Outcomes in treatment-resistant schizophrenia: symptoms, function and clozapine plasma concentrations

Background: Clozapine is the only medication licenced for treating patients with treatment-refractory schizophrenia. However, there are no evidence-based guidelines as to the optimal plasma level of clozapine to aim for, and their association with clinical and functional outcome. Objective: We assessed the relationship between clinical and functional outcome measures and blood concentrations of clozapine among patients with treatment-refractory psychosis. Methods: Data were reviewed in 82 patients with treatment-refractory psychosis admitted to a specialised tertiary-level service and treated with clozapine. Analysis focussed on the relationship between clozapine and norclozapine plasma concentrations and the patient’s clinical symptoms and functional status. Results: Clinical symptom improvement was positively correlated with norclozapine plasma concentrations and inversely correlated with clozapine to norclozapine plasma concentrations ratio. Clozapine concentrations showed a bimodal association with clinical improvement (peaks around 350 and 660 ng/ml). Clinical symptom improvement correlated with functional outcomes, although there was no significant correlation between the latter and clozapine or norclozapine plasma concentrations. Conclusion: Clozapine treatment was associated with optimal clinical improvement at two different peak plasma concentrations around 350 and 650 ng/ml. Clinical improvement was associated with functional outcome; however, functionality was not directly associated with clozapine concentrations. A subset of patients may require higher clozapine plasma concentrations to achieve clinical improvement.

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Surgery for ‘asymptomatic’ mild primary hyperparathyroidism improves some clinical symptoms postoperatively

Acta Endocrinologica ◽

10.1530/eje-13-0502 ◽

2013 ◽

Vol 169 (5) ◽

pp. 665-672 ◽

Cited By ~ 14

Author(s):

Claire Blanchard ◽

Muriel Mathonnet ◽

Frédéric Sebag ◽

Cécile Caillard ◽

Antoine Hamy ◽

...

Keyword(s):

Primary Hyperparathyroidism ◽

Clinical Improvement ◽

Clinical Symptoms ◽

Clinical Score ◽

Symptom Improvement ◽

Asymptomatic Group ◽

Postoperative Symptom ◽

International Panel ◽

Asymptomatic Patients ◽

Mild Primary Hyperparathyroidism

Objective and backgroundMost primary hyperparathyroidism (pHPT) patients do not conform to the guidelines for parathyroidectomy established by an international panel of specialists and have a mild pHPT. This group is typically defined as ‘asymptomatic’. The primary aim of this study was to determine symptom improvement in this ‘asymptomatic’ group after parathyroidectomy. Secondly, we aimed to create a preoperative clinical score predicting postoperative symptom resolution.DesignA prospective nonrandomized study included patients with mild pHPT.MethodsA questionnaire (22 items) was given to ‘asymptomatic’ patients preoperatively and at 3, 6, and 12 postoperative months. A logistic regression was performed to create a preoperative clinical score.ResultsOne hundred and sixteen patients were included. Postoperatively, HPT was resolved in 98% of patients. Twelve of 22 nonspecific symptoms were improved at 1 year. Subgroups analysis showed a greater improvement in patients <70 years and those with a serum calcium level ≥2.6 mmol/l preoperatively. A clinical score, based on age and five symptoms, was established to predict the clinical improvement after surgery in mild pHPT patients with a positive predictive value of 81%.ConclusionPatients with asymptomatic pHPT have clinical improvement of their symptoms postoperatively even after 1 year. Younger patients and those with higher preoperative calcium levels show the best improvement.

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Phase I Study of Paclitaxel in Combination With a Multidrug Resistance Modulator, PSC 833 (Valspodar), in Refractory Malignancies

Journal of Clinical Oncology ◽

10.1200/jco.2000.18.5.1124 ◽

2000 ◽

Vol 18 (5) ◽

pp. 1124-1124 ◽

Cited By ~ 57

Author(s):

Paula M. Fracasso ◽

Peter Westerveldt ◽

Carole A. Fears ◽

D. Marc Rosen ◽

Eleanor G. Zuhowski ◽

...

Keyword(s):

Peak Plasma ◽

Plasma Concentrations ◽

Maximum Tolerated Dose ◽

Terminal Phase ◽

Time Curve ◽

Blood Concentrations ◽

Psc 833 ◽

Starting Dose ◽

Disease Stabilization ◽

Paclitaxel Treatment

PURPOSE: To determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetics of paclitaxel when given with PSC 833 (valspodar) to patients with refractory solid tumors. PATIENTS AND METHODS: Patients were initially treated with paclitaxel 175 mg/m2 continuous intravenous infusion (CIVI) over 3 hours. Subsequently, 29 hours of treatment with CIVI PSC 833 was started 2 hours before paclitaxel treatment was initiated. In this combination, the starting dose of paclitaxel was 52.5 mg/m2. Paclitaxel doses were escalated by 17.5 mg/m2 increments for four subsequent cohorts. Each cohort consisted of three patients with the exception of the last cohort, which consisted of six patients. Data for the pharmacokinetics of paclitaxel with and without concurrent PSC 833 administration were obtained. RESULTS: All 18 patients completed at least one course of concurrent treatment (median, two courses; range, one to six) and were evaluable for toxicity. The MTD for paclitaxel with PSC 833 was 122.5 mg/m2. Neutropenia was the DLT. All patients had PSC 833 blood concentrations greater than 1,000 ng/mL before, during, and 24 hours after the paclitaxel infusion. PSC 833 produced small increases in the paclitaxel peak plasma concentrations and areas under the concentration-time curve. However, PSC 833 greatly prolonged the terminal phase of paclitaxel, resulting in plasma paclitaxel concentrations of more than 0.05 μmol/L for much longer than expected. As a result, myelosuppression was comparable to that produced by full-dose paclitaxel given without PSC 833. Of the 16 patients who were assessable for response, one patient experienced a partial response and an additional nine patients experienced disease stabilization after paclitaxel treatment alone. CONCLUSION: Treatment with paclitaxel 122.5 mg/m2 as a 3-hour CIVI concurrent with a 29-hour CIVI of PSC 833 results in acceptable toxicity. The addition of PSC 833 alters the pharmacokinetics of paclitaxel, which explains the enhanced neutropenia experienced by patients treated with this drug combination.

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T15. MISMATCH NEGATIVITY INDICES AS A PROGNOSTIC FACTOR FOR REMISSION IN SCHIZOPHRENIA

Schizophrenia Bulletin ◽

10.1093/schbul/sbaa029.575 ◽

2020 ◽

Vol 46 (Supplement_1) ◽

pp. S236-S237

Author(s):

Se-Hoon Shim ◽

Eunsung Lim ◽

Sung-Yong Park ◽

Seung-Ho Jang ◽

Won-Myong Bahk ◽

...

Keyword(s):

Regression Analysis ◽

Functional Outcome ◽

Symptom Severity ◽

Mismatch Negativity ◽

Functional Outcomes ◽

Electrode Site ◽

Event Related Potential ◽

Symptom Improvement ◽

Relationship Of ◽

The Relationship

Abstract Background Mismatch negativity (MMN) is an event-related potential component when a sequence of relatively standard stimuli is interrupted by the infrequent presentation of deviant stimuli. MMN is known to be associated with neuro-cognition and functional outcomes. Also, abnormally decreased MMN has often been reported in schizophrenia. Remission and recovery rates are related to the neuro-cognition of patients with schizophrenia. The present study explored the relationship of MMN with remission in patients with schizophrenia. Methods Forty patients with schizophrenia were recruited and divided into two groups, with or without remission, according to the Remission in Schizophrenia Working Group criteria (RSWGcr). For assessments of symptom severity, cognitive function and functional outcome, scale such as Positive and Negative Syndrome Scale (PANSS), K-WAIS-IV, and Global Assessment of Functioning (GAF) were measured. MMN of the patients were evaluated at the frontocentral site. A regression analysis was used to identify the factors that significantly predicted symptom improvement and remission including MMN at frontal site assessed at baseline, and anticipated clinical variables as predictive factors. Results MMN amplitudes in frontal sites were further decreased in the groups without remission compared to the groups with remission. MMN amplitude was significantly correlated with measures of symptom change and functional outcome measurements in patients with schizophrenia. Regression analysis revealed that symptom severity and MMN significantly predicted remission in patients with schizophrenia. Symptom improvement significantly predicted PANSS at baseline, illness duration, and antipsychotic dose, as did MMN amplitude at frontal site. Discussion This study explored the relationship of MMN with remission in patients with schizophrenia. The remitted patients with schizophrenia showed larger MMN amplitude in frontal electrode site than those of non-remitted patients. MMN in frontal sites was correlated with symptom improvement and functional outcomes through PANSS and GAF scales. The present study found that MMN was significantly correlated with variables related to remission such as PANSS and GAF evaluated at 6 months later. MMN indexes appears to be a promising candidate for predicted factor of remission of schizophrenia.

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Oral Fluid and Plasma Cannabinoid Ratios after Around-the-Clock Controlled Oral Δ9-Tetrahydrocannabinol Administration

Clinical Chemistry ◽

10.1373/clinchem.2011.169490 ◽

2011 ◽

Vol 57 (11) ◽

pp. 1597-1606 ◽

Cited By ~ 21

Author(s):

Garry Milman ◽

David M Schwope ◽

Eugene W Schwilke ◽

William D Darwin ◽

Deanna L Kelly ◽

...

Keyword(s):

Whole Blood ◽

Oral Fluid ◽

Plasma Concentrations ◽

Interindividual Variation ◽

Blood Concentrations ◽

Drugged Driving ◽

Cannabis Smoking ◽

Time Courses ◽

The Relationship ◽

Over Time

BACKGROUND Oral fluid (OF) testing is increasingly important for drug treatment, workplace, and drugged-driving programs. There is interest in predicting plasma or whole-blood concentrations from OF concentrations; however, the relationship between these matrices is incompletely characterized because of few controlled drug-administration studies. METHODS Ten male daily cannabis smokers received around-the-clock escalating 20-mg oral Δ9-tetrahydrocannabinol (THC, dronabinol) doses (40–120 mg/day) for 8 days. Plasma and OF samples were simultaneously collected before, during, and after dosing. OF THC, 11-hydroxy-THC and 11-nor-9-carboxy-THC (THCCOOH) were quantified by GC-MS at 0.5-μg/L, 0.5-μg/L, and 7.5-ng/L limits of quantification (LOQs), respectively. In plasma, the LOQs were 0.25 μg/L for THC and THCCOOH, and 0.5 μg/L for 11-hydroxy-THC. RESULTS Despite multiple oral THC administrations each day and increasing plasma THC concentrations, OF THC concentrations generally decreased over time, reflecting primarily previously self-administered smoked cannabis. The logarithms of the THC concentrations in oral fluid and plasma were not significantly correlated (r = −0.10; P = 0.065). The OF and plasma THCCOOH concentrations, albeit with 1000-fold higher concentrations in plasma, increased throughout dosing. The logarithms of OF and plasma THCCOOH concentrations were significantly correlated (r = 0.63; P < 0.001), although there was high interindividual variation. A high OF/plasma THC ratio and a high OF THC/THCCOOH ratio indicated recent cannabis smoking. CONCLUSIONS OF monitoring does not reliably detect oral dronabinol intake. The time courses of THC and THCCOOH concentrations in plasma and OF were different after repeated oral THC doses, and high interindividual variation was observed. For these reasons, OF cannabinoid concentrations cannot predict concurrent plasma concentrations.

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Comparative Plasma Heparin Levels after Subcutaneous Sodium and Calcium Heparin

Thrombosis and Haemostasis ◽

10.1055/s-0038-1648673 ◽

1978 ◽

Vol 40 (02) ◽

pp. 397-406 ◽

Cited By ~ 8

Author(s):

Joyce Low ◽

J C Biggs

Keyword(s):

Peak Plasma ◽

Plasma Concentrations ◽

Factor Xa ◽

Normal Subjects ◽

Sodium Salts ◽

Sodium Heparin ◽

Significant Difference ◽

Heparin Plasma ◽

Calcium Heparin ◽

Plasma Heparin

SummaryComparative plasma heparin levels were measured in normal subjects injected subcutaneously with 5,000 units of the sodium and calcium salts of heparin. Plasma heparin levels were measured up to 7 hr post-injection by an anti-factor Xa assay (Denson and Bonnar 1973). Preliminary studies indicated that heparin levels were reproducible in subjects who received two injections of the same heparin. Peak plasma concentrations (Cmax) and the time at which peak concentration was reached (Tmax) varied greatly from subject to subject. In one group of subjects (15) two commonly used heparins, a sodium heparin (Evans) and a calcium heparin (Choay) were compared. Peak heparin concentrations were not significantly different. However the Tmax for the sodium heparin (1.5 hr) was significantly earlier than the Tmax for the calcium heparin (3 hr) and this was not due to a difference in the volume of the two heparin injections. No significant difference could be detected in the plasma clearance rate and the molecular weight distribution of the two heparins.In two other groups of subjects, sodium and calcium preparations from two manufacturers were compared. In general, the sodium salts gave rise to significantly higher plasma concentrations, which could be interpreted as a greater bioavailability of sodium salts. These results indicate that the salt of the heparin can influence the plasma concentration achieved after subcutaneous injection.

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Bioavailability in Rats of Human Recombinant Tissue Plasminogen Activator After Subcutaneous and Intramuscular Injection

Thrombosis and Haemostasis ◽

10.1055/s-0038-1661671 ◽

1986 ◽

Vol 56 (03) ◽

pp. 299-301 ◽

Cited By ~ 5

Author(s):

L J Garcia Frade ◽

S Poole ◽

S Hanley ◽

L J Creighton ◽

A D Curtis ◽

...

Keyword(s):

Plasminogen Activator ◽

Tissue Plasminogen Activator ◽

Fibrinolytic Activity ◽

Inferior Vena ◽

Peak Plasma ◽

Plasma Concentrations ◽

Vena Cava ◽

Recombinant Tissue Plasminogen Activator ◽

Fibrin Plate ◽

Tissue Plasminogen

SummaryThe bioavailability of human recombinant tissue plasminogen activator (rt-PA) in rats was measured after subcutaneous (s.c.) and intramuscular (i.m.) injection. Rt-PA was absorbed after both i.m. and s.c. injection, giving peak plasma concentrations within 30 min and 1 h, respectively, with detectable concentrations up to 6 h. These peak values of bioavailable t-PA were obtained in a functional fibrin plate assay of euglobulin precipitates and expressed as +88% and +243% (for s.c. and i.m. routes respectively) above basal rat fibrinolytic activity. Prior injection of rt-PA, s.c. or i.m., significantly reduced the weights of thrombi induced in the inferior vena cava after injection.

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Eosinophil-to-monocyte ratio is a potential biomarker in the prediction of functional outcome among patients with acute ischemic stroke

BMC Neuroscience ◽

10.1186/s12868-021-00610-x ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Shuhong Yu ◽

Yi Luo ◽

Tan Zhang ◽

Chenrong Huang ◽

Yu Fu ◽

...

Keyword(s):

Ischemic Stroke ◽

Acute Ischemic Stroke ◽

Functional Outcome ◽

Odds Ratio ◽

Poor Outcome ◽

Net Reclassification Improvement ◽

Potential Biomarker ◽

The Impact ◽

The Relationship ◽

Integrated Discrimination Improvement

Abstract Background It has been shown that eosinophils are decreased and monocytes are elevated in patients with acute ischemic stroke (AIS), but the impact of eosinophil-to-monocyte ratio (EMR) on clinical outcomes among AIS patients remains unclear. We aimed to determine the relationship between EMR on admission and 3-month poor functional outcome in AIS patients. Methods A total of 521 consecutive patients admitted to our hospital within 24 h after onset of AIS were prospectively enrolled and categorized in terms of quartiles of EMR on admission between August 2016 and September 2018. The endpoint was the poor outcome defined as modified Rankin Scale score of 3 to 6 at month 3 after admission. Results As EMR decreased, the risk of poor outcome increased (p < 0.001). Logistic regression analysis revealed that EMR was independently associated with poor outcome after adjusting potential confounders (odds ratio, 0.09; 95% CI 0.03–0.34; p = 0.0003), which is consistent with the result of EMR (quartile) as a categorical variable (odds ratio, 0.23; 95% CI 0.10–0.52; ptrend < 0.0001). A non-linear relationship was detected between EMR and poor outcome, whose point was 0.28. Subgroup analyses further confirmed these associations. The addition of EMR to conventional risk factors improved the predictive power for poor outcome (net reclassification improvement: 2.61%, p = 0.382; integrated discrimination improvement: 2.41%, p < 0.001). Conclusions EMR on admission was independently correlated with poor outcome in AIS patients, suggesting that EMR may be a potential prognostic biomarker for AIS.

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Decision making under ambiguity and risk in adolescent-onset schizophrenia

BMC Psychiatry ◽

10.1186/s12888-021-03230-1 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Dandan Li ◽

Fengyan Zhang ◽

Lu Wang ◽

Yifan Zhang ◽

Tingting Yang ◽

...

Keyword(s):

Decision Making ◽

Executive Function ◽

Iowa Gambling Task ◽

Clinical Symptoms ◽

Healthy Controls ◽

Syndrome Scale ◽

Significant Difference ◽

Abnormal Pattern ◽

Negative Syndrome ◽

The Relationship

Abstract Objective Numerous studies have identified impaired decision making (DM) under both ambiguity and risk in adult patients with schizophrenia. However, the assessment of DM in patients with adolescent-onset schizophrenia (AOS) has been challenging as a result of the instability and heterogeneity of manifestations. The Iowa Gambling Task (IGT) and Game of Dice Task (GDT), which are frequently used to evaluate DM respectively under ambiguity and risk, are sensitive to adolescents and neuropsychiatric patients. Our research intended to examine the performance of DM in a relatively large sample of patients with AOS using the above-mentioned two tasks. We also aimed to take a closer look at the relationship between DM and symptom severity of schizophrenia. Methods We compared the performance of DM in 71 patients with AOS and 53 well-matched healthy controls using IGT for DM under ambiguity and GDT for DM under risk through net scores, total scores and feedback ration. Neuropsychological tests were conducted in all participants. Clinical symptoms were evaluated by using Positive and Negative Syndrome Scale (PANSS) in 71 patients with AOS. Pearson’s correlation revealed the relationship among total score of DM and clinical and neuropsychological data. Results Compared to healthy controls, patients with AOS failed to show learning effect and had a significant difference on the 5th block in IGT and conducted more disadvantageous choices as well as exhibited worse negative feedback rate in GDT. Apart from DM impairment under risk, diminished DM abilities under ambiguity were found related to poor executive function in AOS in the present study. Conclusions Our findings unveiled the abnormal pattern of DM in AOS, mainly reflected under the risky condition, extending the knowledge on the performance of DM under ambiguity and risk in AOS. Inefficient DM under risk may account for the lagging impulse control and the combined effects of developmental disease. In addition, our study demonstrated that the performance on IGT was related to executive function in AOS.

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Identification of Anti-Severe Acute Respiratory Syndrome-Related Coronavirus 2 (SARS-CoV-2) Oxysterol Derivatives In Vitro

International Journal of Molecular Sciences ◽

10.3390/ijms22063163 ◽

2021 ◽

Vol 22 (6) ◽

pp. 3163

Author(s):

Hirofumi Ohashi ◽

Feng Wang ◽

Frank Stappenbeck ◽

Kana Tsuchimoto ◽

Chisa Kobayashi ◽

...

Keyword(s):

Severe Acute Respiratory Syndrome ◽

Viral Replication ◽

Cultured Cells ◽

Peak Plasma ◽

Plasma Concentrations ◽

Membrane Vesicles ◽

Drug Candidates ◽

Increased Risk ◽

Derivatives Of

The development of effective antiviral drugs targeting the severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) is urgently needed to combat the coronavirus disease 2019 (COVID-19). We have previously studied the use of semi-synthetic derivatives of oxysterols, oxidized derivatives of cholesterol as drug candidates for the inhibition of cancer, fibrosis, and bone regeneration. In this study, we screened a panel of naturally occurring and semi-synthetic oxysterols for anti-SARS-CoV-2 activity using a cell culture infection assay. We show that the natural oxysterols, 7-ketocholesterol, 22(R)-hydroxycholesterol, 24(S)-hydroxycholesterol, and 27-hydroxycholesterol, substantially inhibited SARS-CoV-2 propagation in cultured cells. Among semi-synthetic oxysterols, Oxy210 and Oxy232 displayed more robust anti-SARS-CoV-2 activities, reducing viral replication more than 90% at 10 μM and 99% at 15 μM, respectively. When orally administered in mice, peak plasma concentrations of Oxy210 fell into a therapeutically relevant range (19 μM), based on the dose-dependent curve for antiviral activity in our cell-based assay. Mechanistic studies suggest that Oxy210 reduced replication of SARS-CoV-2 by disrupting the formation of double-membrane vesicles (DMVs); intracellular membrane compartments associated with viral replication. Our study warrants further evaluation of Oxy210 and Oxy232 as a safe and reliable oral medication, which could help protect vulnerable populations with increased risk of developing COVID-19.

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To hydrate or not to hydrate? The effect of hydration on survival, symptoms and quality of dying among terminally ill cancer patients

BMC Palliative Care ◽

10.1186/s12904-021-00710-9 ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Chien-Yi Wu ◽

Ping-Jen Chen ◽

Tzu-Lin Ho ◽

Wen-Yuan Lin ◽

Shao-Yi Cheng

Keyword(s):

Cancer Patients ◽

Proportional Hazards Model ◽

Clinical Symptoms ◽

Terminally Ill ◽

Good Death ◽

Artificial Nutrition ◽

Symptom Improvement ◽

Terminally Ill Cancer Patients ◽

Quality Of Dying

Abstract Background Artificial nutrition and hydration do not prolong survival or improve clinical symptoms of terminally ill cancer patients. Nonetheless, little is known about the effect of artificial hydration (AH) alone on patients’ survival, symptoms or quality of dying. This study explored the relationship between AH and survival, symptoms and quality of dying among terminally ill cancer patients. Methods A pilot prospective, observational study was conducted in the palliative care units of three tertiary hospitals in Taiwan between October 2016 and December 2017. A total of 100 patients were included and classified into the hydration and non-hydration group using 400 mL of fluid per day as the cut-off point. The quality of dying was measured by the Good Death Scale (GDS). Multivariate analyses using Cox’s proportional hazards model were used to assess the survival status of patients, the Wilcoxon rank-sum test for within-group analyses and the Mann-Whitney U test for between-groups analyses to evaluate changes in symptoms between day 0 and 7 in both groups. Logistic regression analysis was used to assess the predictors of a good death. Results There were no differences in survival (p = 0.337) or symptom improvement between the hydration and non-hydration group, however, patients with AH had higher GDS scores. Conclusions AH did not prolong survival nor significantly improve dehydration symptoms of terminally ill cancer patients but it may influence the quality of dying. Communication with patients and their families on the effect of AH may help them better prepared for the end-of-life experience.

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