Search

Introduction: While prognosis for patients with chronic lymphocytic leukemia (CLL) has improved over time in younger adults, only modest improvements have occurred in older adults. We conducted a descriptive study of prognosis in older adults with CLL., Materials and Methods: We used data from the Surveillance, Epidemiology, and End Results (SEER)-Medicare database from 2003 to 2016. We identified older adults (≥66 years) diagnosed with primary CLL between 2004 and 2015 (Overall Cohort). A subset who initiated CLL-directed therapy during the year following diagnosis was also identified (Treated Cohort). Both cohorts were matched to Medicare beneficiaries without cancer based on age, sex, and region. For each year from 2004 to 2013, three-year survival for patients with CLL and non-cancer comparators was described using Kaplan-Meier analysis. Inverse probability weighted Cox regression models were used to compare survival in the CLL and non-cancer comparator cohorts, accounting for demographic information and comorbidity and frailty indices. Among older adults with CLL, ten-year cause-specific cumulative mortality was estimated using Aalen-Johansen estimators that accounted for competing risks. Predictors of cause-specific mortality, including comorbidity and frailty burden, were assessed using sub-distribution hazards models., Results: In the Overall Cohort, three-year survival increased non-monotonically from 71.4% in 2004 to 73.4% in 2013, with a peak of 74.4% in 2011, and was lower than survival in non-cancer comparators (78.3% in 2004 to 83.2% in 2013). In the Treated Cohort, three-year survival was 56.3% in 2004 and 56.5% in 2013, with a peak of 64.2% in 2011. Cox models suggested that survival in the Treated Cohort was approaching survival in non-cancer comparators after 2011 (hazard ratio = 1.04, 95% confidence interval, 0.93-1.17). Ten-year cumulative mortality was 68.6% in the Overall Cohort and 81.7% in the Treated Cohort, with most deaths attributed to non-CLL causes. In the sub-distribution hazards models, age, year of diagnosis, frailty, and comorbidities were all associated with prognosis., Discussion: Prognosis in older adults has been stable over time and most patients with CLL die from non-CLL causes. CLL-directed treatment decision-making in older adults should consider age-related factors, such as comorbidity and frailty., Competing Interests: Declaration of Competing Interest AM is employed by AbbVie, Inc., a publicly-traded company that produces medications for CLL. WS was employed by AbbVie, Inc. at the time this work was conducted. AM, JL, and WS hold equity in pharmaceutical companies that produce medications for CLL. JL's spouse was employed by GlaxoSmithKline (GSK) at the time this work was conducted and holds equity in GSK, a publicly-traded company that produces cancer therapies, but not for CLL. ED and JL received salary support from AbbVie Inc. for this work. ED is supported by the Cancer Care Quality Training Program at the Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill (grant T32CA116339)., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Early treatment is the mainstay of sepsis therapy. We suspected that early recognition of sepsis by prehospital healthcare providers may shorten the time for antibiotic administration in the emergency department. We retrospectively evaluated all patients above 18 years of age who were diagnosed with sepsis or severe infection in our emergency department between 2018 and 2020. We recorded the suspected diagnosis at the time of presentation, the type of referring healthcare provider, and the time until initiation of antibiotic treatment. Differences between groups were calculated using the Kruskal-Wallis rank sum test. Of the 277 patients who were diagnosed with severe infection or sepsis in the emergency department, an infection was suspected in 124 (44.8%) patients, and sepsis was suspected in 31 (11.2%) patients by referring healthcare providers. Time to initiation of antibiotic treatment was shorter in patients where sepsis or infection had been suspected prior to arrival for both patients with severe infections ( p = 0.022) and sepsis ( p = 0.004). Given the well-described outcome benefits of early sepsis therapy, recognition of sepsis needs to be improved. Appropriate scores should be used as part of routine patient assessment to reduce the time to antibiotic administration and improve patient outcomes.

Point-of-care (POC) diagnostics, in particular lateral flow assays (LFA), represent a great opportunity for rapid, precise, low-cost and accessible diagnosis of disease. Especially with the ongoing coronavirus disease 2019 (COVID-19) pandemic, rapid point-of-care tests are becoming everyday tools for identification and prevention. Using smartphones as biosensors can enhance POC devices as portable, low-cost platforms for healthcare and medicine, food and environmental monitoring, improving diagnosis and documentation in remote, low-resource locations. We present an open-source, all-in-one smartphone-based system for quantitative analysis of LFAs. It consists of a 3D-printed photo box, a smartphone for image acquisition, and an R Shiny software package with modular, customizable analysis workflow for image editing, analysis, data extraction, calibration and quantification of the assays. This system is less expensive than commonly used hardware and software, so it could prove very beneficial for diagnostic testing in the context of pandemics, as well as in low-resource countries.

Venetoclax (Ven), an orally administered, potent BCL-2 inhibitor, has demonstrated efficacy in chronic lymphocytic leukaemia (CLL) in combination with rituximab (R) or obinutuzumab (G). Our aim was to investigate the addition of bendamustine (B) to these Ven-containing regimens in relapsed/refractory (R/R) or first-line (1L) CLL. This multi-arm, non-randomized, open-label, phase 1b study was designed to evaluate the maximum tolerated dose (MTD) and safety/tolerability of Ven with BR/BG, with 3+3 dose-escalation followed by safety expansion. Patients received Ven (schedule A) or BR/BG first (schedule B) to compare safety and determine dose/schedule for expansion. Six Ven-BR/-BG cycles were to be administered, then Ven monotherapy until disease progression (R/R) or fixed-duration 1-year treatment (1L). Overall, 33 R/R and 50 1L patients were enrolled. No dose-limiting toxicities were observed (doses 100-400-mg), and the MTD was not reached. Safety was similar between schedules; no tumour lysis syndrome (TLS) occurred during dose-finding. Schedule B and Ven 400-mg were chosen for expansion. The most frequent grade 3-4 toxicity was neutropenia: R/R 64%, 1L Ven-BR 85%, 1L Ven-BG 55%. Grade 3-4 infection rate was: R/R 27%, 1L Ven-BR 0%, 1L Ven-BG 27%. During expansion, one clinical and two laboratory TLS cases occurred. Fewer than half the patients completed six combination therapy cycles with all study drugs; rates of bendamustine discontinuation were high. Overall response rate was 91% in R/R and 100% in 1L patients (16/49 1L patients received Ven for >1 year). In conclusion, addition of bendamustine to Ven-R/-G increased toxicity without apparent efficacy benefit.

As plastic pollution is becoming an increasing worldwide problem, a variety of different techniques for the detection and in-depth characterization of plastics, including spectroscopy and chromatography methods, were introduced to the public. Recently we presented fluorescence lifetime imaging microscopy (FLIM) a new approach for the identification and characterization of microplastics using their fluorescence lifetime (τ) for differentiation. A very powerful extension of the recently established FLIM could be phasor analysis, which allows data representation in an interactive 2D graphical phasor plot thereby enabling a global view of the fluorescence decay in each pixel of the measured image. Microplastic particles generated from six different types of plastics were subjected to excitation wavelengths of 440 nm, upon which specific fluorescence lifetimes as well as the photon yield were determined using FLIM and phasor analysis. We could show that phasor analysis for FLIM with a laser pulse repetition frequency of 40 MHz was able to generate specific locations in the phasor plot for the plastics for fast differentiation, e.g. resulting in well-defined phasor plot positions for ABS at 3.019 ns, PPE at 6.239 ns, PET bottle from Germany at 2.703 ns and PET bottle from USA at 2.711 ns. Phasor analysis for FLIM proves to be a fast, label-free, and sensitive method for the identification and differentiation of plastics also with the aid of visualization variation enabling techniques such as heat treatment of plastics., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Venetoclax plus obinutuzumab has been established as a fixed-duration treatment regimen for patients with chronic lymphocytic leukaemia. We compared the long-term efficacy after treatment cessation of the combination of venetoclax plus obinutuzumab with chlorambucil plus obinutuzumab in patients with previously untreated chronic lymphocytic leukaemia., Methods: CLL14 is a multicentre, randomised, open-label, phase 3 trial done at 196 sites in 21 countries. Eligible patients were aged 18 years or older, had untreated chronic lymphocytic leukaemia, and coexisting conditions with a cumulative illness rating scale greater than 6, a creatinine clearance of 30-69 mL/min, or both. Patients were randomly assigned (1:1) via a web and voicemail system with allocation concealment and based on a computer-generated randomisation schedule with a block size of six and stratified by Binet stage and geographical region. Patients received either venetoclax plus obinutuzumab (oral venetoclax initiated on day 22 of cycle 1 [28-day cycles], with a 5-week dose ramp-up [20 mg, 50 mg, 100 mg, and 200 mg, then 400 mg daily for 1 week], thereafter continuing at 400 mg daily until completion of cycle 12; combined with intravenous obinutuzumab for six cycles starting with 100 mg on day 1 and 900 mg on day 2 [or 1000 mg on day 1], 1000 mg on days 8 and day 15 of cycle 1, and subsequently 1000 mg on day 1 of cycles 2 through 6) or chlorambucil plus obinutuzumab (oral chlorambucil at 0·5 mg/kg bodyweight on days 1 and 15 of each cycle for 12 cycles combined with the same obinutuzumab regimen). The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. Patient enrolment is complete, and the study is registered with ClinicalTrails.gov, NCT02242942., Findings: Between Aug 7, 2015, and Aug 4, 2016, 432 patients were enrolled and randomly assigned to receive either venetoclax plus obinutuzumab (n=216) or chlorambucil plus obinutuzumab (n=216). All patients had been off treatment for at least 24 months at data collection. At a median follow-up of 39·6 months (IQR 36·8-43·0), patients given venetoclax plus obinutuzumab had a significantly longer progression-free survival than did patients given chlorambucil plus obinutuzumab (HR 0·31, 95% CI 0·22-0·44; p<0·0001). Median progression-free survival was not reached (95% CI not estimable to not estimable) in the venetoclax plus obinutuzumab group vs 35·6 months (33·7-40·7) in the chlorambucil plus obinutuzumab group. The most common grade 3 or 4 adverse event in both groups was neutropenia (112 [53%] of 212 patients in the venetoclax plus obinutuzumab group versus 102 [48%] of 214 patients in the chlorambucil plus obinutuzumab group). Serious adverse events occurred in 115 (54%) of 212 patients in the venetoclax plus obinutuzumab group and 95 (44%) of 214 patients in the chlorambucil plus obinutuzumab group. Venetoclax or chlorambucil treatment-related deaths were reported in one (1%) of 212 patients in the venetoclax plus obinutuzumab group (n=1 sepsis) and two (1%) of 214 patients in the chlorambucil plus obinutuzumab group (n=1 septic shock, n=1 metastatic skin squamous carcinoma)., Interpretation: 2 years after treatment cessation, venetoclax plus obinutuzumab continues to significantly improve progression-survival compared with chlorambucil plus obinutuzumab, thereby providing a limited duration treatment option for patients with previously untreated chronic lymphocytic leukaemia., Funding: F Hoffmann-La Roche and AbbVie., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Genetic parameters are established prognostic factors in chronic lymphocytic leukemia (CLL) treated with chemoimmunotherapy, but are less well studied with novel compounds. We assessed immunoglobulin heavy variable chain (IGHV) mutation status, common genomic aberrations, and gene mutations in 421 untreated patients within the CLL14 trial (NCT02242942), comparing obinutuzumab+chlorambucil (GClb) vs obinutuzumab+venetoclax (VenG). The incidences of genomic aberrations considering the hierarchical model were del(17p) 7%, del(11q) 18%, +12 18%, and del(13q) 35%, whereas IGHV was unmutated in 60% of patients. NOTCH1 mutations were most common (23%), followed by SF3B1 (16%), ATM (13%), and TP53 (10%). Although the overall response rate (ORR) for GClb was lower in patients with del(17p), del(11q), mutated TP53, ATM, and BIRC3, none of these parameters reduced complete remission (CR) rate and ORR with VenG. At a median follow-up of 28 months, del(17p) and mutated TP53 were the only abnormalities with an effect on progression-free survival (PFS) for both treatment groups: GClb (hazard ratio [HR], 4.6 [P < .01]; HR, 2.7 [P < .01], respectively) and VenG (HR, 4.4 [P < .01]; HR, 3.1 [P < .01], respectively). No other factors affected outcome with VenG, whereas for GClb del(11q), BIRC3, NOTCH1, and unmutated IGHV were associated with shorter PFS. Multivariable analysis identified del(17p), del(11q), unmutated IGHV, and mutated TP53, BIRC3, and SF3B1 as independent prognostic factors for PFS with GClb, whereas for VenG, only del(17p) was significant. VenG was superior to GClb across most genetic subgroups. Patients with adverse genetic markers had the strongest benefit from VenG, particularly subjects with unmutated IGHV, which was identified as a predictive factor in a multivariable treatment-interaction analysis., (© 2020 by The American Society of Hematology.)

Introduction: More and more researchers are studying the effects of microplastics on the environment and the organisms living in it. Existing detection methods still require a heavy workload, complex sample preparation and high costs. In this study, autofluorescence of plastic was used as a new method for microplastic detection., Material and Methods: Particles of common plastics were incubated at various temperatures (21-230 °C) for different time periods to investigate the influence of these conditions on their autofluorescence using methods like fluorescence microscopy, and measurement of absorption and emission. To give an example of an autofluorescence application, ImageJ was used to determine the contamination of microplastic in sea salt samples., Results: After treatment at 140 °C for 12 h the plastics ABS, PVC and PA showed a distinct increase in their fluorescence intensity. For PET higher temperatures were necessary to achieve higher fluorescence intensities. Using ImageJ, the particle contamination in sea salt samples was determined as 4903±2522 (aluminium membrane) / 5053±2167 (silicone membrane) particles in 10 g salt, which is a much higher number than counted in other publications., Discussion: Probably the increase in fluorescence intensity is due to the movement of atomic bonds caused by the thermic energy during the heat treatment. The high number of counted particles by using ImageJ is most likely based on the smaller pore size of the used filter membranes and other contaminations like dust and fibers, which could be avoided by alternative sample treatment., Conclusion: Considering the outcomes of this study, heat treatment is a useful tool to make microplastic particles more visible in microscopic applications without readable destruction of their composition. The heat treatment of plastics for defined incubation times and temperatures can lead to a distinct increase in autofluorescence intensity of the plastics and therefore serve as an easy and cost-effective applicable method for microplastic detection.

Introduction: Since the beginning of industrial production in 1950, plastic production has continued to grow strongly worldwide and is now at 322 million tonnes in the year 2015. From these very high production volumes ever larger quantities are found in the environment. There the plastics degradate to microplasticity and spread ubiquitously in the world. The present work deals with the possible uptake of microplastic particles in human organisms. For the detection of these plastic particles, an extraction method was developed and validated., Materials and Methods: Biological materials consist of human blood (healthy volunteers, n = 4) and different tissues of pigs and cattles. Various lysis solutions were tested for degradation efficiency of biological material and for effects on the plastics. The mass loss, surfaces and structure variations as well as the physicochemical spectrum of the material were observed after treatment by atomic force (AFM) and electron microscopy (EM) and Fourier transform infrared spectrometry (FTIR)., Results: The different plastic types as polyamide (PA), polycarbonate (PC), polyethylene (PE), polypropylene (PP), polystyrene (PS) and polyvinyl chloride (PVC) could be clearly differentiated and identified by FTIR. Regarding the surface control, especially PVC showed detectable alterations: After extraction an irregular surface structure caused by protuberances or bubbles could be observed. However, instead of these alterations an equivalent count of plastic particles was found in correlation to the applied plastic amount (recovery rate overall was 99,12±0,67%)., Conclusion: The applied method can be used for plastic extractions from human or animal tissues without remarkable effects on the plastics.

Moricizine HCl, a new orally active antiarrhythmic agent, induces its own hepatic metabolism and consequently may interfere with the metabolism of warfarin, a drug used commonly by cardiac patients that also is subject to extensive hepatic metabolism. Both drugs are also highly protein bound in plasma. To assess the possibility of an interaction, single-dose sodium warfarin (25 mg oral Coumadin, Du Pont Pharmaceuticals, Wilmington, DE) pharmacokinetics, pharmacodynamics; and plasma protein binding were examined in 12 healthy male volunteers 14 days before and 14 days after starting chronic oral moricizine HCl administration (250 mg every 8 hours). The terminal elimination rate constant of warfarin was increased by about 10% when measured in the presence of chronic moricizine administration. However, oral plasma clearance, apparent volume of distribution, maximum peak plasma concentration, time to reach peak concentration, and protein binding were unaffected. More importantly, there was no evidence of a pharmacodynamic interaction based on the prothrombin time profile. It was concluded that no clinically significant interaction occurs under these conditions.

Moricizine, a unique Class I antiarrhythmic agent, was orally administered with and without a meal to 24 healthy male subjects to determine the effect of food on moricizine absorption and bioavailability. Relative to the fasting state, a standardized breakfast delayed the time to peak plasma moricizine concentration (1.2 vs. 0.9 hr; P less than .03) and lowered peak plasma moricizine concentration by 24% (0.55 vs. 0.72 microgram/mL; P less than .03). Bioavailability, as measured by area under the plasma moricizine concentration versus time curve, was not significantly altered by the meal.

Healthy male volunteers (N = 24) participated in a four-way crossover study to compare the rate and extent of absorption of naltrexone after administration of 50 mg tablets as 50, 100, and 200 mg doses and a 10 mg/ml reference syrup. A high-performance liquid chromatographic method was employed to measure naltrexone and 6-beta-naltrexol in plasma and urine. Compared to the syrup, the 50 mg tablets were absorbed more slowly but equally well. There was excellent linearity between the administered dose and the area under the plasma concentration-time profile, as well as total urinary recovery of both drug and metabolite. The mean half-lives for naltrexone and beta-naltrexol were approximately 4 and 12 hours, respectively. The fraction of drug reaching the systemic circulation was estimated to be 5% of the administered dose because of extensive first-pass metabolism. Less than 1% of the dose was excreted in the urine as naltrexone after 48 hours, while 25% was recovered as unconjugated beta-naltrexol. The renal clearance of naltrexone and beta-naltrexol was approximately 127 ml/min and 283 ml/min, respectively. The total systemic clearance for naltrexone was approximately 94 L/hr.

The effect of phenylbutazone on the disposition of warfarin was studied in a subject given warfarin daily for one month. During concomitant phenylbutazone administration, the total plasma warfarin concentration declined from 4.2 to 2.0 mg/L. In contrast, the unbound warfarin plasma concentration rose from 0.020 to 0.033 mg/L. The plasma concentration and daily urinary excretion of 7-hydroxywarfarin fell during phenylbutazone administration. Warfarin is administered as a racemate. Exclusive to and the major metabolic route of the more potent S-isomer is 7-hydroxylation. It is concluded that inhibition of S-warfarin metabolism can help explain the increased anticoagulation seen when phenylbutazone is added to the dosage regimen of a patient stabilized on warfarin.

The pharmacokinetics of intravenous and oral nalbuphine were studied in 24 healthy male volunteers ranging in age from 21 to 30 years. On separate test days over a five-week period, subjects received single doses of each of four different formulations of nalbuphine, with a one-week washout period between treatments: 10 mg intravenously administered over two minutes, 45 mg orally given as a solution, and 45 mg orally administered in two tablet formulations (formulation A and formulation B). Blood samples were collected over 48 hours postadministration, and plasma nalbuphine concentrations were determined by reversed-phase high-performance liquid chromatography (HPLC) with electrochemical detection. The mean nalbuphine plasma concentration five minutes after 10 mg intravenously was 53 ng/mL, and the half-life of nalbuphine with this route of administration was 2.3 hours. In contrast, mean maximum nalbuphine concentrations (Cmax) after the three orally administered preparations ranged from 14.4 to 15.5 ng/mL, and occurred 0.9 to 1.2 hours after dose administration. Mean elimination half-lives after administration of the three nalbuphine oral formulations were essentially identical, ranging from 6.9 to 7.7 hours. Nalbuphine plasma concentration curves decayed biexponentially regardless of route of administration or type of formulation. Absolute bioavailability of the orally administered forms of nalbuphine ranged from 16.4 to 17.4% and Cmax and AUC data further established the bioequivalence of the three oral formulations. The low absolute bioavailability and prolonged elimination half-life of nalbuphine associated with oral administration are likely due to extensive first-pass metabolism and enterohepatic circulation, respectively.

An examination of the metabolic fate of the R and the S isomers of warfarin revealed that the two isomers were metabolized by different routes. R warfarin was oxidized to 6-hydroxywarfarin and was reduced to the (R,S) warfarin alcohol. In contrast, S warfarin was oxidized to 7-hydroxywarfarin and was reduced to the (S,S) warfarin alcohol. S warfarin was also oxidized to 6-hydroxywarfarin. These observations suggested that interactions between warfarin and other drugs might be manifest stereo-specifically, i.e., have a different effect on the isomers of warfarin, so a series of experiments were conducted with each isomer of warfarin, before and after phenylbutazone. The plasma clearance of S warfarin was slowed from 3.1 to 1.1% per h in one subject and from 2.3 to 1.6% per h in another. In contrast, the clearance of R warfarin was increased from 1.5 to 3.0% per h and from 0.9 to 1.6% per h in two subjects after phenylbutazone. The rate of clearance of racemic warfarin was unaffected by phenylbutazone; the depression of the rate of clearance of the S isomer masked the stimulation of the clearance of the R isomer. Since S warfarin is five times more potent an anticoagulant than R warfarin, it is concluded that inhibition of the metabolism of S warfarin provides one mechanism for the augmented anticoagulation which follows phenylbutazone.

The binding interactions between warfarin-salicylate and warfarin-phenylbutazone in the presence of 4 g percent bovine serum albumin at 37 degrees C were studied using equilibrium dialysis. Methods of representing and analysing drug binding interactions are discussed. Scatchard plots, double reciprocal plots and the like are shown to be of no use in representing drug displacement interactions since they display only one drug and they can be potentially misleading. It is argued that a preferable method of analysing drug displacement interaction data is in terms of a stepwise multiple equilibria model. The numerical problems associated with fitting this kind of model to the data are discussed. A three-dimensional representation of the binding surface is proposed as a superior means of visualizing drug displacement interactions.

A three-way crossover study was conducted with 24 healthy male volunteers to determine the relative bioavailability of four different 100-mg phenobarbital tablets compared with a reference elixir. Each subject received two of the tablets and the elixir at 30-d intervals. Blood samples were collected daily for 19 d after each dose. Plasma phenobarbital concentrations achieved with the five dosage forms differed by less than 20% within 2-3 h after dosing. The extent of absorption for all dosage forms, as determined from area under the plasma concentration-time profiles, were within 10% of each other. The peak plasma concentration was the greatest and the time to peak concentration was the shortest for the elixir. One of the tablets exhibited a time to peak concentration of 8.6 h, which was significantly longer than any of the other dosage forms. The time to peak concentration correlated with the percent of drug dissolved in 60 min, as determined in 0.1 M HCl, using the USP XX paddle method at 50 rpm.

Five patients received a small oral dose of warfarin during and after recovery from acute viral hepatitis. Mean (+/- SD) clearance, volume of distribution, and half-life of the drug were 6.1 +/- 0.9 ml/hr/kg, 0.09 +/- 0.04 L/kg, and 23 +/- 5 hr, respectively, during the acute period. After apparent recovery, observed values were 6.1 +/- 0.7 ml/hr/kg, 0.21 +/- 0.02 L/kg, and 25 +/- 3 hr. These differences were not significant. Pattern of renal elimination of warfarin metabolites and drug protein binding did not change between the two phases. During the acute period of illness, prothrombin time increased in 2 of the 5 subjects, but remained within normal limits in all participants during the recovery period. This study shows that warfarin disposition may not change as a consequence of mild or moderate hepatic impairment.

This study was designed to assess the bioequivalence of intramuscular molindone hydrochloride and marketed oral molindone. Ten schizophrenic patients (mean age, 30.2 years) received oral molindone in single daily doses of 100 or 150 mg for four to eight days followed by intramuscular molindone in single daily doses of 50 or 75 mg for four days. On the last day each molindone formulation was given, plasma samples were collected at baseline and at 0.5, 1, 2, 4, 6, 8, and 12 hours after administration. The pharmacokinetic measures of area under the curve and maximum concentration show that intramuscular molindone is 1.49 to 1.67 times more bioavailable than oral molindone. This finding indicates that once a patient's acute psychotic episode has been stabilized with intramuscular molindone, therapy can continue without interruption by substituting 1.5 mg of oral molindone for every 1 mg of intramuscular molindone. The time to maximum concentration occurred significantly earlier (P = 0.05) with intramuscular molindone (0.6 hours) than with oral molindone (1.1 hours). Elimination half-life values were approximately two hours for both formulations.

The influence of altered drug binding on the hepatic elimination of tolbutamide, a drug of low intrinsic clearance, and on the formation of its metabolite, hydroxytolbutamide, was examined under linear conditions at steady state in the isolated in situ single-pass perfused rat liver preparation, with perfusate flow fixed at 15 ml/min. The fraction of tulbutamide unbound in the perfusate was varied (from 0.06 to 1.0) by either varying the perfusate concentration of albumin or using albumin of different animal species. The intrinsic clearance of tolbutamide varied fourfold between preparations (0.08-0.36 ml/min/g liver). Within each preparation the data were normalized to observations with a perfusate containing no protein. Both the extraction ratio (and clearance) of tolbutamide and the fraction of tulbutamide appearing as hydroxytolbutamide in effluent perfusate, a measure of hepatic metabolism, were directly proportional to the fraction of tolbutamide unbound in the perfusate.