[Withdrawal syndrome following chronic use of gamma-hydroxybutyric acid (GHB)]. / Syndrome de sevrage lors d'une consommation chronique d'acide gamma-hydroxybutyrique (GHB).

Chronic use of gamma-hydroxybutyric acid (GHB) and its precursors can rapidly lead to physical dependence with the emergence of a withdrawal syndrome. This complication is similar to the one linked to alcohol or benzodiazepines. The onset of symptoms and specially neuro-psychiatric symptoms is, however, more rapid in the case of the GHB and precursors. There is currently no consensus on the therapeutic management of GHB withdrawal syndrome. High-dose benzodiazepines are the most commonly used treatment. The use of GHB by titration and tapering could show fewer side effects and withdrawal symptoms. It appears necessary to reflect on and pursue research on the use of GHB and its precursors, which remains poorly understood, on the management of withdrawal syndrome due to the lack of protocol and on its probably underestimated impact on public health.

La consommation chronique d'acide gamma-hydroxybutyrique (GHB) et de ses précurseurs peut rapidement entraîner une dépendance physique avec l'émergence d'un syndrome de sevrage à l'arrêt des consommations. Ce syndrome de sevrage présente des similitudes avec celui lié à l'alcool ou aux benzodiazépines. On retrouvera, cependant, une apparition et une évolution plus brutales ainsi que l'émergence, plus précoce, de symptômes neuropsychiatriques. Il n'y a actuellement pas de consensus concernant la prise en charge thérapeutique de ce syndrome de sevrage. Dès lors, le recours aux benzodiazépines à hautes doses constitue le traitement le plus régulièrement utilisé. L'utilisation de GHB médical, titré et avec une posologie progressivement diminuée, pourrait démontrer moins d'effets secondaires et de symptômes de sevrage. Il apparaît nécessaire de réfléchir et de poursuivre les recherches sur la consommation du GHB et ses précurseurs, qui reste largement méconnue, ainsi que sur la prise en charge du sevrage, au vu de l'absence de protocole et de son impact en santé publique, probablement sous-estimé.

Therapeutic response to leflunomide in combo therapy and monotherapy is associated to serum teriflunomide (A77 1726) levels.

There is a significant rate of therapeutic failure in rheumatoid arthritis (RA) patients treated with leflunomide (LEF). This study investigates the utility values of teriflunomide levels (A77 1726) in identifying RA patients who remained with moderate or severe disease activity after the treatment with LEF. In this cross-sectional study, we compared: (a) RA patients who achieved a DAS28-ESR ≤ 3.2, and (b) RA patients who maintained a DAS28-ESR > 3.2 after treatment. ROC curves determined the cut-off of A77 1726 with the better performance to identify patients achieving a DAS28-ESR ≤ 3.2. Of the 115 patients treated with LEF, 69 (60%) remained with moderate/severe disease activity and 46 (40%) achieved low disease activity/remission. Higher A77 1726 levels showed a negative correlation with DAS28-ESR (r = - 0.42, p < 0.001) and other parameters of disease activity. We obtained the following utility values with the cut-off of A77 1726 > 10 µg/mL to identify RA patients who achieved a DAS28-ESR ≤ 3.2: sensitivity of 91.31%; specificity of 73.91%; positive predictive value of 70.00%; and negative predictive value of 92.73%. Serum A77 1726 discriminated between RA patients who remained with moderate/severe disease activity despite the treatment with LEF both as monotherapy and LEF as combo therapy.

Hepatotoxicity associated with the use of teriflunomide in a patient with multiple sclerosis: A case report.

RATIONALE: Teriflunomide is an inhibitor of pyrimidine synthesis available as a first-line treatment for relapsing-remitting multiple sclerosis. Drug-induced liver damage is a relevant problem in clinical practice, representing a frequent cause of treatment discontinuation. This case report describes the occurrence of liver injury, with a 33.7-fold increase in the upper limit of normality of the liver enzyme alanine aminotransferase during treatment with teriflunomide 14 mg. PATIENT CONCERN: A 44-year-old woman receiving teriflunomide 14 mg for the treatment of multiple sclerosis presented symptoms suggestive of liver dysfunction 54 days after starting treatment. The patient had no history of using disease-modifying therapy, neither previous liver disease nor other comorbidities. DIAGNOSTICS: The suggested diagnosis was drug-induced liver injury, classified as hepatocellular. Other possible hepatic and autoimmune etiologies were ruled out. INTERVENTIONS: Replacement of teriflunomide treatment with glatiramer acetate and follow-up of the disease. OUTCOMES: Signs and symptoms regressed after treatment with teriflunomide 14 mg was discontinued, with normalization of liver enzyme activity in ∼5 months. The causality assessment of the adverse drug reaction was determined by the Naranjo scaling system, resulting in probable, with a final score of 7. CONCLUSIONS: Teriflunomide-induced liver injury in patients with multiple sclerosis is a serious adverse reaction. The report of this case contributes to updating knowledge about the safety aspects of treatment with teriflunomide and planning of monitoring strategies and patient risk management.

Teriflunomide Treatment of Multiple Sclerosis Selectively Modulates CD8 Memory T Cells.

Background and Objectives: Inhibition of de novo pyrimidine synthesis in proliferating T and B lymphocytes by teriflunomide, a pharmacological inhibitor of dihydroorotate dehydrogenase (DHODH), has been shown to be an effective therapy to treat patients with MS in placebo-controlled phase 3 trials. Nevertheless, the underlying mechanism contributing to the efficacy of DHODH inhibition has been only partially elucidated. Here, we aimed to determine the impact of teriflunomide on the immune compartment in a longitudinal high-dimensional follow-up of patients with relapse-remitting MS (RRMS) treated with teriflunomide. Methods: High-dimensional spectral flow cytometry was used to analyze the phenotype and the function of innate and adaptive immune system of patients with RRMS before and 12 months after teriflunomide treatment. In addition, we assessed the impact of teriflunomide on the migration of memory CD8 T cells in patients with RRMS, and we defined patient immune metabolic profiles. Results: We found that 12 months of treatment with teriflunomide in patients with RRMS does not affect the B cell or CD4 T cell compartments, including regulatory TREG follicular helper TFH cell and helper TH cell subsets. In contrast, we observed a specific impact of teriflunomide on the CD8 T cell compartment, which was characterized by decreased homeostatic proliferation and reduced production of TNFα and IFNγ. Furthermore, we showed that DHODH inhibition also had a negative impact on the migratory velocity of memory CD8 T cells in patients with RRMS. Finally, we showed that the susceptibility of memory CD8 T cells to DHODH inhibition was not related to impaired metabolism. Discussion: Overall, these findings demonstrate that the clinical efficacy of teriflunomide results partially in the specific susceptibility of memory CD8 T cells to DHODH inhibition in patients with RRMS and strengthens active roles for these T cells in the pathophysiological process of MS.

Resorbable Synthetic Ventral Hernia Repair in Contaminated Fields: Outcomes with Poly-4-Hydroxybutyrate Mesh.

BACKGROUND: Hernia repair in the setting of contamination poses unique challenges, including complications such as recurrence and mesh infection. The ideal contaminated hernia repair including type of mesh use remains controversial. Poly-4-hydroxybutyrate is a biosynthetic scaffold for soft-tissue reinforcement and hernia repair and is potentially useful in contaminated hernia repair. The authors aim to describe postoperative outcomes, recurrence, and patient-reported outcomes after contaminated hernia repair with poly-4-hydroxybutyrate. METHODS: Adult patients (≥18 years) undergoing a contaminated hernia repair with poly-4-hydroxybutyrate (Phasix) performed by a single plastic surgeon between January of 2015 and May of 2020 were identified. Patients with a ventral hernia defect and a Centers for Disease Control and Prevention wound class of II, III, or IV were included. Primary outcomes included recurrence, surgical-site infection, surgical-site occurrences, and surgical-site infection/occurrences requiring procedural interventions. As a secondary outcome, the authors assessed patient-reported outcomes as defined by the Abdominal Hernia-Q and Hernia-Related Quality of Life Survey. RESULTS: Sixty patients were included with a median age of 52.5 and body mass index of 31 kg/m2. Median defect size was 300 cm2. Twenty-eight patients (46.7 percent) experienced a complication. The most common complications were surgical-site occurrence [n = 20 (33.3 percent)] and surgical-site infection [n = 10 (16.7 percent)]. Median follow-up was 24.2 months, with a recurrence rate of 8.3 percent (n = 4). Overall patient-reported outcomes improved postoperatively, and improvement was not affected by the presence of a complication. CONCLUSIONS: Poly-4-hydroxybutyrate use in contaminated hernia repair shows promising results with an acceptable safety profile. Although complications are frequent in this complex cohort, patient-reported outcomes improvement was significant even in patients with complications. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Potential risk of disease modifying therapies on neoplasm development and coadjutant factors in multiple sclerosis outpatients.

Neoplasm development in Multiple Sclerosis (MS) patients treated with disease-modifying therapies (DMTs) has been widely discussed. The aim of this work is to determine neoplasm frequency, relationship with the prescription pattern of DMTs, and influence of the patients' baseline characteristics. Data from 250 MS outpatients were collected during the period 1981-2019 from the medical records of the Neurology Service of the HUPM (Hospital Universitario Puerta del Mar)-in Southern Spain-and analysed using Cox models. Neoplasm prevalence was 24%, mainly located on the skin, with cancer prevalence as expected for MS (6.8%). Latency period from MS onset to neoplasm diagnosis was 10.4 ± 6.9 years (median 9.30 [0.9-30.5]). During the observation period ß-IFN (70.4% of patients), glatiramer acetate (30.4%), natalizumab (16.8%), fingolimod (24.8%), dimethyl fumarate (24.0%), alemtuzumab (6.0%), and teriflunomide (4.8%) were administered as monotherapy. Change of pattern in step therapy was significantly different in cancer patients vs unaffected individuals (p = 0.011) (29.4% did not receive DMTs [p = 0.000]). Extended Cox model: Smoking (HR = 3.938, CI 95% 1.392-11.140, p = 0.010), being female (HR = 2.006, 1.070-3.760, p = 0.030), and age at MS diagnosis (AGE-DG) (HR = 1.036, 1.012-1.061, p = 0.004) were risk factors for neoplasm development. Secondary progressive MS (SPMS) phenotype (HR = 0.179, 0.042-0.764, p = 0.020) and treatment-time with IFN (HR = 0.923, 0.873-0.977, p = 0.006) or DMF (HR = 0.725, 0.507-1.036, p = 0.077) were protective factors. Tobacco and IFN lost their negative/positive influence as survival time increased. Cox PH model: Tobacco/AGE-DG interaction was a risk factor for cancer (HR = 1.099, 1.001-1.208, p = 0.049), followed by FLM treatment-time (HR = 1.219, 0.979-1.517). In conclusion, smoking, female sex, and AGE-DG were risk factors, and SPMS and IFN treatment-time were protective factors for neoplasm development; smoking/AGE-DG interaction was the main cancer risk factor.

Efficacy and safety of dihydroorotate dehydrogenase (DHODH) inhibitors "leflunomide" and "teriflunomide" in Covid-19: A narrative review.

Dihydroorotate dehydrogenase (DHODH) is rate-limiting enzyme in biosynthesis of pyrimidone which catalyzes the oxidation of dihydro-orotate to orotate. Orotate is utilized in the biosynthesis of uridine-monophosphate. DHODH inhibitors have shown promise as antiviral agent against Cytomegalovirus, Ebola, Influenza, Epstein Barr and Picornavirus. Anti-SARS-CoV-2 action of DHODH inhibitors are also coming up. In this review, we have reviewed the safety and efficacy of approved DHODH inhibitors (leflunomide and teriflunomide) against COVID-19. In target-centered in silico studies, leflunomide showed favorable binding to active site of MPro and spike: ACE2 interface. In artificial-intelligence/machine-learning based studies, leflunomide was among the top 50 ligands targeting spike: ACE2 interaction. Leflunomide is also found to interact with differentially regulated pathways [identified by KEGG (Kyoto Encyclopedia of Genes and Genomes) and reactome pathway analysis of host transcriptome data] in cogena based drug-repurposing studies. Based on GSEA (gene set enrichment analysis), leflunomide was found to target pathways enriched in COVID-19. In vitro, both leflunomide (EC50 41.49 ± 8.8 µmol/L) and teriflunomide (EC50 26 µmol/L) showed SARS-CoV-2 inhibition. In clinical studies, leflunomide showed significant benefit in terms of decreasing the duration of viral shredding, duration of hospital stay and severity of infection. However, no advantage was seen while combining leflunomide and IFN alpha-2a among patients with prolonged post symptomatic viral shredding. Common adverse effects of leflunomide were hyperlipidemia, leucopenia, neutropenia and liver-function alteration. Leflunomide/teriflunomide may serve as an agent of importance to achieve faster virological clearance in COVID-19, however, findings needs to be validated in bigger sized placebo controlled studies.

Pulmonary embolism in patients with multiple sclerosis treated with teriflunomide: A series of three cases.

Teriflunomide is an oral disease modifying therapy for patients with relapsing remitting multiple sclerosis. It is moderately effective while having a favourable safety profile with liver toxicity being the major concern. We present a series of three patients who developed pulmonary embolism within two years of initiation of teriflunomide treatment. They had stable multiple sclerosis with low level of disability, with immobility presenting a negligible risk for the development of pulmonary embolism. The estimated prevalence of pulmonary embolism in our cohort is 2.8%. Thus, we believe additional attention to the general risk factors for PE is warranted before teriflunomide is introduced to patients with multiple sclerosis.

Teriflunomide-associated urolithiasis: a new adverse reaction explained by its uricosuric effect.

In clinical trials, few investigations have been conducted to determine the mechanism involved in teriflunomide-associated kidney stone formation. We report the first case of recurrent teriflunomide-induced uric acid urolithiasis. A 55-year-old man with relapsing-remitting multiple sclerosis experienced three occurrences of urolithiasis several months after the initiation of teriflunomide. While serum uric acid remained stable at 280 mmol/L, 24-h urine uric acid was increased to 2195 mmol/24 h. For the third episode, computed tomography showed three bladder stones and one stone in the right calyceal group. Endovesical lithotripsy was used to extract four orange-colored stones of more than 20 mm. Stone analysis exhibited morphology subtype IIIb with 100% of anhydrous uric acid. Given the disease control, teriflunomide was continued. After urinary alkalinization by potassium citrate, the patient remained asymptomatic at 18 months follow-up. An inhibitory effect of dihydroorotate and/or teriflunomide on urate tubular reabsorption could explain teriflunomide-associated uric acid urolithiasis. This case in a patient without risk factors suggests that multiple sclerosis patients may be at greater risk of forming uric acid urinary stones when taking teriflunomide. Alkalinization of the urine may reduce the risk of recurrence, allowing further treatment with teriflunomide.

Tapering with Pharmaceutical GHB or Benzodiazepines for Detoxification in GHB-Dependent Patients: A Matched-Subject Observational Study of Treatment-as-Usual in Belgium and The Netherlands.

BACKGROUND: The gamma-hydroxybutyric acid (GHB) withdrawal syndrome often has a fulminant course, with a rapid onset and swift progression of severe complications. In clinical practice, two pharmacological regimens are commonly used to counteract withdrawal symptoms during GHB detoxification: tapering with benzodiazepines (BZDs) or tapering with pharmaceutical GHB. In Belgium, standard treatment is tapering with BZDs, while in the Netherlands, pharmaceutical GHB is the preferred treatment method. Though BZDs are cheaper and readily available, case studies suggest GHB tapering results in less severe withdrawal and fewer complications. OBJECTIVES: This study aimed to compare two treatments-as-usual in tapering methods on withdrawal, craving and adverse events during detoxification in GHB-dependent patients. METHODS: In this multicentre non-randomised indirect comparison of two treatments-as-usual, patients with GHB dependence received BZD tapering (Belgian sample: n = 42) or GHB tapering (Dutch sample: n = 42, matched historical sample). Withdrawal was assessed using the Subjective and Objective Withdrawal Scales, craving was assessed with a Visual Analogue Scale and adverse events were systematically recorded. Differences in withdrawal and craving were analysed using a linear mixed-model analysis, with 'days in admission' and 'detoxification method' as fixed factors. Differences in adverse events were analysed using a Chi-square analysis. RESULTS: Withdrawal decreased over time in both groups. Withdrawal severity was higher in patients receiving BZD tapering (subjective mean = 36.50, standard deviation = 21.08; objective mean = 8.05, standard deviation = 4.68) than in patients receiving pharmaceutical GHB tapering (subjective mean = 15.90; standard deviation = 13.83; objective mean = 3.72; standard deviation = 2.56). No differences in craving were found. Adverse events were more common in the BZD than the GHB group, especially delirium (20 vs 2.5%, respectively). CONCLUSIONS: These results support earlier work that BZD tapering might not always sufficiently dampen withdrawal in GHB-dependent patients. However, it needs to be taken into account that both treatments were assessed in separate countries. Based on the current findings, tapering with pharmaceutical GHB could be considered for patients with GHB dependence during detoxification, as it has potentially less severe withdrawal and fewer complications than BZD tapering.

Pregnancy outcomes in patients with multiple sclerosis treated with teriflunomide: Clinical study data and 5 years of post-marketing experience.

BACKGROUND: Teriflunomide is contraindicated in pregnancy. Some pregnancies have occurred despite guidance to use effective contraception. OBJECTIVES: To report outcomes of pregnancies occurring in teriflunomide clinical trials and the post-marketing setting. METHODS: Outcomes are summarized for pregnancies in teriflunomide monotherapy clinical trials and the post-marketing setting (data cutoff: December 2017). RESULTS: Of 437 confirmed teriflunomide-exposed pregnancies, 222 had known outcomes (70 from clinical trials; 152 from the post-marketing setting); 161 were reported prospectively and 61 retrospectively. There were 107 (48.2%) live births, 63 (28.4%) elective abortions, 47 (21.2%) spontaneous abortions, 3 (1.4%) ectopic pregnancies, 1 (0.5%) stillbirth, and 1 (0.5%) maternal death leading to fetal death. Four birth defects were reported among cases with known pregnancy outcome: ureteropyeloectasia (only defect considered major); congenital hydrocephalus; ventricular septal defect; and malformation of right foot valgus. A case of cystic hygroma was identified on antenatal ultrasound (pregnancy outcome unknown). One elective abortion followed prenatal diagnosis of fetal anomaly (blighted ovum). The risk of major birth defects in prospectively reported live birth/stillbirth outcomes was 3.6% (1/28) in clinical trials and 0.0% (0/51) in post-marketing reports. CONCLUSIONS: Outcomes were consistent with the general population. Current human data do not indicate a teratogenic signal in teriflunomide-exposed pregnancies.

Severe illicit gamma-hydroxybutyric acid withdrawal in a pregnant woman: what to do?

This case report presents the case of a 29 weeks pregnant woman in her late twenties who was seen at the emergency department of a hospital with a seizure of unknown cause. By anamnesis and hetero-anamnesis the use of illicit gamma-hydroxybutyric acid (GHB) was revealed. Examination showed dilated pupils, sweating, tremor, tachycardia and bradyphrenic thinking. Subsequently, the seizure was indicated as a severe illicit GHB withdrawal symptom. Thereafter, treatment had to be decided on in the absence of evidence-based and practiced-based guidelines and treatment options for this specific patient population. Initially diazepam was started, which was later on substituted by sodium oxybate. Despite the critical professional situation the patient gave birth to a healthy daughter after 37 weeks of pregnancy.

Influence of Gamma-Hydroxybutyric Acid-Use and Gamma-Hydroxybutyric Acid-Induced Coma on Affect and the Affective Network.

BACKGROUND: Gamma-hydroxybutyric acid (GHB) is a drug of abuse associated with increased emergency room attendances, due to GHB-induced comas. Withdrawal from GHB often increases social anxiety and is linked to alterations in emotion processing. However, little is known about the effects of GHB-use and GHB-induced comas on affect regulation in humans. OBJECTIVES: We aimed to assess the effect of GHB-use and GHB-induced comas on the affective network. METHOD: We recruited 27 GHB users with ≥4 GHB-induced comas (GHB-Coma), 27 GHB users without a GHB-induced coma (GHB-NoComa), and 27 polydrug users who never used GHB (No-GHB). Participants completed self-report questionnaires assessing negative affect (depression, anxiety and stress) and performed an emotional face matching task during functional magnetic resonance imaging to probe activity of the amygdala and the hippocampus. RESULTS: The GHB-Coma group reported higher levels of depression, anxiety, and stress; showed decreased activity of the hippocampus; and increased functional connectivity of the left hippocampus with the left fusiform gyrus and a cluster on the left temporal-parietal-occipital junction, when compared with the 2 other groups. The GHB-NoComa group showed decreased functional connectivity of the left hippocampus with the amygdala in comparison with the No-GHB group. CONCLUSIONS: GHB-use but in particular GHB-induced comas, are associated with altered emotion identification and hippocampal functioning. Awareness campaigns are required to raise consciousness about the adverse effects of GHB-induced comas on affect regulation, despite the absence of subjective side effects.

Effect of GHB-use and GHB-induced comas on dorsolateral prefrontal cortex functioning in humans.

BACKGROUND: Gamma-hydroxybutyric acid (GHB) is a recreational drug associated with increasing numbers of GHB-dependent patients and emergency attendances often related to GHB-induced comas. Working memory (WM) deficits have been reported in association with GHB use, and animal studies have shown that GHB induces oxidative stress in vulnerable WM-related brain areas such as the dorsolateral prefrontal cortex (DLPFC). However, the effects of chronic GHB use and multiple GHB-induced comas on WM-related brain function in humans remains unknown. METHODS: We recruited 27 GHB users with ≥4 GHB-induced comas (GHB-Coma), 27 GHB users who never experienced GHB-induced coma (GHB-NoComa), and 27 polydrug users who never used GHB (No-GHB). Participants performed an n-back WM task during functional magnetic resonance imaging (fMRI) to probe DLPFC functioning. RESULTS: The GHB-Coma group had lower premorbid IQ (p = .006) than the GHB-NoComa group despite comparable age and education level. There were also group differences in the use of other drugs than GHB. Therefore, all group comparisons were adjusted for IQ and drug use other than GHB. Compared with the GHB-NoComa and the No-GHB groups, the GHB-Coma group showed increased activity in the right DLPFC (pSVC = 0.028) and increased functional connectivity of the right DLPFC with a cluster comprising the left anterior cingulate and medial frontal gyrus (pFWE = 0.003). No significant fMRI differences were observed between the GHB-NoComa and No-GHB groups. Due to technical problems, no behavioural data were collected. DISCUSSION: These results suggest that multiple GHB-induced comas, but not GHB-use per se, are associated with alterations in WM-related brain function. Public awareness campaigns are required to minimize the potential adverse effects induced by GHB recreational use, and especially GHB-induced comas, even if no immediate side effects are experienced.

Adverse effects of GHB-induced coma on long-term memory and related brain function.

BACKGROUND: Gamma-Hydroxybutyric acid (GHB) is a drug of abuse associated with increasing numbers of GHB-dependent patients and emergency attendances often related to GHB-induced coma. Animal studies suggest that GHB induces oxidative stress in the hippocampus, resulting in memory impairments. However, the consequences of chronic GHB use and GHB-induced coma on human brain function and cognition are unknown. METHODS: We recruited 27 GHB users with ≥4 GHB-induced comas (GHB-Coma), 27 GHB users without a coma (GHB-NoComa), and 27 polydrug users who never used GHB (No-GHB). Participants completed verbal and spatial memory tests and an associative memory encoding task during functional magnetic resonance imaging (fMRI) to probe hippocampus functioning. RESULTS: The GHB-Coma group showed a lower premorbid IQ (p = 0.006) and performed worse on the verbal memory test (p = 0.017) compared to the GHB-NoComa group, despite exhibiting similar levels of education. Compared with the other two groups, the GHB-Coma group showed lower left hippocampus (pSVC = 0.044) and left lingual gyrus (pFWE = 0.017) activity, and a trend for lower hippocampal functional connectivity with the left superior temporal cortex during performance of the associative memory encoding task (pFWE = 0.063). No significant differences were observed between the GHB-NoComa group and the No-GHB group. CONCLUSIONS: These results suggest that multiple GHB-induced comas, but not the use of GHB per se, are associated with alterations of memory performance and memory-related brain, although no causal link can be inferred from this cross-sectional study. The results highlight the need for public awareness to minimize the negative health consequences of recreational GHB use, in particular when related with GHB-induced comas.

The Use of Poly-4-Hydroxybutyrate (P4HB) Scaffold in the Ptotic Breast: A Multicenter Clinical Study.

BACKGROUND: Mastopexy and reduction mammaplasty are often limited by the patient's poor native soft tissue quality, resulting in ptosis recurrence and loss of rejuvenated surgical results. Surgical scaffolds and acellular dermal matrices are used in these procedures to provide physical and mechanical stabilization of weakened or compromised tissue. GalaFLEX scaffold, made from poly-4-hydroxybutyrate (P4HB), is a next-generation product for soft tissue reinforcement that resorbs gradually while aiding tissue regeneration to achieve excellent outcomes. OBJECTIVES: To assess the clinical performance of GalaFLEX scaffold in soft tissue reinforcement during elective mastopexy and reduction mammaplasty. METHODS: This multicenter, single-arm, observational study assessed product performance and outcomes of GalaFLEX scaffold when used in breast surgery. Outcomes included ptosis correction and maintenance, associated adverse events, patient and surgeon satisfaction, and mammographic and ultrasound imaging evaluation. RESULTS: At 6 centers in the US, 62 of 69 enrolled patients were treated. Of this population, 89.7% had successful ptosis correction and maintenance at 1 year, with high patient and surgeon satisfaction for breast shape, droop/sag of the breast, and maintenance of results at 1 year. There were 5 adverse events deemed related to the device (8.0%), including nerve pain, breast swelling, ptosis, and 2 instances of asymmetry. CONCLUSIONS: GalaFLEX scaffold safely and successfully supports and elevates breast tissue in mastopexy and reduction mammaplasty, with maintained support at 1 year. Surgeon and patient satisfaction were high. No mammogram or ultrasound interference was detected.

The Drug of Abuse Gamma-Hydroxybutyric Acid Exhibits Tissue-Specific Nonlinear Distribution.

The drug of abuse γ-hydroxybutyric acid (GHB) demonstrates complex toxicokinetics with dose-dependent metabolic and renal clearance. GHB is a substrate of monocarboxylate transporters (MCTs) which are responsible for the saturable renal reabsorption of GHB. MCT expression is observed in many tissues and therefore may impact the tissue distribution of GHB. The objective of the present study was to evaluate the tissue distribution kinetics of GHB at supratherapeutic doses. GHB (400, 600, and 800 mg/kg iv) or GHB 600 mg/kg plus L-lactate (330 mg/kg iv bolus followed by 121 mg/kg/h infusion) was administered to rats and blood and tissues were collected for up to 330 min post-dose. K p values for GHB varied in both a tissue- and dose-dependent manner and were less than 0.5 (except in the kidney). Nonlinear partitioning was observed in the liver (0.06 at 400 mg/kg to 0.30 at 800 mg/kg), kidney (0.62 at 400 mg/kg to 0.98 at 800 mg/kg), and heart (0.15 at 400 mg/kg to 0.29 at 800 mg/kg), with K p values increasing with dose consistent with saturation of transporter-mediated efflux. In contrast, lung partitioning decreased in a dose-dependent manner (0.43 at 400 mg/kg to 0.25 at 800 mg/kg) suggesting saturation of active uptake. L-lactate administration decreased K p values in liver, striatum, and hippocampus and increased K p values in lung and spleen. GHB demonstrates tissue-specific nonlinear distribution consistent with the involvement of monocarboxylate transporters. These observed complexities are likely due to the involvement of MCT1 and 4 with different affinities and directionality for GHB transport.