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Therapeutic Advances in... 2024This case report examines the possible correlation between the clozapine/norclozapine ratio and the occurrence of constipation and paralytic ileus. We present the case...
This case report examines the possible correlation between the clozapine/norclozapine ratio and the occurrence of constipation and paralytic ileus. We present the case of a 42-year-old patient diagnosed with schizoaffective disorder undergoing clozapine therapy. Despite intensive treatment with clozapine, haloperidol, valproic acid and biweekly electroconvulsive therapy sessions for over a year, florid psychotic symptoms and fluctuating mood swings persisted. Therefore, valproic acid was replaced by carbamazepine, a potent inducer of several CYP450-enzymes. To maintain clozapine plasma levels, fluvoxamine, a CYP1A2-inhibitor, was introduced at a dose of 25 mg before this switch. After addition of carbamazepine, there was a significant decline in clozapine levels, necessitating an increase in fluvoxamine dosage to 50 mg. Five weeks later the patient was admitted to a general hospital with a diagnosis of paralytic ileus. Treatment with enemas proved effective. Drug concentration analysis revealed a 2.5-fold increase in norclozapine levels in the weeks preceding hospital admission, resulting in an inverted clozapine/norclozapine ratio. Treatment with clozapine, carbamazepine and fluvoxamine was continued as the patient demonstrated clinical improvement on carbamazepine. Concurrently, an intensive laxative regimen was initiated. Two weeks later, the patient was readmitted to the general hospital due to suspected paralytic ileus and faecal vomiting, once again displaying an inverted clozapine/norclozapine ratio. We discuss potential mechanisms contributing to the occurrence of the paralytic ileus in this patient, including the antagonism of muscarinic M3 receptors by both clozapine and norclozapine, as well as the agonism of delta-opioid receptors by norclozapine. This case highlights the potential significance of both the clozapine/norclozapine ratio and absolute norclozapine levels as risk factors for constipation and paralytic ileus in patients on clozapine therapy.
PubMed: 38827014
DOI: 10.1177/20451253241255487 -
Science Advances May 2024Visceral myopathy is a life-threatening disease characterized by muscle weakness in the bowel, bladder, and uterus. Mutations in smooth muscle γ-actin (ACTG2) are the...
Visceral myopathy is a life-threatening disease characterized by muscle weakness in the bowel, bladder, and uterus. Mutations in smooth muscle γ-actin (ACTG2) are the most common cause of the disease, but the mechanisms by which the mutations alter muscle function are unknown. Here, we examined four prevalent ACTG2 mutations (R40C, R148C, R178C, and R257C) that cause different disease severity and are spread throughout the actin fold. R178C displayed premature degradation, R148C disrupted interactions with actin-binding proteins, R40C inhibited polymerization, and R257C destabilized filaments. Because these mutations are heterozygous, we also analyzed 50/50 mixtures with wild-type (WT) ACTG2. The WT/R40C mixture impaired filament nucleation by leiomodin 1, and WT/R257C produced filaments that were easily fragmented by smooth muscle myosin. Smooth muscle tropomyosin isoform Tpm1.4 partially rescued the defects of R40C and R257C. Cryo-electron microscopy structures of filaments formed by R40C and R257C revealed disrupted intersubunit contacts. The biochemical and structural properties of the mutants correlate with their genotype-specific disease severity.
Topics: Humans; Actins; Mutation, Missense; Intestinal Pseudo-Obstruction; Cryoelectron Microscopy; Muscle, Smooth; Models, Molecular; Protein Binding
PubMed: 38820162
DOI: 10.1126/sciadv.adn6615 -
Global Spine Journal May 2024Randomised controlled trial.
Effectiveness of a Preoperative Bowel Preparation Protocol for Patients With Adolescent Idiopathic Scoliosis to Decrease Postoperative Gastrointestinal Morbidities and the Hospital Length of Stay.
STUDY DESIGN
Randomised controlled trial.
OBJECTIVE
This study aimed to determine the effectiveness of a preoperative bowel preparation protocol comprising bisacodyl to minimize postoperative gastrointestinal morbidities and the hospital length of stay for patients with adolescent idiopathic scoliosis.
SUMMARY OF BACKGROUND DATA
Patients who undergo scoliosis correction surgery frequently experience postoperative gastrointestinal morbidities and a prolonged hospital length of stay. Emesis, paralytic ileus and constipation are the most common gastrointestinal morbidities. Opioid medication is a well-known risk factor for gastrointestinal complications after scoliosis correction surgery.
METHODS
Eighty-seven patients (22 boys [25.3%] and 65 girls [74.7%]) with a mean age of 17.7 years (standard deviation [SD], ±2.2 years) diagnosed with adolescent idiopathic scoliosis were enrolled in this study and randomized into 2 groups. Group A comprised 44 patients who received a preoperative bowel preparation comprising bisacodyl. Group B comprised 43 patients who did not receive any preoperative medication. Demographic data, height, weight, medical and surgical comorbidities, Risser status, number of instrumented levels and preoperative opioid consumption of all patients were evaluated.
RESULTS
Group A experienced fewer postoperative abdominal symptoms than group B. The mean hospital length of stay was 4.1 days (SD, ±.6 days; median, 4 days; range, 3-5 days) for group A; however, it was 5.3 days (SD, ±.8 days; median, 5 days; range, 4-7 days) for group B ( = .01).
CONCLUSION
The use of a bowel preparation protocol before scoliosis correction surgery for patients with adolescent idiopathic scoliosis can effectively decrease postoperative gastrointestinal morbidities and the hospital length of stay.
PubMed: 38767157
DOI: 10.1177/21925682241249107 -
Journal of Translational Medicine May 2024Inherited deficiency of thymidine phosphorylase (TP), encoded by TYMP, leads to a rare disease with multiple mitochondrial DNA (mtDNA) abnormalities, mitochondrial...
Inherited deficiency of thymidine phosphorylase (TP), encoded by TYMP, leads to a rare disease with multiple mitochondrial DNA (mtDNA) abnormalities, mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). However, the impact of TP deficiency on lysosomes remains unclear, which are important for mitochondrial quality control and nucleic acid metabolism. Muscle biopsy tissue and skin fibroblasts from MNGIE patients, patients with m.3243 A > G mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) and healthy controls (HC) were collected to perform mitochondrial and lysosomal functional analyses. In addition to mtDNA abnormalities, compared to controls distinctively reduced expression of LAMP1 and increased mitochondrial content were detected in the muscle tissue of MNGIE patients. Skin fibroblasts from MNGIE patients showed decreased expression of LAMP2, lowered lysosomal acidity, reduced enzyme activity and impaired protein degradation ability. TYMP knockout or TP inhibition in cells can also induce the similar lysosomal dysfunction. Using lysosome immunoprecipitation (Lyso- IP), increased mitochondrial proteins, decreased vesicular proteins and V-ATPase enzymes, and accumulation of various nucleosides were detected in lysosomes with TP deficiency. Treatment of cells with high concentrations of dThd and dUrd also triggers lysosomal dysfunction and disruption of mitochondrial homeostasis. Therefore, the results provided evidence that TP deficiency leads to nucleoside accumulation in lysosomes and lysosomal dysfunction, revealing the widespread disruption of organelles underlying MNGIE.
Topics: Humans; Lysosomes; Thymidine Phosphorylase; Mitochondrial Encephalomyopathies; Fibroblasts; DNA, Mitochondrial; Mitochondria; Nucleosides; Intestinal Pseudo-Obstruction; Ophthalmoplegia; Muscular Dystrophy, Oculopharyngeal; Male; Female; Skin; Lysosomal-Associated Membrane Protein 2
PubMed: 38741129
DOI: 10.1186/s12967-024-05275-8 -
BMC Infectious Diseases May 2024Amidst limited influenza treatment options, evaluating the safety of Oseltamivir and Baloxavir Marboxil is crucial, particularly given their comparable efficacy. This...
BACKGROUND AND OBJECTIVES
Amidst limited influenza treatment options, evaluating the safety of Oseltamivir and Baloxavir Marboxil is crucial, particularly given their comparable efficacy. This study investigates post-market safety profiles, exploring adverse events (AEs) and their drug associations to provide essential clinical references.
METHODS
A meticulous analysis of FDA Adverse Event Reporting System (FAERS) data spanning the first quarter of 2004 to the fourth quarter of 2022 was conducted. Using data mining techniques like reporting odds ratio (ROR), proportional reporting ratio, Bayesian Confidence Propagation Neural Network, and Multiple Gamma Poisson Shrinkage, AEs related to Oseltamivir and Baloxavir Marboxil were examined. Venn analysis compared and selected specific AEs associated with each drug.
RESULTS
Incorporating 15,104 Oseltamivir cases and 1,594 Baloxavir Marboxil cases, Wain analysis unveiled 21 common AEs across neurological, psychiatric, gastrointestinal, dermatological, respiratory, and infectious domains. Oseltamivir exhibited 221 significantly specific AEs, including appendicolith [ROR (95% CI), 459.53 (340.88 ∼ 619.47)], acne infantile [ROR (95% CI, 368.65 (118.89 ∼ 1143.09)], acute macular neuroretinopathy [ROR (95% CI), 294.92 (97.88 ∼ 888.64)], proctitis [ROR (95% CI), 245.74 (101.47 ∼ 595.31)], and Purpura senile [ROR (95% CI), 154.02 (81.96 ∼ 289.43)]. designated adverse events (DMEs) associated with Oseltamivir included fulminant hepatitis [ROR (95% CI), 12.12 (8.30-17.72), n=27], ventricular fibrillation [ROR (95% CI), 7.68 (6.01-9.83), n=64], toxic epidermal necrolysis [ROR (95% CI), 7.21 (5.74-9.05), n=75]. Baloxavir Marboxil exhibited 34 specific AEs, including Melaena [ROR (95% CI), 21.34 (14.15-32.18), n = 23], cystitis haemorrhagic [ROR (95% CI), 20.22 (7.57-54.00), n = 4], ileus paralytic [ROR (95% CI), 18.57 (5.98-57.71), n = 3], and haemorrhagic diathesis [ROR (95% CI), 16.86 (5.43-52.40)), n = 3]. DMEs associated with Baloxavir Marboxil included rhabdomyolysis [ROR (95% CI), 15.50 (10.53 ∼ 22.80), n = 26].
CONCLUSION
Monitoring fulminant hepatitis during Oseltamivir treatment, especially in patients with liver-related diseases, is crucial. Oseltamivir's potential to induce abnormal behavior, especially in adolescents, necessitates special attention. Baloxavir Marboxil, with lower hepatic toxicity, emerges as a potential alternative for patients with liver diseases. During Baloxavir Marboxil treatment, focused attention on the occurrence of rhabdomyolysis is advised, necessitating timely monitoring of relevant indicators for those with clinical manifestations. The comprehensive data aims to provide valuable insights for clinicians and healthcare practitioners, facilitating an understanding of the safety profiles of these influenza treatments in real-world scenarios.
Topics: Humans; Dibenzothiepins; Triazines; United States; Oseltamivir; Antiviral Agents; United States Food and Drug Administration; Female; Male; Morpholines; Adult; Middle Aged; Pharmacovigilance; Adverse Drug Reaction Reporting Systems; Adolescent; Pyridones; Young Adult; Aged; Influenza, Human; Child; Triazoles; Thiepins; Pyrazines; Pyridines; Child, Preschool; Oxazines
PubMed: 38724914
DOI: 10.1186/s12879-024-09339-4 -
Cureus Mar 2024Hirschsprung disease is an uncommon medical condition caused by the lack of migration of ganglion cells to the rectum during embryonic development, affecting the...
Hirschsprung disease is an uncommon medical condition caused by the lack of migration of ganglion cells to the rectum during embryonic development, affecting the peristaltic movements of the intestine. It is a chronic medical condition responsible for chronic constipation and intestinal obstruction. We present the case of a 10-year-old female with a history of Hirschsprung disease and colectomy admitted to a pediatric hospital for the management of multiple colonic ulcers and severe anemia who subsequently developed a rectovaginal fistula. This patient's admission was complicated by perianal and vaginal excoriations, a paralytic ileus, and fecal incontinence. This case report is unique due to the development of a rare pediatric complication of Hirschsprung disease.
PubMed: 38690493
DOI: 10.7759/cureus.57316 -
World Journal of Gastroenterology Apr 2024Digestion and intestinal absorption allow the body to sustain itself and are the emblematic functions of the bowel. On the flip side, functions also arise from its role...
Digestion and intestinal absorption allow the body to sustain itself and are the emblematic functions of the bowel. On the flip side, functions also arise from its role as an interface with the environment. Indeed, the gut houses microorganisms, collectively known as the gut microbiota, which interact with the host, and is the site of complex immune activities. Its role in human pathology is complex and scientific evidence is progressively elucidating the functions of the gut, especially regarding the pathogenesis of chronic intestinal diseases and inflammatory conditions affecting various organs and systems. This editorial aims to highlight and relate the factors involved in the pathogenesis of intestinal and systemic inflammation.
Topics: Humans; Gastrointestinal Microbiome; Gastrointestinal Motility; Intestines; Inflammation; Inflammatory Bowel Diseases; Intestinal Mucosa; Animals
PubMed: 38681124
DOI: 10.3748/wjg.v30.i14.1963 -
Frontiers in Pharmacology 2024Vincristine (VCR), an antineoplastic drug, induces peripheral neuropathy characterized by nerve damage, limiting its use and reducing the quality of life of patients....
Vincristine (VCR), an antineoplastic drug, induces peripheral neuropathy characterized by nerve damage, limiting its use and reducing the quality of life of patients. VCR causes myenteric neuron damage, inhibits gastrointestinal motility, and results in constipation or paralytic ileus in patients. Oxytocin (OT) is an endogenous neuropeptide produced by the enteric nerve system, which regulates gastrointestinal motility and exerts neuroprotective effects. This study aimed to investigate whether OT can improve VCR-induced gastrointestinal dysmotility and evaluate the underlying mechanism. Mice were injected either with saline or VCR (0.1 mg/kg/d, i. p.) for 14 days, and OT (0.1 mg/kg/d, i.p.) was applied 1 h before each VCR injection. Gastrointestinal transit and the contractile activity of the isolated colonic segments were assessed. The concentration of OT in plasma was measured using ELISA. Immunofluorescence staining was performed to analyze myenteric neurons and reactive oxygen species (ROS) levels. Furthermore, the indicators of oxidative stress were detected. The protein expressions of Nrf2, ERK1/2, P-ERK1/2, p38, and P-p38 in the colon were tested using Western blot. VCR reduced gastrointestinal transit and the responses of isolated colonic segments to electrical field stimulation and decreased the amount of neurons. Furthermore, VCR reduced neuronal nitric oxide synthase and choline acetyltransferase immunopositive neurons in the colonic myenteric nerve plexus. VCR increased the concentration of OT in plasma. Exogenous OT pretreatment ameliorated the inhibition of gastrointestinal motility and the injury of myenteric neurons caused by VCR. OT pretreatment also prevented the decrease of superoxide dismutase activity, glutathione content, total antioxidative capacity, and Nrf2 expression, the increase of ROS levels, and the phosphorylation of ERK1/2 and p38 MAPK following VCR treatment. Our results suggest that OT pretreatment can protect enteric neurons from VCR-induced injury by inhibiting oxidative stress and MAPK pathways (ERK1/2, p38). This may be the underlying mechanism by which it alleviates gastrointestinal dysmotility.
PubMed: 38655179
DOI: 10.3389/fphar.2024.1270612 -
Trauma Surgery & Acute Care Open 2024Gastrointestinal complications after cardiac surgery are relatively rare entities but carry a high mortality. We identified over 70 articles written since 2010 using the... (Review)
Review
Gastrointestinal complications after cardiac surgery are relatively rare entities but carry a high mortality. We identified over 70 articles written since 2010 using the PubMed database. We included 40 in our review. The most common complications include paralytic ileus, gastrointestinal bleeding, and bowel ischemia. Patients who undergo cardiac procedures are at risk for poor perfusion of the gastrointestinal tract and, thus, at risk for resulting complications. Risk factors for these complications include peri-operative use of vasopressors, prolonged operative time, and the time of cardiopulmonary bypass. Presentation of gastrointestinal complications tends to differ as patients after open heart surgery can remain intubated, and exams can be limited. Early recognition and aggressive therapy are paramount. We aim to provide a review that will help the reader get familiar with the most common gastrointestinal complications that can negatively affect outcomes after cardiac surgery.
PubMed: 38616788
DOI: 10.1136/tsaco-2023-001324 -
Frontiers in Pharmacology 2024Patients with systemic autoimmune rheumatic diseases are at a high risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and effective...
Patients with systemic autoimmune rheumatic diseases are at a high risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and effective antiviral treatments including nirmatrelvir/ritonavir can improve their outcomes. However, there might be potential drug-drug interactions when these patients take nirmatrelvir/ritonavir together with immunosuppressants with a narrow therapeutic window, such as tacrolimus and cyclosporine. We present a case of paralytic ileus resulting from tacrolimus toxicity mediated by the use of nirmatrelvir/ritonavir in a patient with systemic lupus erythematosus (SLE). A 37-year-old female SLE patient was prescribed nirmatrelvir/ritonavir without discontinuing tacrolimus. She presented to the emergency room with symptoms of paralytic ileus including persistent abdominal pain, nausea, and vomiting, which were verified to be associated with tacrolimus toxicity. The blood concentration of tacrolimus was measured >30 ng/mL. Urgent medical intervention was initiated, while tacrolimus was withheld. The residual concentration was brought within the appropriate range and tacrolimus was resumed 8 days later. Physicians must be aware of the potential DDIs when prescribing nirmatrelvir/ritonavir, especially to those taking immunosuppresants like tacrolimus.
PubMed: 38601471
DOI: 10.3389/fphar.2024.1389187