxine is imperative. Due to better diagnostics and survival, the number of adult patients is expected to rise.

Current evidence for adjunct pyridoxine (vitamin B6) for the treatment of behavioral adverse effects associated with levetiracetam: A systematic review.

BACKGROUND: Levetiracetam (LVT), while an effective treatment for multiple seizure types, is associated with a high incidence of neuropsychiatric adverse events (NPAEs). In predominantly retrospective studies, supplementation with pyridoxine/vitamin B6 (PN) was associated with improvement in NPAEs in some people. A previous review highlighted a lack of double-blind, controlled trials of PN for the treatment of NPAEs in individuals treated with LVT. The current paper updates the findings from the previous review to include evidence from studies published since June 2019. METHODS: An updated systematic review of the published literature was performed in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed, Embase, the Cochrane Library, and Google Scholar were searched to identify studies published between June 2019 and 2nd November 2022 in which supplementary PN was initiated for the treatment of LVT-associated NPAEs. All study types were eligible. The risk of bias in randomized trials was assessed using the Cochrane risk-of-bias tool. RESULTS: Seven additional studies were identified: two double-blind, randomized controlled trials (RCTs), four retrospective studies, and one retrospective case series. One RCT reported significant improvements from baseline in behavioral adverse events (BAEs) in both the intervention (PN) group and the low-dose control group (both p < 0.05), with a significantly greater improvement in the intervention group (p < 0.001). In the second RCT, differences in BAE severity between PN and placebo groups at the endpoint were not statistically significant. In one retrospective study, subjective irritability was reported to have improved from baseline in 9/20 individuals (45%) treated with supplementary PN. Data for systematic assessments (PHQ-9 and GAD-7) were available for 10 individuals. Assessment by PHQ-9 showed that six individuals improved, two worsened and two had no change. Based on the GAD-7, three people improved, two worsened and five had no change. In the second retrospective study, 18/41 individuals (44%) who commenced PN following the emergence of BAEs showed "significant" improvement. In a separate group of individuals with pre-existing behavioral problems in whom PN treatment was initiated at the same time as commencing LVT, 3/18 (16.7%) developed BAEs. This compared with 79/458 people (17.2%) who were initially treated only with LVT. The third retrospective study compared treatment-related irritability in individuals who had been treated with both LVT and perampanel, either sequentially or concomitantly. Two people who developed irritability while receiving LVT monotherapy were able to continue treatment with the addition of PN. The fourth study reported a significantly lower LVT discontinuation rate in individuals taking PN and a higher rate of improved behavior in those who were able to continue LVT. The case series reported improvements in behavioral symptoms in six people within two to three weeks of commencing supplementary PN. CONCLUSION: Data published within the last three years add to earlier evidence suggesting that PN might be effective in the treatment of NPAEs associated with LVT. However, the quality of evidence remains poor and only a few prospective trials have been published. Data from placebo-controlled trials are still largely lacking. Currently, there is insufficient evidence to justify any firm recommendation for PN supplementation to treat NPAEs associated with LVT. Further well-designed, prospective trials are warranted.

The effects of pyridoxine (vitamin B6) supplementation in nausea and vomiting during pregnancy: a systematic review and meta-analysis.

PURPOSE: Nausea and vomiting during pregnancy (NVP) are common symptoms in pregnancy. Although no definitive treatment option for NVP, pyridoxine (Vitamin B6) supplementation has been used widely. The present study aims to systematically evaluate the current evidence regarding pyridoxine for the treatment of NVP. METHODS: Data were obtained using a stepwise search process using keywords in the following online medical databases; PubMed®, Web of Science®, and Scopus® for studies published before 1st May 2021. Studies reporting intervention with pyridoxine supplementation alone and/or with other active substances were included. A meta-analysis was performed on the PUQE score and Rhode's score for nausea and vomiting. FINDINGS: Initial database searching indicated 548 potentially eligible articles, of which 18 studies satisfying the inclusion criteria were selected. Eight studies showed beneficial effects with pyridoxine alone as the supplementation, while six others found that the supplementation of pyridoxine in combination with another active substance had favourable effects. Supplementation of pyridoxine alone as well as combined treatment of pyridoxine with an active ingredient as the intervention significantly improved the symptoms of nausea according to Rhode's score [0.78 [95% CI: 0.26, 1.31; p = 0.003; I2 = 57%, p = 0.10)] and PUQE score [0.75 (95% CI: 0.28, 1.22; p = 0.002; I2 = 0%, p = 0.51)], respectively. CONCLUSION: Supplementation of pyridoxine alone as well as with an active ingredient demonstrated beneficial effects for women suffering from NVP.

Mechanisms of action of vitamin B1 (thiamine), B6 (pyridoxine), and B12 (cobalamin) in pain: a narrative review.

Pain is a complex sensory and emotional experience with nociceptive, nociplastic, and neuropathic components. An involvement of neurotropic B vitamins (B1 - thiamine, B6 - pyridoxine, and B12 - cyanocobalamin) as modulators of inflammation and pain has been long discussed. New evidence suggests their therapeutic potential in different pain conditions. In this review, we discuss the main role of neurotropic B vitamins on different nociceptive pathways in the nervous system and to describe their analgesic action mechanisms. The performed literature review showed that, through different mechanisms, these vitamins regulate several inflammatory and neural mediators in nociceptive and neuropathic pain. Some of these processes include aiming the activation of the descending pain modulatory system and in specific intracellular pathways, anti-inflammatory, antioxidative and nerve regenerative effects. Moreover, recent data shows the antinociceptive, antiallodynic, and anti-hyperalgesic effects of the combination of these vitamins, as well as their synergistic effects with known analgesics. Understanding how vitamins B1, B6, and B12 affect several nociceptive mechanisms can therefore be of significance in the treatment of various pain conditions.