Efficacy and safety of phospholipid nanoparticles (VBI-S) in reversing intractable hypotension in patients with septic shock: a multicentre, open-label, repeated measures, phase 2a clinical pilot trial.

Background: Since the 1990's attempts to favorably modulate nitric oxide (NO) have been unsuccessful. We hypothesized that because NO is lipophilic it would preferentially localize into intravascularly infused hydrophobic nanoparticles, thereby reducing its bioavailability and adverse effects without inhibiting its production. We aimed to determine the efficacy and safety of intravenous infusion of a fluid comprised of hydrophobic phospholipid nanoparticles (VBI-S) that reversibly absorb NO in the treatment of hypotension of patients in severe septic shock. Methods: This is a multicentre, open-label, repeated measures, phase 2a clinical pilot trial done at six hospital centers in the USA. Patients in severe septic shock were enrolled after intravenous fluid therapy had failed to raise mean arterial blood pressure (MAP) to at least the generally accepted level of 65 mmHg, requiring the use of vasopressors. The primary endpoint of this study is the proportion of patients in whom MAP increased by at least 10 mmHg. VBI-S was administered intravenously to patients as boluses of 100 ml, 200 ml, 400 ml, and 800 ml at 999 ml/min until the blood pressure goal was reached after which the infusion was stopped, and the MAP was recorded. All patients who received any volume of VBI-S were included in the primary and safety analysis. The study is registered with ClinicalTrials.gov, NCT04257136. Findings: Between February 17, 2020 and January 3, 2023, 20 eligible patients were enrolled in the study. In all 20 (100%) patients, the goal of increasing MAP by at least 10 mmHg using VBI-S was achieved (p = 0.0087, effect size = 0.654). Mean VBI-S volume required to meet the primary goal was 561.0 ± 372.3 ml. The goal of lowering vasopressor dose was also achieved (p = 0.0017). Within 48 h or less after VBI-S, there was a statistically significant improvement in oxygenation, serum creatinine, clotting variables, procalcitonin, lactic acid, and the sequential organ failure assessment (SOFA) score. At 24 h and 48 h following administration of VBI-S, 12/15 (80%) and 9/12 (75%) patients developed hyperlipidemia, respectively. No severe adverse events of VBI-S were observed, and there were no treatment-related deaths. Interpretation: These preliminary findings suggest the safety and efficacy of VBI-S in treating hypotension in patients with septic shock. However, a definitive mortality benefit cannot be demonstrated without a randomized controlled study. Funding: The Naval Medical Research Command-Naval Advanced Medical Development program via the Medical Technology Enterprise Consortium.

Posterior Reversible Encephalopathy Syndrome in a Patient With SARS-CoV-2 Infection Treated With Tocilizumab.

As the world has struggled to adapt to the coronavirus disease (COVID-19) pandemic, new evidence has emerged suggesting that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may manifest with a wide variety of neurologic symptoms. We present the case of a 70-year-old patient hospitalized for COVID-19 related pneumonia who was treated with off-label interleukin (IL)-6 inhibitor tocilizumab and eventually developed prolonged delirium. MRI findings were consistent with posterior reversible encephalopathy syndrome (PRES). PRES was felt to be from SARS-CoV-2 infection, tocilizumab, or a combination. The patient received symptomatic treatment without success. These findings are consistent with few other recent reports, which have chronicled PRES findings in patients with SARS-CoV-2 infections. However, this is only the second example of PRES in a COVID-19 patient treated with tocilizumab. While cases of PRES have been noted to occur with other infectious diseases, clinicians should be aware of the association with SARS-CoV-2 infection and tocilizumab therapy, particularly when considering tocilizumab treatment outside its approved indication. Future research efforts are needed to establish evidence-based guidelines for the management of these patients.

Intra-Arterial Perimortem Resuscitation Using a Micellar Colloid.

OBJECTIVE: The following were studied in a perimortem mouse model of rapid blood loss: (a) efficacy of a prototypical micellar colloid, Intralipid 20%, (IL20), compared to albumin (b) comparison of intra-arterial and intravenous resuscitation, (c) efficacy of IL20 at a volume 2 × the volume of blood removed, and (d) efficacy of oxygenated IL20 after clinical death (CD). METHODS: CD, the absence of breathing and zero blood pressure (BP), was produced by removing 55% of the blood volume within 3 minutes. After CD, the chest was opened to observe ventricular contraction. IL20, Ringer's lactate (RL), or albumin was infused perimortem. RESULTS: Without resuscitation CD occurred in 2.85 ± 0.40 minutes. Ventricular contraction persisted 20.50 ± 1.11 minutes after CD. RL infused immediately after CD restored breathing if given intra-arterially but not intravenously. IL20 was superior to the prototypical colloid, albumin in maintaining the BP. Increasing the volume of IL20 further increased BP. Delayed RL infusion after CD failed to restore breathing. Delayed resuscitation after CD with oxygenated IL20 restored breathing and BP. CONCLUSIONS: Micellar colloid is superior to the prototypical colloid albumin and can possibly be of use when signs of life are no longer present. In extremis, intra-arterial infusion is superior to intravenous infusion.

Socioeconomic status and self-management in epilepsy: comparison of diverse clinical populations in Houston, Texas.

We compared the scores on self-management and associated psychosocial scales of patients with epilepsy at two clinics in Houston, TX, USA, to determine if there were systematic differences associated with socioeconomic status (SES). Patients of low SES reported higher scores on overall, information, and safety management (P<0.03) and no differences on medication, seizure, and lifestyle management. The two groups were similar with respect to the pattern of high and low scores. Reported levels of self-efficacy, depression, social support, stigma, desire for control, and outcome expectations were higher for those of high SES (P<0.01). Knowledge of epilepsy and satisfaction with care were lower (P<0.01). Again, the patterns of high and low scores were similar. Tests of association between psychosocial factors and self-management revealed that people with higher levels of self-efficacy and social support also reported higher self-management (P<0.01) regardless of demographics, seizure frequency, and SES (P<0.05). These findings provide little support for SES-related disparities in self-management and suggest that the focus of strategies to improve self-management may be similar across diverse populations.

A comparison of serum prolactin concentrations after administration of paliperidone extended-release and risperidone tablets in patients with schizophrenia.

Increases in serum prolactin concentrations after administration of risperidone have been attributed, by some, to the availability of paliperidone in plasma. This double-blind, randomized, parallel-group study in patients with schizophrenia compared serum prolactin concentrations following the administration of paliperidone extended-release and risperidone immediate-release tablets. At steady state, the doses administered resulted in a similar exposure to paliperidone and the pharmacologically active fraction of risperidone (i.e. risperidone + paliperidone), respectively. Eligible patients were randomized to either paliperidone extended-release 12 mg on days 1-6 or risperidone immediate-release 2 mg on day 1 and 4 mg on days 2-6. Mean serum prolactin concentrations increased on day 1 (C(max): 71.8 ng/ml and 89.7 ng/ml reached at 6.5 hours and 2.6 hours for paliperidone extended-release and risperidone immediate-release, respectively). On day 6, serum prolactin concentration-time profiles were similar for both treatments, with overall higher serum prolactin concentrations than on day 1 (AUC(0-24 h): 1389 and 842 ng h/ml, and 1306 and 741 ng.h/ml on day 6 and day 1 for paliperidone extended-release and risperidone immediate-release, respectively). These results indicate that paliperidone extended-release 12 mg and risperidone immediate-release 4 mg, administered over a period of 6 days, lead to similar elevations in serum prolactin concentrations.

No pharmacokinetic interaction between paliperidone extended-release tablets and trimethoprim in healthy subjects.

OBJECTIVE: The effect of trimethoprim, a potent organic cation transport inhibitor, on the pharmacokinetics (PK) of paliperidone extended-release tablets (paliperidone ER), an organic cation mainly eliminated via renal excretion, was assessed. METHODS: Open-label, two-period, randomized, crossover study in 30 healthy males. Single dose of paliperidone ER 6 mg was administered either alone on day 1 or day 5 during an 8-day treatment period of trimethoprim 200 mg twice daily. Serial blood and urine samples were collected for PK and plasma protein binding of paliperidone and its enantiomers. The 90% confidence interval (CI) of ratios with/without trimethoprim for PK parameters of paliperidone and its enantiomers calculated. RESULTS: Creatinine clearance decreased from 119 to 102 mL min(-1) with trimethoprim. Addition of trimethoprim increased unbound fraction of paliperidone by 16%, renal clearance by 13%, AUC(infinity) by 9%, and t((1/2)) by 19%. The 90% CIs for ratios with/without trimethoprim were within the 80-125% range for C(max), AUC(last), and renal clearance. For AUC(infinity), 90% CI was 79.37-101.51, marginally below the lower bound of the acceptance range. Paliperidone did not affect steady-state plasma concentrations of trimethoprim. CONCLUSIONS: No clinically important drug interactions are expected when paliperidone ER is administered with organic cation transport inhibitors.

Single- and multiple-dose pharmacokinetics and dose proportionality of the psychotropic agent paliperidone extended release.

Paliperidone extended-release tablet (paliperidone ER) is a centrally active dopamine D(2)- and serotonergic 5-HT(2A)-receptor antagonist that is registered for the treatment of schizophrenia. The controlled rate of release of paliperidone from the ER formulation is designed to have a slower absorption rate, which results in gradual ascending plasma concentrations with observed maximum plasma concentrations occurring at 24 hours after dosing on the first dosing day. On subsequent treatment days, the ER formulation provides minimal fluctuations in plasma concentrations. Paliperidone is eliminated with a terminal half-life of approximately 24 hours. Steady state is achieved after 4 daily doses. Paliperidone ER exhibits time-invariant pharmacokinetics. It shows a 3.5-fold accumulation upon steady state, mainly caused by the controlled release characteristics of the formulation. Paliperidone ER displays dose proportionality over the dose range of 3 to 15 mg; the 90% confidence intervals of the pairwise dose comparisons are all included in the 80% to 125% bioequivalence limits.

Economic evaluation of an intensified disease management system for patients with type 2 diabetes.

We evaluated the effect of a disease management (DM) program on adherence with recommended laboratory tests, health outcomes, and health care expenditures for patients with type 2 diabetes. The study was a natural experiment in a primary care setting in which the intervention was available to 1 group and then compared to the experience of a matched control group. Univariate analysis and difference in differences analysis were used to test for any significant differences between the 2 groups following a 12-month intervention period. A payer perspective was used to estimate the health care cost consequences based on hospital and physician utilization weighted by Medicare prices. The results were nonsignificant at the .10 level, except for compliance with recommended tests, which showed significant results in the univariate analysis. The intervention increased compliance with testing for HbA1c, microalbuminuria, and lipids, and decreased HbA1c value and the percent of patients with HbA1c >or=9.5%. The point estimates showed small reductions in health care cost; only reductions in costs for office visits were significant at the .10 level. We concluded that while there were signs of improvement in adherence to testing, the low effectiveness may be attributed to existing diabetes management activities in this primary care setting, high compliance rates for testing at the beginning of the study, and a steep learning curve for this complex, information-technology-based DM system. The study raises questions about the incremental gains from complex systems approaches to DM and illustrates a rigorous method to assess DM programs under "real-world" conditions, with control for possible selection bias.

Absorption, metabolism, and excretion of paliperidone, a new monoaminergic antagonist, in humans.

Absorption, metabolism, and excretion of paliperidone, an atypical antipsychotic, was studied in five healthy male subjects after a single dose of 1 mg of [(14)C]paliperidone oral solution ( approximately 16 microCi/subject). One week after dosing, 88.4 to 93.8% (mean 91.1%) of the administered radioactivity was excreted: 77.1 to 87.1% (mean 79.6%) in urine and 6.8 to 14.4% (mean 11.4%) in the feces. Paliperidone was the major circulating compound (97% of the area under the plasma concentration-time curve at 24 h). No metabolites could be detected in plasma. Renal excretion was the major route of elimination with 59% of the dose excreted unchanged in urine. About half of the renal excretion occurred by active secretion. Unchanged drug was not detected in feces. Four metabolic pathways were identified as being involved in the elimination of paliperidone, each of which accounted for up to a maximum of 6.5% of the biotransformation of the total dose. Biotransformation of the drug occurred through oxidative N-dealkylation (formation of the acid metabolite M1), monohydroxylation of the alicyclic ring (M9), alcohol dehydrogenation (formation of the ketone metabolite M12), and benzisoxazole scission (formation of M11), the latter in combination with glucuronidation (M16) or alicyclic hydroxylation (M10). Unchanged drug, M1, M9, M12, and M16 were detected in urine; M10 and M11 were detected in feces. The monohydroxylated metabolite M9 was solely present in urine samples of extensive CYP2D6 metabolizers, whereas M10, another metabolite monohydroxylated at the alicyclic ring system, was present in feces of poor metabolizers as well. In conclusion, paliperidone is not metabolized extensively and is primarily renally excreted.

A double-blind, placebo-controlled, randomized study evaluating the effect of paliperidone extended-release tablets on sleep architecture in patients with schizophrenia.

The effects of paliperidone extended-release on sleep architecture in patients with schizophrenia-related insomnia were evaluated in this multicenter, double-blind, randomized, placebo-controlled study. Patients received paliperidone extended-release 9 mg/day or matching placebo during the 14-day double-blind phase. Sleep architecture and sleep continuity were evaluated using polysomnograms. Subjective sleep measures were evaluated daily using the Leeds Sleep Evaluation Questionnaire. Efficacy and safety were also assessed. Thirty-six patients (17 on paliperidone extended-release, 19 on placebo; mean age 32.2 years) completed the study. Paliperidone extended-release treatment vs. placebo resulted in clinically and statistically significant differences in sleep measurements from baseline to endpoint including a reduction in: persistent sleep latency (41 min), sleep onset latency (35 min), number of awakenings after sleep onset (7), time awake in bed (50 min), and stage 1 sleep duration (12 min); prolongation in: total sleep time (53 min), sleep period time (42 min), stage 2 sleep duration (51 min), and rapid eye movement sleep duration (18 min); and an increase in sleep efficiency index (11%). Paliperidone extended-release, compared with placebo, did not exacerbate daytime somnolence and improved symptoms of schizophrenia. Paliperidone extended-release was well tolerated and improved sleep architecture and sleep continuity in patients diagnosed with schizophrenia and concomitant insomnia.