Withdrawal Of Medication Research Articles

Ten missteps in the management of inflammatory bowel disease in Asia: An expert report by the Asian Pacific Association of Gastroenterology Working Group on Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is rapidly emerging in the Asia Pacific region. However, there are many challenges in the diagnosis and management of this condition. The Asian Pacific Association of Gastroenterology (APAGE) Working Group on IBD conducted a round table meeting to identify 10 common mistakes in the management of IBD in Asia. To summarize, many physicians still over rely on a definitive histological diagnosis before starting treatment and do not fully establish disease extent such as perianal and proximal gastrointestinal involvement in Crohn's disease (CD) or extent of involvement in ulcerative colitis (UC). It is also essential to actively look for evidence of extra-intestinal manifestations, which may influence choice of therapy. In terms of conventional therapy, underuse of topical 5 aminosalicylates (5-ASAs) in UC and inappropriate dosing of corticosteroids are also important considerations. Acute severe UC remains a life-threatening condition and delay in starting rescue therapy after inadequate response to intravenous steroids is still common. Anti-tumor necrosis factors should be considered first line in all cases of complex perianal fistulizing CD. Most patients with IBD are on potent immunosuppressive therapy and should be screened for latent infections and offered vaccinations according to guidelines. Under-recognition and management of significant complications such as anemia, osteoporosis, malnutrition, and thromboembolism should also be addressed. Colonoscopy is still not properly performed for dysplasia/cancer surveillance and for evaluating post-op recurrence of CD. Another common misstep is inappropriate withdrawal of medications during pregnancy leading to increased complications for the mother and the newborn.

Measles Outbreaks in Modern Times: Vaccination Problems in the Territory of Jalal-Abad Region of the Kyrgyz Republic for 2023

An analysis of the incidence of measles infection among the population showed an increasing trend in the incidence of measles, which amounted to 1823 cases, of which 92.2% (n = 1682) were children under 14 years of age. The vast majority of outbreaks of this disease are associated with limited coverage of the population in vaccination programs. This study revealed low vaccination coverage of children in 2020 — 94-95%, for 2022 — 93.8-94.8%, which is associated with various reasons (not reaching age, medical withdrawal, parental refusal to vaccinate, population migration and with unknown vaccination status, etc.).

Current practice and safety measures in epilepsy monitoring units in the Gulf Cooperation Council Countries: A cross-sectional study

BackgroundAn increasing number of Epilepsy Monitoring Units (EMU) display various practices and safety protocols. EMU settings should meet clear, standardized safety protocols to avoid seizure adverse events (SAE). We aim to provide the foundational framework facilitating the establishment of unified evidence-based safety regulations to address the practices and safety measures implemented within the Gulf Cooperation Council (GCC). MethodsIn this cross-sectional study, EMU directors in the GCC were contacted directly by phone to personally complete an electronic 37-item questionnaire sent via text messages and email. From January 2021–December 2021. ResultsSeventeen EMUs from six GCC countries participated in the study. All EMU directors responded to the study. Twelve (70.6%) EMUs monitored adults and children, five (29.4%) monitored adults, and none monitored children only. The number of certified epileptologists in the EMUs ranged from one to eight per unit. Fifteen (88.2%) EMUs applied a continuous observation pattern, whereas two (11.8%) performed daytime only. The precautions most commonly used in the video Electroencephalogram (EEG) were seizure pads and bedside oxygen in 15 EMUs (88.2%). For invasive EEG, seizure pads were used in 9 EMUs (52.9%), %) and IV access in 8 EMUs (47.1%). The occurrence of adverse events varied among EMUs. The most common conditions were postictal psychosis 10 (58.8%), injuries 7 (41.2%), and status epilepticus 6 (35.3%). Falls were mainly related to missed seizures or delayed recognition by video monitors in 8 EMUs (47.1%). The extended EMU stay was because of an insufficient number of recorded seizures in 16 EMUs (94.1%), poor seizure lateralization and localization in 10 (58.8%), and re-introduction of AEDs in nine (52.9%). All EMUs had written acute seizure and status epilepticus management protocols. A postictal psychosis management protocol was available for 10 (58.8%). Medications were withdrawn before admission in 6 EMUs (35.3%). The specific medication withdrawal speed protocol upon admission was available in 7 EMUs (41.2%). Pre-admission withdrawal of medication demonstrated a shorter length of stay in both video and invasive EEG, which was statistically significant (ρ (15) = −.529, p =.029; ρ (7) = −.694, p =.038; respectively). ConclusionThe practice and safety regulations of EMUs in the GCC vary widely. Each EMU reported the occurrences of SAE and injuries. Precautions, protective measures, and management protocols must be reassessed to minimize the number of SAEs and increase the safety of the EMU.

Discontinuation of therapy in inflammatory bowel disease: Current views.

The timely introduction and adjustment of the appropriate drug in accordance with previously well-defined treatment goals is the foundation of the approach in the treatment of inflammatory bowel disease (IBD). The therapeutic approach is still evolving in terms of the mechanism of action but also in terms of the possibility of maintaining remission. In patients with achieved long-term remission, the question of de-escalation or discontinuation of therapy arises, considering the possible side effects and economic burden of long-term therapy. For each of the drugs used in IBD (5-aminosalycaltes, immunomodulators, biological drugs, small molecules) there is a risk of relapse. Furthermore, studies show that more than 50% of patients who discontinue therapy will relapse. Based on the findings of large studies and meta-analysis, relapse of disease can be expected in about half of the patients after therapy withdrawal, in case of monotherapy with aminosalicylates, immunomodulators or biological therapy. However, longer relapse-free periods are recorded with withdrawal of medication in patients who had previously been on combination therapies immunomodulators and anti-tumor necrosis factor. It needs to be stressed that randomised clinical trials regarding withdrawal from medications are still lacking. Before making a decision on discontinuation of therapy, it is important to distinguish potential candidates and predictive factors for the possibility of disease relapse. Fecal calprotectin level has currently been identified as the strongest predictive factor for relapse. Several other predictive factors have also been identified, such as: High Crohn's disease activity index or Harvey Bradshaw index, younger age (< 40 years), longer disease duration (> 40 years), smoking, young age of disease onset, steroid use 6-12 months before cessation. An important factor in the decision to withdraw medication is the success of re-treatment with the same or other drugs. The decision to discontinue therapy must be based on individual approach, taking into account the severity, extension, and duration of the disease, the possibility of side adverse effects, the risk of relapse, and patient's preferences.

Modulation of subthalamic beta oscillations by movement, dopamine, and deep brain stimulation in Parkinson’s disease

Subthalamic beta band activity (13–35 Hz) is known as a real-time correlate of motor symptom severity in Parkinson’s disease (PD) and is currently explored as a feedback signal for closed-loop deep brain stimulation (DBS). Here, we investigate the interaction of movement, dopaminergic medication, and deep brain stimulation on subthalamic beta activity in PD patients implanted with sensing-enabled, implantable pulse generators. We recorded subthalamic activity from seven PD patients at rest and during repetitive movements in four conditions: after withdrawal of dopaminergic medication and DBS, with medication only, with DBS only, and with simultaneous medication and DBS. Medication and DBS showed additive effects in improving motor performance. Distinct effects of each therapy were seen in subthalamic recordings, with medication primarily suppressing low beta activity (13–20 Hz) and DBS being associated with a broad decrease in beta band activity (13–35 Hz). Movement suppressed beta band activity compared to rest. This suppression was most prominent when combining medication with DBS and correlated with motor improvement within patients. We conclude that DBS and medication have distinct effects on subthalamic beta activity during both rest and movement, which might explain their additive clinical effects as well as their difference in side-effect profiles. Importantly, subthalamic beta activity significantly correlated with motor symptoms across all conditions, highlighting its validity as a feedback signal for closed-loop DBS.

Feasibility of primary aldosteronism diagnosis in initial evaluation without medication withdrawal or confirmatory tests.

Primary aldosteronism (PA), a frequent cause of hypertension, is highly associated with cardiovascular risk and mortality. PA diagnosis is often difficult due to the need to discontinue antihypertensive medication interfering with the renin-angiotensin-aldosterone system (I-RAAS). Our objective was to ascertain diagnosis of PA through biochemical assessments during screening while maintaining I-RAAS medications. Hypertensive patients assessed for PA were involved. Patients were grouped according to the use of I-RAAS drugs during screening and the presence of PA. The diagnostic accuracy of the aldosterone-to-renin ratio (ARR), and other biochemical features were evaluated. 265 patients included, 122/265 with PA, and 192/265 were on I-RAAS therapy. The area under ROC curve (AUROC) of ARR for PA in patients without I-RAAS was 0.769 (95%CI: 0.66-0.877), and was 0.877 (95%CI: 0.828-0.926) in those with I-RAAS drugs. Sensitivity, specificity, positive predictive value, and negative predictive value (PPV) of cut-off of ARR > 50 were: 76%, 81%, 77.5%, and 79.6%. ARR > 50 plus hypokalemia had a PPV of 92.6% for PA. AUROC values of ARR evaluated in each group of antihypertensive drugs were >0.850 in all cases. ARR during I-RAAS therapy demonstrates reliability and accuracy for PA diagnosis. An ARR > 50 combined with hypokalemia while on I-RAAS medication could be considered indicative of PA diagnosis.

Discordance between pain specialists and patients on the perception of dependence on pain medication: A multi-centre cross-sectional study

Patients with chronic non-cancer pain are referred to pain centres to improve their pain treatment. The discontinuation of pain medications in case of poor efficacy can be difficult to accept for patients, particularly opioid analgesics. Previous research has described that from the patients' perspective, the psychological relief of a negative effect of chronic pain and withdrawal symptoms of prescription opioids represent drivers of persistent use and first stage of opioid use disorder, despite insufficient pain relief. There is no validated tool to investigate this psychological dependence. This study aimed to assess discordance between patients and pain specialists in their perception of dependence on pain medication and investigate associations with characteristics of patients, type of pain and iatrogenic pharmacodependence. Self-administered questionnaires (patients and physicians) were administered in six pain centres in France. A question on perceived dependence on pain medications was addressed to the patient and the physician in a matched pair. Discordance between them was evaluated by the Cohen kappa coefficient. Demographics, pain, anxiety and depression, pain medication withdrawal symptoms, diverted use, and craving represented variables studied in a multivariate model as potentially associated with patient-physician discordance. According to the 212 pairs of completed questionnaires, a perceived dependence was reported by the majority of patients (65.6%) and physicians (68.4%). However, the concordance was fair (kappa=0.38; CI [95%]: 0.25-0.51). Almost all patients (89.3%) were treated with an opioid analgesic. A higher likelihood of discordance was observed when patients suffered from nociplastic pain (odds ratio [OR]: 2.72, 95% [CI]: 1.29-5.84). Medical shared-decision for changing pain treatment could be improved by taking into account the perception of patient dependence on medications for pain relief and or psychoactive effects, particularly in nociplastic pain for which the treatment is challenging.

Exit Strategy: Balancing the Risks and Rewards of Antiseizure Medication Withdrawal.

The majority of people with epilepsy achieves long-term seizure-freedom and may consider withdrawal of their anti-seizure medications (ASMs). Withdrawal of ASMs can yield substantial benefits but may be associated with potential risks. This review critically examines the existing literature on ASM withdrawal, emphasizing evidence-based recommendations, where available. Our focus encompasses deprescribing strategies for individuals who have attained seizure freedom through medical treatment, those who have undergone successful epilepsy surgery, and individuals initiated on ASMs following acute symptomatic seizures. We explore state-of-the-art prognostic models in these scenarios that could guide the decision-making process. The review underscores the importance of a collaborative shared-decision approach between patients, caregivers, and physicians. We describe the subjective and objective factors influencing these decisions and illustrate how trade-offs may be effectively managed in practice.

Evaluation of medication withdrawal in patients with non-systemic juvenile idiopathic arthritis in Japan using a web-based survey.

Although treatments for juvenile idiopathic arthritis (JIA) have seen considerable advancements, there remains a lack of clear guidelines on withdrawing medications. This study aimed to investigate the current strategies for discontinuing non-systemic JIA treatment. A web-based questionnaire was distributed to members of the Pediatric Rheumatology Association of Japan. According to 126 responses, the most significant factors influencing JIA treatment tapering were the duration of clinically inactive disease, medication toxicity, and a history of arthritis flares. Respondents were often cautious about discontinuing medication if symptoms, e.g. 'morning stiffness' or 'intermittent joint pain', persisted. Among subtypes, oligoarticular JIA was more amenable to treatment tapering, whereas rheumatoid factor-positive polyarticular JIA proved less amenable. Most respondents started medication tapering after a continuous clinical inactive duration exceeding 12 months, and >50% of them required >6 months to achieve treatment discontinuation. Additionally, 40% of the respondents consistently underwent imaging before treatment tapering. The relative risks of treatment continuation and withdrawal should be considered, and decisions should be made accordingly. To obtain improved understanding of and more robust evidence for the optimal strategies for safely discontinuing JIA treatment, it is crucial to continue investigations including long-term outcomes.

Mechanisms of adverse mammary effect induced by olanzapine and therapeutic interventions in rat model.

BackgroundOlanzapine antagonizes dopamine receptors and is prescribed to treat multiple psychiatric conditions. The main side effect of concern for olanzapine is weight gain and metabolic syndrome. Olanzapine induces hyperprolactinemia, however its effect on the mammary gland is poorly documented. MethodsRats received olanzapine by gavage or in drinking water at 1, 3, and 6 mg/kg/day for 5–40 days or 100 days, with and without coadministration of bromocriptine or aripiprazole and using once daily or continuous administration strategies. Histomorphology of the mammary gland, concentrations of prolactin, estradiol, progesterone, and olanzapine in serum, mammary gland and adipose tissue, and mRNA and protein expressions of prolactin receptors were analyzed. ResultsIn adult and prepubescent female rats and male rats, olanzapine induced significant development of mammary glands in dose- and time-dependent manners, with histopathological hyperplasia of mammary ducts and alveoli with lumen dilation and secretion, marked increase of mammary prolactin receptor expression, a marker of breast tissue, and with mild increase of circulating prolactin. This side effect can be reversed after medication withdrawal, but long-term olanzapine treatment for 100 days implicated tumorigenic potentials indicated by usual ductal epithelial hyperplasia. Olanzapine induced mammary development was prevented with the coaddition of the dopamine agonist bromocriptine or partial agonist aripiprazole, or by continuous administration of medication instead of a once daily regimen. ConclusionsThese results shed light on the previously overlooked effect of olanzapine on mammary development and present experimental evidence to support current clinical management strategies of antipsychotic induced side effects in the breast.

Neuro-ophthalmic complications of modern anti-cancer drugs

PurposeTargeted cancer therapies have been responsible for a dramatic shift in treatment strategies for cancer, and the number of drugs, classes, and indications are continually growing. Neuro-ophthalmic complications of these medications are an uncommon but important subset of adverse events which profoundly impact vision. This review aims to collate studies and reports of known neuro-ophthalmic complications of targeted therapies and describe their management.MethodsThe anti-cancer drugs included in the review were any drugs targeting specific molecules involved in the cancer disease process. PubMed, EMBASE, and Web of Science were searched using the generic names of each drug and keywords of neuro-ophthalmic conditions. The prescribing information published by the US Food and Drug Administration (FDA) for each drug was also reviewed.ResultsSeveral classes of targeted anti-cancer drugs were found to cause neuro-ophthalmic adverse effects. Immune checkpoint inhibitors are responsible for a raft of immune-related adverse events such as optic neuritis, ischemic optic neuropathy, PRES, and myasthenia gravis. Therapies with anti-VEGF activity can provoke posterior reversible leukoencephalopathy, which commonly presents with visual loss and can be fatal if not treated promptly. Inhibitors of BCR-ABL1, VEGF, ALK, and proteasomes have all been linked to optic nerve disorders which can have debilitating consequences for vision.ConclusionThe neuro-ophthalmic complications of modern anti-cancer drugs can limit or necessitate the withdrawal of these life-prolonging medications. Ophthalmologists should be alert for neuro-ophthalmic complications in these medications to facilitate prompt diagnosis and treatment and reduce the risk of severe and permanent consequences.

Oestrus induction and fertility response in post-partum anoestrus dairy cows treated with homeopathic medicine

The study was carried out to evaluate the effect of two homeopathic medicines to induce oestrus in 36 postpartum anoestrus crossbred Jersey dairy cows. Group 1 cows were fed a mineral mixture, and group 2 and 3 were medicated with Pulsatilla and Sepia drenched at the dose rate of 20 mL twice daily for 8 days, respectively. The mean plasma progesterone level (ng/mL) estimated using a radio immunoassay kit was significantly higher in group 2, followed by group 3 before and after medication on day 28 and 60, post artificial insemination (AI). Out of 12 induced for oestrus, 10 cows (83.33 %) and 9 cows (75.0 %) in group 2 and 3 were confirmed pregnant by rectal palpation on day 60 post AI, respectively. Both the homeopathic medicines showed 100% oestrus induction with a mean interval of 25.17 to 25.50 days, and Pulsatilla medicated cows showed improved fertility response than Sepia. The significantly higher level of progesterone after the withdrawal of homeopathic medication might be due to the release of circulating hormone, which blocks estradiol negative feedback. The subsequent increase reduces uterine PGF2 alpha secretion for a better conception rate.

Prevalence and management of proteinuria associated with vascular endothelial growth factor receptor-targeted tyrosine kinase inhibitor treatment in advanced renal cell carcinoma, hepatocellular carcinoma, and thyroid cancer.

Vascular endothelial growth factor receptor-targeted tyrosine kinase inhibitors (VEGFR-TKIs) are often used for treatment of several types of cancer; however, they are associated with an increased risk of proteinuria, sometimes leading to treatment discontinuation. We searched PubMed and Scopus to identify clinical studies examining the incidence and risk factors for proteinuria caused by VEGFR-TKIs in patients with renal cell carcinoma, thyroid cancer, and hepatocellular carcinoma. The global incidence of proteinuria ranged from 6% to 34% for all grades of proteinuria, and from 1% to 10% for grade ≥3 proteinuria. The incidence of proteinuria did not differ significantly by cancer type, but in all three cancer types, there was a trend toward a higher incidence of proteinuria with lenvatinib than with other VEGFR-TKIs. In terms of risk factors, the incidence of proteinuria was significantly higher among Asians (including Japanese) compared with non-Asian populations. Other risk factors included diabetes mellitus, hypertension, and previous nephrectomy. When grade 3/4 proteinuria occurs, patients should be treated according to the criteria for dose reduction or withdrawal specified for each drug. For grade 2 proteinuria, treatment should be continued when the benefits outweigh the risks. Referral to a nephrologist should be considered for symptoms related to decreased renal function or when proteinuria has not improved after medication withdrawal. These management practices should be implemented universally, regardless of the cancer type.

Conversion to Brivaracetam Monotherapy in Clinical Practice: A Retrospective Study.

The study aimed to evaluate the effectiveness and safety of brivaracetam (BRV) as conversion monotherapy in adults with focal epilepsy treated in the context of real-world clinical practice. This was a retrospective, observational, non-interventional study in adults with focal epilepsy who converted to BRV monotherapy following the withdrawal of background antiseizure medications (ASMs). Primary effectiveness outcome was the retention rate of BRV as single ASM at 6 and 12months. Secondary outcomes included the 6- and 12-month rates of seizure freedom. Safety and tolerability outcomes included the frequency and type of adverse events (AEs) and the occurrence of treatment discontinuation due to AEs. A total of 44 participants with a median age of 63.5 (interquartile range 44-73.5) years were included; 17 subjects were seizure free at baseline, and 9 of them switched from levetiracetam because of lack of tolerability. The retention rate of BRV monotherapy was 88.6% (39/44) at 6months and 83.9% (26/31) at 12months. The rates of seizure freedom were 72.7% (32/44) in subjects with 6-month follow-up and 58.1% (18/31) in subjects with 12-month follow-up. The median maintenance dosage of BRV monotherapy was 150 (100-200) mg/day at 6months and 125 (100-200) mg/day in subjects with 12-month follow-up. Adverse events were recorded in 6/44 (13.6%) participants and led to BRV discontinuation in 2/44 (4.5%) cases. The reported AEs were somnolence (n = 3), fatigue (n = 2), and irritability (n = 1); no serious AEs were experienced. In 21/44 (47.7%) participants, BRV monotherapy resulted from the direct switch from levetiracetam. The rates of treatment retention and seizure freedom at 6 and 12months were higher among people who switched from levetiracetam to BRV monotherapy. Brivaracetam may be a valuable treatment of focal seizures in people who converted to monotherapy in a real-life setting.

Analysis of the impact of different schemes of preparation to trabeculectomy on the healing markers using in vitro model of the Tenon fibroblast cultures isolated directly from the patient

Aims/Purpose: The aim of the study was to assess the influence of different regimes of patient's preparation before trabeculectomy on the markers of healing process in Tenon's fibroblast cultures.Methods: The studied group consisted of 66 patients with open angle glaucoma undergoing primary trabeculectomy. The patients were divided into 5 groups with different regimes of preparation before the surgery based on application or withdrawal of topical antiglaucoma medications and steroids. During trabeculectomy the samples of Tenon's capsule were obtained. Tenon fibroblasts were isolated directly from the explants to test their proliferation ability and the level of released healing markers. Following factors typical of healing process were evaluated using commercially available ELISA kits: IL 1‐β, IL‐6, IL‐8, VEGF‐A, TGF‐ β1 and MMP‐9.Results: Concentrations of IL‐1β, IL‐6 and TGF‐ β1 were significantly higher in the group obtaining antiglaucoma drops. Additionally, in this group the fibroblasts revealed the highest proliferation potential, indicating the active healing process. The levels of IL‐8, VEGF‐A and MMP‐9 were similar between the groups.Conclusions: Our study shows that for the best conjunctival anti‐inflammatory control, the most influential factor is the withdrawal of antiglaucoma medications.

DRUG INDUCED LIVER INJURY: A SYSTEMATIC REVIEW

Drug-induced liver injury (DILI), which has a variety of pathophysiological characteristics, is an important clinical problem. This review offers a thorough analysis of DILI, covering its pathophysiological mechanisms, the interaction between the microbiota and liver disease, the potential benefit of probiotics in preventing or treating DILI, diagnostic and prognostic methods, risk factors for DILI, current prevalence rates, and available treatments. The emergence of liver damage is influenced by the complex interplay of drug metabolism, immunological responses, and hereditary variables. An extensive list of medications, nutritional supplements, herbal products, and chemotherapeutic medicines that have been linked to DILI is provided based on the various research papers. The impact of the gut microbiota on healthy liver function and liver disease has been clarified by recent studies. Drug metabolism, immunological responses, and hepatic inflammation can all be affected by changes in gut microbial makeup and function, thereby worsening DILI. Probiotics’ impact on the gut-liver axis and their potential therapeutic advantages in the prevention and treatment of DILI are investigated. For effective management of DILI, a precise diagnosis and prognosis are essential. The outcomes of patients are predicted and treatment choices are guided by prognostic variables, such as liver function tests and drug causality evaluation tools. Inherited liver illnesses, genetic differences, patient characteristics, concurrent medication use, and other risk factors all have a role in the development of DILI. Identification of those at higher risk and the facilitation of specialized preventative interventions and patient monitoring is made possible by the recognition of these risk factors. DILI prevalence rates differ between populations and geographical areas. Planning for public health and allocating resources depend on tracking the incidence and prevalence of DILI. Although supportive care and medication withdrawal are the mainstays of DILI treatment, severe cases may call for a liver transplant. As a result, DILI is a multifactorial disorder that necessitates a thorough understanding of its processes, risk factors, diagnosis, and therapy. New insights into the gut microbiota and the possible impact of probiotics present intriguing directions for further study and treatment approaches to reduce liver damage caused by DILI.

Effects of dopaminergic treatment on inhibitory control differ across Hoehn and Yahr stages of Parkinson's disease.

Motor inhibitory control, a core component of cognitive control, is impaired in Parkinson's disease, dramatically impacting patients' abilities to implement goal-oriented adaptive strategies. A progressive loss of the midbrain's dopamine neurons characterizes Parkinson's disease and causes motor features responsive to dopaminergic treatments. Although such treatments restore motor symptoms, their impact on response inhibition is controversial. Most studies failed to show any effect of dopaminergic medicaments, although three studies found that these drugs selectively improved inhibitory control in early-stage patients. Importantly, all previous studies assessed only one domain of motor inhibition, i.e. reactive inhibition (the ability to react to a stop signal). The other domain, i.e. proactive inhibition (the ability to modulate reactive inhibition pre-emptively according to the current context), was utterly neglected. To re-examine this issue, we recruited cognitively unimpaired Parkinson's patients under dopaminergic treatment in the early (Hoehn and Yahr, 1-1.5, n = 20), intermediate (Hoehn and Yahr 2, n = 20), and moderate/advanced (Hoehn and Yahr, 2.5-3, n = 20) stages of the disease. Using a cross-sectional study design, we compared their performance on a simple reaction-time task and a stop-signal task randomly performed twice on dopaminergic medication (ON) and after medication withdrawal (OFF). Normative data were collected on 30 healthy controls. Results suggest that medication effects are stage-dependent. In Hoehn and Yahr 1-1.5 patients, drugs selectively impair reactive inhibition, leaving proactive inhibition unaffected. In the ON state, Hoehn and Yahr two patients experienced impaired proactive inhibition, whereas reactive inhibition is no longer affected, as it deteriorates even during the OFF state. By contrast, Hoehn and Yahr 2.5-3 patients exhibited less efficient reactive and proactive inhibition in the OFF state, and medication slightly improved proactive inhibition. This evidence aligns with the dopamine overdose hypothesis, indicating that drug administration may overdose intact dopamine circuitry in the earliest stages, impairing associated cognitive functions. In later stages, the progressive degeneration of dopaminergic neurons prevents the overdose and can exert some beneficial effects. Thus, our findings suggest that inhibitory control assessment might help tailor pharmacological therapy across the disease stage to enhance Parkinson's disease patients' quality of life by minimizing the hampering of inhibitory control and maximizing the reduction of motor symptoms.

Clinical Implications of the Relationship Between Naltrexone Plasma Levels and the Subjective Effects of Heroin in Humans.

Extended-release naltrexone (NTX) is an opioid antagonist approved for relapse prevention after medical withdrawal. Its therapeutic effect is dependent on the NTX plasma level, and as it decreases, patients may lack protection against relapse and overdose. Therefore, identifying the minimally effective NTX level needed to block opioid-induced subjective effects has important clinical implications. This secondary, individual-level analysis of data collected in a human laboratory study was conducted to evaluate the relationship between NTX levels and subjective effects of an intravenously administered 25-mg challenge dose of heroin in non-treatment-seeking participants with opioid use disorder (N = 12). Subjective ratings of drug liking using a 100-mm visual analog scale (VAS) and NTX levels were measured across 6 weeks after participants received a single injection of either extended-release NTX 192 mg (N = 6) or 384 mg (N = 6). Cubic spline mixed-effects models were used to provide 95% prediction intervals for individual changes in liking scores as a function of NTX levels. Naltrexone levels above 2 ng/mL blocked nearly all VAS ratings of drug liking after intravenous heroin administration. Participants with NTX levels ≥ 2 ng/mL had minimal (≤20 mm) changes from placebo in VAS ratings of drug liking based on 95% prediction intervals. In contrast, NTX levels < 2 ng/mL were associated with greater variability in individual-level subjective responses. In clinical practice, a plasma level range of 1 to 2 ng/mL is considered to be therapeutic in providing heroin blockade. The current findings suggest that a higher level (>2 ng/mL) may be needed to produce a consistent blockade.

Variation in seizure risk increases from antiseizure medication withdrawal among patients with well-controlled epilepsy: A pooled analysis.

Guidelines suggest considering antiseizure medication (ASM) discontinuation in seizure-free patients with epilepsy. Past work has poorly explored how discontinuation effects vary between patients. We evaluated (1) what factors modify the influence of discontinuation on seizure risk; and (2) the range of seizure risk increase due to discontinuation across low- versus high-risk patients. We pooled three datasets including seizure-free patients who did and did not discontinue ASMs. We conducted time-to-first-seizure analyses. First, we evaluated what individual patient factors modified the relative effect of ASM discontinuation on seizure risk via interaction terms. Then, we assessed the distribution of 2-year risk increase as predicted by our adjusted logistic regressions. We included 1626 patients, of whom 678 (42%) planned to discontinue all ASMs. The mean predicted 2-year seizure risk was 43% [95% confidence interval (CI) 39%-46%] for discontinuation versus 21% (95% CI 19%-24%) for continuation. The mean 2-year absolute seizure risk increase was 21% (95% CI 18%-26%). No individual interaction term was significant after correcting for multiple comparisons. The median [interquartile range (IQR)] risk increase across patients was 19% (IQR 14%-24%; range 7%-37%). Results were unchanged when restricting analyses to only the two RCTs. No single patient factor significantly modified the influence of discontinuation on seizure risk, although we captured how absolute risk increases change for patients that are at low versus high risk. Patients should likely continue ASMs if even a 7% 2-year increase in the chance of any more seizures would be too much and should likely discontinue ASMs if even a 37% risk increase would be too little. In between these extremes, individualized risk calculation and a careful understanding of patient preferences are critical. Future work will further develop a two-armed individualized seizure risk calculator and contextualize seizure risk thresholds below which to consider discontinuation. Understanding how much antiseizure medications (ASMs) decrease seizure risk is an important part of determining which patients with epilepsy should be treated, especially for patients who have not had a seizure in a while. We found that there was a wide range in the amount that ASM discontinuation increases seizure risk-between 7% and 37%. We found that no single patient factor modified that amount. Understanding what a patient's seizure risk might be if they discontinued versus continued ASM treatment is critical to making informed decisions about whether the benefit of treatment outweighs the downsides.

Alterations in DNA methylation associate with reduced migraine and headache days after medication withdrawal treatment in chronic migraine patients: a longitudinal study

BackgroundChronic migraine, a highly disabling migraine subtype, affects nearly 2% of the general population. Understanding migraine chronification is vital for developing better treatment and prevention strategies. An important factor in the chronification of migraine is the overuse of acute headache medication. However, the mechanisms behind the transformation of episodic migraine to chronic migraine and vice versa have not yet been elucidated. We performed a longitudinal epigenome-wide association study to identify DNA methylation (DNAm) changes associated with treatment response in patients with chronic migraine and medication overuse as part of the Chronification and Reversibility of Migraine clinical trial. Blood was taken from patients with chronic migraine (n = 98) at baseline and after a 12-week medication withdrawal period. Treatment responders, patients with ≥ 50% reduction in monthly headache days (MHD), were compared with non-responders to identify DNAm changes associated with treatment response. Similarly, patients with ≥ 50% versus < 50% reduction in monthly migraine days (MMD) were compared.ResultsAt the epigenome-wide significant level (p < 9.42 × 10–8), a longitudinal reduction in DNAm at an intronic CpG site (cg14377273) within the HDAC4 gene was associated with MHD response following the withdrawal of acute medication. HDAC4 is highly expressed in the brain, plays a major role in synaptic plasticity, and modulates the expression and release of several neuroinflammation markers which have been implicated in migraine pathophysiology. Investigating whether baseline DNAm associated with treatment response, we identified lower baseline DNAm at a CpG site (cg15205829) within MARK3 that was significantly associated with MMD response at 12 weeks.ConclusionsOur findings of a longitudinal reduction in HDAC4 DNAm status associated with treatment response and baseline MARK3 DNAm status as an early biomarker for treatment response, provide support for a role of pathways related to chromatin structure and synaptic plasticity in headache chronification and introduce HDAC4 and MARK3 as novel therapeutic targets.