Bioavailability of vitamin D biofortified pork meat: results of an acute human crossover study in healthy adults.

Vitamin D intakes are concerningly low. Food-based strategies are urgently warranted to increase vitamin D intakes and subsequently improve 25-hydroxyvitamin D (25(OH)D) concentrations. This acute randomised three-way crossover study investigated the efficacy of vitamin D biofortified pork derived from pigs exposed to UVB light to increase serum 25(OH)D3 concentrations, compared to a dose-matched vitamin D3 supplement and control pork in adults (n = 14). Blood samples were obtained at baseline and then 1.5, 3, 6, 9 and 24 h postprandially. There was a significant effect of time (p < 0.01) and a significant treatment*time interaction (p < 0.05). UV pork and supplement significantly increased within-group serum 25(OH)D3 concentrations over timepoints (p < 0.05) (max. change 0.9 nmol/L (2.2%) UV pork, 1.5 nmol/L (3.5%) supplement, 0.7 nmol/L (1.9%) control). Vitamin D biofortified pork modestly increased 25(OH)D3 concentrations and produced a similar response pattern as a dose-matched vitamin D supplement, but biofortification protocols should be further optimised to ensure differentiation from standard pork.

Therapeutic Listening for Preterm Children with Sensory Dysregulation, Attention and Cognitive Problems.

Introduction Is Therapeutic Listening effective for children born preterm presenting with sensory dysregulation, attention and cognitive problems? Methods 22 children (BW<1500g) 3-4 years were enrolled in a single centre, prospective, assessor-blinded RTC. Outcome measures: Winnie-Dunn Sensory Profile; Peabody Developmental Motor Scales; Reynell Attention Scale; Preschool Language Scales - 3; RAPT; WPPSI - IV; Parent Review Questionnaires. Results The intervention group (n=9) showed better improvement in sensory processing, compared to controls (n=9) (6.4 fold improvement in sensation seeking; 5.0 in auditory processing; 4.0 in tactile processing). Six intervention children (67%) improved in vestibular processing. Attention levels improved for 9 (100%) children in the intervention group and for 7 (78%) in the control group. Higher level domains (Peabody motor skills, Auditory Comprehension, Expressive Communication, RAPT scale, and WPPSI scores) showed mixed results. Parents reported positive changes in their child's development. Conclusion Therapeutic Listening (TL) is a feasible intervention for preterm children to improve attention levels and sensory processing skills.

Exploring organizational support for the provision of structured self-management education for people with Type 2 diabetes: findings from a qualitative study.

AIM: To explore the organizational context in which Type 2 diabetes structured group education is provided. METHODS: Four Clinical Commissioning Groups in England providing Type 2 diabetes structured self-management education participated in a qualitative study exploring the context for provision of that education. Using UK National Diabetes Audit returns, two Clinical Commissioning Groups were selected that had non-attendance rates of ≤25%, and two that had non-attendance rates of ≥50%. Between May 2016 and August 2017, 20 interviews were conducted with Clinical Commissioning Group staff including: commissioners, healthcare professionals, managers, general practitioners and diabetes educators. Data gathering was prolonged as it proved challenging to engage with healthcare staff as a result of frequent local restructuring and service disruption. RESULTS: Local audits revealed discrepancies in basic data such as referral and attendance numbers compared with national audit data. There was a commonality in the themes identified from interviews: diabetes education was rarely embedded in service structure; where education uptake was poor, a lack of central support to delivery teams was noticeable; and where education uptake was positive, delivery teams were actively engaged, sometimes relying on enthusiastic individuals. Both situations put the local sustainability of diabetes education at risk. CONCLUSIONS: There appears to be a link between attendance rates and organizational issues, therefore, when considering how to increase attendance rates, the state of the diabetes education infrastructure should be reviewed. Good uptake of diabetes education can be too reliant on the enthusiastic commitment of small teams or individuals delivering the education.

Neurodevelopmental outcome of preterm babies of 1999-2009.

The Bayley scale of infant development is employed as the performance indicator at 2 years corrected gestational age for high risk paediatric groups. We compare neurodevelopmental outcomes in two cohorts of VLBW infants born in 1999 to a cohort born a decade later, while also examining the challenges of direct comparison of modified scales: BSID-II (2nd edition of the scales) with Bayley-III, BSID-II was used in the 1999 group and Bayley-III for the 2009 cohort. We demonstrated that over a ten year period there was an improvement in neurodevelopmental scores achieved in VLBW babies. Overall there was almost an 8 point increase in the cognitive scores from the 2009 cohort compared with the 1999 cohort in this time period. The mean motor score increased by 6 points when comparing 1999 and 2009. However we highlight the difficulties in comparing developmental scales, and consider whether Bayley-III overestimates developmental ability?

Author Correction: Association of monomeric C-Reactive Protein (m-CRP) with hypothalamic neurons after CRP hippo-campal administration in a model of dementia.

Correction to: European Review for Medical and Pharmacological Sciences 2022; 26 (22): 8713-8718. DOI: 10.26355/eurrev_202212_30543- PMID: 36524490-published online on December 15, 2022. After publication, the authors applied a correction to the funding statement: The authors extend their appreciation to the deputyship for Research & Innovation, Ministry of Education in Saudi Arabia for funding this research work through the project number (lFP-2020-36). There are amendments to this paper. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/30543.

Brain natriuretic peptide is associated with worsening and mortality in acute stroke patients but adds no prognostic value to clinical predictors of outcome.

BACKGROUND: At the present time, the determination of the outcome of stroke patients is based on the analysis of clinical and neuroimaging data. The use of prognostic blood biomarkers could aid in decision-making processes, e.g. admitting patients to specialized stroke units. Although the prognostic role of natriuretic peptides has been studied in heart failure and coronary diseases, the value of brain natriuretic peptide (BNP) is less known within the field of strokes. OBJECTIVE: We aimed to study the relationship between plasma levels of BNP and acute neurological worsening or mortality after stroke in a large cohort of patients (investigating both ischemic and hemorrhagic disease). METHODS: Consecutive stroke patients (ischemic and hemorrhagic) admitted to the Stroke Unit of our University Hospital within 24 h of the onset of symptoms were included. Stroke severity was assessed according to the National Institutes of Health Stroke Scale (NIHSS) at admission and at discharge. Neurological worsening was defined as an increase of 4 or more points in the NIHSS score or death during the patient's stay at the Stroke Unit. Blood samples were drawn upon admission to measure plasma levels of BNP (Biosite Inc., San Diego, Calif., USA). Statistical analysis was performed using SPSS 15.0 and R software. RESULTS: Altogether, 896 patients were included in the study. BNP plasma levels were higher among patients who deteriorated the most over time (n = 112; 90.5 vs. 61.2 ng/l; p = 0.006) or died (n = 83; 118.2 vs. 60.9 ng/l; p < 0.001). Multivariate logistic regression analysis indicated that plasma BNP level was an independent predictor of neurological worsening [BNP >56.7 ng/l; odds ratio (OR) = 1.64; p = 0.04] and death after stroke (BNP >65.3 ng/l; OR = 1.97; p = 0.034). Adding BNP level to other well-known clinical predictors of bad outcome did not significantly increase the predictive value. CONCLUSIONS: Plasma levels of BNP measured during the acute phase of stroke are associated both with early neurological worsening and mortality. However, this biological information does not supply prognostic information which would add to clinical variables, which limits its use as a biomarker. Further investigation and systematic reviews are needed to clarify the role of natriuretic peptides in stroke outcome.

Association of monomeric C-Reactive Protein (m-CRP) with hypothalamic neurons after CRP hippo-campal administration in a model of dementia.

OBJECTIVE: The ensuing ischemia due to the disruption of blood supply to the brain is one of the most common causes of stroke. Evidence suggests a clear association of the ischemic injury with vascular dementia and Alzheimer's disease (AD). In response to the brain ischemia, a cascade reaction starts leading to neuronal damage due to oxidative stress and other inflammatory mediators. A pilot study was done, which showed that following stroke, monomeric-C-reactive protein (mCRP) is expressed in large quantities around the infarcted zone and this CRP is able to induce neurodegeneration and inflammation potentially perpetuating dementia. MATERIALS AND METHODS: We examined both patient brain samples and excised mouse brain tissue, previously injected with 1.75 mg/mL mCRP into the CA1 area of the hippocampus through the stereotactic surgical procedures and followed them over a period of over 6 months. The distribution of mCRP was examined through immunohistochemistry (mouse anti-human mCRP-specific antibodies 8C10). RESULTS: We observed a novel finding: those micro vessels close to the injection location were strongly stained with mCRP only in the mice that had been injected with mCRP, indicating that this small blood vessel can spread it throughout the brain. CONCLUSIONS: mCRP found in the brain after a hemorrhagic stroke promotes damage over a large area via the induction of inflammation and degeneration of perivascular compartments.

Identification of a 'snapshot' of co-expressed angiogenic markers in laser-dissected vessels from unstable carotid plaques with targeted arrays.

BACKGROUND/AIMS: Angiogenesis is a feature of the atherogenic process, with intimal neovascularisation arising from vessels in the adventitia, adjacent to a plaque. Immature, leaky blood vessels from unstable plaques proliferate abnormally and, being poorly invested with smooth muscle cells, may contribute to instability of the plaque by facilitation of inflammatory cell infiltration and haemorrhagic complications. METHODS: We used laser-capture microdissection to isolate angiogenic areas of the extracellular matrix (containing CD105/flt-1-positive, fragile thin-walled vessels) and non-angiogenic vascular areas (CD105-negative, with smooth muscle cell covering) of complicated endarterectomy plaques, and specifically designed angiogenesis-TaqMan real-time PCR microarrays to identify gene expression. RESULTS: Important pro-angiogenic components, including Notch-3, delta-like-4 (DLL4), Tie-2, angiopoietin-1 (Angio-1) and receptor for advanced glycation end products (RAGE), and one anti-angiogenic factor, endostatin, were up-regulated in these regions. Immunohistochemistry demonstrated localisation within intimal, active (CD105-positive) microvessels and co-localisation of Notch-3 and DLL4/Tie-2 and Angio-1 in the same vessels indicating multiple/synergistic signalling mechanisms associated with vessel development. CONCLUSION: These data, although providing only a snapshot of information, demonstrate that plaque vascularisation occurs in the presence of multiple angiogenically active factors. Knowledge of their combined effects could help in the formulation of novel therapeutics designed to stabilise or prevent their formation in the treatment of atherosclerosis.

A comparative study of carotid atherosclerotic plaque microvessel density and angiogenic growth factor expression in symptomatic versus asymptomatic patients.

OBJECTIVE: A challenge facing clinicians is identifying patients with asymptomatic carotid disease at risk of plaque instability. We hypothesise that locally released angiogenic growth factors contribute to plaque instability. METHODS: Carotid endarterectomy specimens from eight symptomatic and eight asymptomatic patients were interrogated for microvessel density and angiogenic growth factor expression histologically using immunofluorescence, and biochemically using quantitative real-time polymerase chain reaction (q-RT-PCR). Bio-Plex suspension array was used to assess circulating biomarkers in venous blood from the same patients and six healthy age-matched controls. RESULTS: Immunofluorescence demonstrated significantly greater neovessel density in symptomatic plaques (P=0.010) with elevated expression of hepatocyte growth factor (HGF) (P=0.001) and its receptor MET (P=0.011) than in asymptomatic plaques. The q-RT-PCR demonstrated up-regulation of Endoglin (CD105), HGF (P=0.001) and MET (P=0.011) in the plaques of symptomatic versus asymptomatic patients. Bio-Plex suspension array demonstrated elevated HGF (P=0.002) serum levels in symptomatic versus asymptomatic patients and healthy controls, and decreased platelet-derived growth factor (PDGF) (P=0.036) serum levels in symptomatic versus asymptomatic patients. CONCLUSION: Plaque instability may be mediated by HGF-induced formation of new microvessels, and decreased vessel stability resulting from decreased PDGF. Suspension array technology has the potential to identify circulating biomarkers that correlate with plaque rupture risk.

B-cell translocation gene 2 is over-expressed in peri-infarct neurons after ischaemic stroke.

OBJECTIVES: Recovery from stroke is dependent on the survival of neurons in the dynamic peri-infarcted region. Although several markers of neuronal injury and apoptotic cell death have been described, administration of neuroprotective drugs directed at specific molecules has had limited success. A complete understanding of deregulated genes associated with neuronal death would be beneficial. Our previous microarray studies identified increased expression of a novel protein, the B-cell translocation gene 2 (BTG2), in infarcted regions. METHODS: We have used immunohistochemistry and Western blotting to examine the expression and localization of BTG2 in stroked brain tissue and immunofluorescent staining of human fetal brain neurons to determine if oxygen-glucose deprivation affected its expression. RESULTS: We show that BTG2 is strongly expressed in peri-infarcted and infarcted regions of brain tissue, localizing in neuronal nuclei and cytoplasm, whilst being absent or very weakly expressed in normal looking contralateral tissue. Exposure of human fetal brain neurons to oxygen-glucose deprivation also induced BTG2 expression in the cytoplasm and perinuclear regions of cells staining positive for propidium iodide (a marker of nuclear damage). CONCLUSIONS: BTG2 may be a modulator of cell survival and differentiation and could help to protect against cell death by inhibition of necrosis and/or apoptotic signalling pathways.

An investigation of the kinetic and anti-angiogenic properties of plant glycoside inhibitors of thymidine phosphorylase.

We investigated the potential of symplocomoside (1) and symponoside (2), glycosides isolated from the bark of Symplocos racemosa to inhibit thymidine phosphorylase (TP) activity and associated angiogenesis. Compound 1 was a reversible, noncompetitive inhibitor of deoxythymidine binding to TP (IC(50) = 65.45 +/- 5.08 microM; K(i) = 62.83 +/- 2.10 microM) and 2 was a reversible, uncompetitive inhibitor (IC(50) = 94.17 +/- 4.05 microM; K(i) = 101.95 +/- 1.65 microM). Molecular modeling analysis indicated that both compounds bound at the active site of the enzyme but not solely to amino acid residues involved in catalysis. Both compounds were active in in vitro angiogenic assays inhibiting endothelial cell migration and invasion in Matrigel, but did not inhibit growth factor-induced proliferation and were not cytotoxic. Compound 1 may have potential as an anti-angiogenic and anti-tumor agent.

Anti-angiogenic activity of sesterterpenes; natural product inhibitors of FGF-2-induced angiogenesis.

Angiogenesis, the growth of new blood vessels from the pre-existing vasculature is of physiological and pathological importance. We have investigated the anti-angiogenic potential of two naturally occurring sesterterpenes, leucosesterterpenone (compound 1) and leucosterlactone (compound 2) isolated from the Himalayan plant Leucosceptrum canum and identified as having biological activity in preliminary screening. Compound 1 inhibited fibroblast growth factor-2-induced proliferation, migration in a wounding assay, chemotaxis and tube formation with small vessel (human dermal) and large vessel (bovine aortic) endothelial cells while compound 2 was largely inactive. Both compounds were also active in an in vivo angiogenic model using the chick chorioallantoic membrane. Neither compounds showed inhibitory activity in the absence of fibroblast growth factor-2. We were able to demonstrate in a binding assay that compounds 1 and 2 bound to the fibroblast growth factor-2 receptor-1 with IC(50) values of 1.4 +/- 0.956 and 132.47 +/- 7.90 muM, respectively, with a concomitant down regulation of phosphorylated ERK1/2 but did not bind to receptor-2. Compound 1 was less hydrophobic than compound 2 and this may contribute to its increased activity. Compound 1 is a new addition to the small number of inhibitors of fibroblast growth factor-2-induced angiogenesis. The compound was a specific inhibitor in that it had no effect on vascular endothelial growth factor or epithelial growth factor-induced angiogenesis. Since angiogenesis is essential for tumour development we conclude that these compounds may have potential as anti-tumour agents.

Leukaemia inhibitory factor is over-expressed by ischaemic brain tissue concomitant with reduced plasma expression following acute stroke.

Leukaemia inhibitory factor (LIF) is a glycoprotein of the interleukin-6 family, which has potent pro-inflammatory properties and is involved in regulation of neuronal differentiation. We have previously identified its upregulation in gene microarrays following acute ischaemic stroke in man. LIF expression and localization was measured in human ischaemic stroke autopsy specimens, in a rat model of middle cerebral artery occlusion (MCAO) and in human foetal neural cell cultures following oxygen-glucose deprivation (OGD) by Western blotting and immunohistochemistry. Circulating LIF was determined in the plasma of patients in the hyper-acute stroke phase using a multiplex enzyme-linked-immunosorbent serologic assay system. Patients demonstrated an increase in LIF expression in peri-infarcted regions with localization in neurons and endothelial cells of microvessels surrounding the infarcted core. The rat MCAO model showed similar upregulation in neurons with a peak increase at 90 min. Circulating serum LIF expression was significantly decreased in the hyper-acute phase of stroke. Brain-derived neurons and glia cultured in vitro demonstrated an increase in gene/protein and protein expression respectively following exposure to OGD. Increased LIF expression in peri-infarcted regions and sequestration from the peripheral circulation in acute stroke patients are characteristic of the pathobiological response to ischaemia and tissue damage.

Atherothrombosis and plaque heterology: different location or a unique disease?

Formation of unstable plaques frequently results in atherothrombosis, the major cause for ischaemic stroke, myocardial infarction and peripheral arterial disease. Patients who have symptomatic thrombosis in one vascular bed are at increased risk of disease in other beds. However, the development of the disease in carotid, coronary and peripheral arteries may have different pathophysiology suggesting that more complex treatment protocols may have to be designed to reduce plaque development at different locations. In this review we describe the known risk factors, compare the developmental features of coronary and carotid plaque development and determine their association with end-point ischaemic events. Differences are also seen in the genetic contribution to plaque development as well as in the deregulation of gene and protein expression and cellular signal transduction activity of active cells in regions susceptible to thrombosis. Differences between carotid and coronary artery plaque development might help to explain the differences in anatomopathological appearance and risk of rupture.

A mathematical model relating response durations to amount of subclinical resistant disease.

A mathematical model is presented which seeks to determine, from examination of the response durations of a group of patients with malignant disease, the mean and distribution of the resistant tumor volume. The mean tumor-doubling time and distribution of doubling times are also estimated. The model assumes that in a group of patients there is a log-normal distribution both of resistant disease and of tumor-doubling times and implies that the shapes of certain parts of an actuarial response-duration curve are related to these two factors. The model has been applied to data from two reported acute leukemia trials: (a) a recent acute myelogenous leukemia trial was examined. Close fits were obtained for both the first and second remission-duration curves. The model results suggested that patients with long first remissions had less resistant disease and had tumors with slower growth rates following second line treatment; (b) an historical study of maintenance therapy for acute lymphoblastic leukemia was used to estimate the mean cell-kill (approximately 10(4) cells) achieved with single agent, 6-mercaptopurine. Application of the model may have clinical relevance, for example, in identifying groups of patients likely to benefit from further intensification of treatment.

Localization of radioiodine conjugated to the monoclonal antibody HMFG2 in human ovarian carcinoma: assessment of intravenous and intraperitoneal routes of administration.

The localization of i.p. injected, radioiodine conjugated monoclonal antibody HMFG2 was studied in 18 patients with ovarian carcinoma. Patients were injected i.p. at time points up to 168 h before laparotomy, at which time tumor, ascites, normal tissue, and blood samples were removed and the contained radioactivity measured. In the first 10 patients, localization was compared with that of a simultaneously injected irrelevant (nonspecific) antibody (UJ13A) of the same immunoglobulin class and, in the subsequent 8 patients, with HMFG2 administered i.v. After i.p. injection, HMFG2-radioiodine was found in concentrations of 0.0001-0.0030% of the injected amount per gram in solid tumor, 0.0363-0.02560%/g in ascites, 0.0003-0.0017%/g in blood, and 0.001-0.0012%/g in normal tissue. Tumor:normal tissue ratios of 0.9-10.0 and tumor:blood ratios of 0.3-4.0 were seen up to 168 h after injection. Localization of the HMFG2 conjugate was consistently greater than that of the irrelevant antibody. For solid tumor, the i.v. route of administration resulted in consistently higher absolute levels of HMFG2 conjugate uptake but tumor:blood and tumor:normal tissue ratios were similar. On the other hand the i.p. route of administration offered consistent advantages of 4- to 71-fold over the i.v. route when HMFG2 conjugate localization on ascites cells was examined. Ascites:normal tissue and ascites:blood ratios of up to 512 and 448, respectively, were achieved. After i.p. injection, radioiodine was cleared from the body exponentially with a half-life of 50 h. Maximum circulating blood levels of 8.6 +/- 2.0% injected activity were seen at 48 h and these then decreased with a t 1/2 value of 38 h. Over 80% of injected activity was cleared in the urine as nonprotein bound iodine by 168 h.

Predicting etoposide toxicity: relationship to organ function and protein binding.

PURPOSE: To investigate the effect of organ function on total and free etoposide pharmacokinetics and hematologic toxicity. PATIENTS AND METHODS: Seventy-two patients who received single-agent intravenous (i.v.) etoposide over 5 or 8 days (total dose, 500 mg/m2) were studied. Pharmacokinetic parameters were derived after analysis of total plasma etoposide by high-performance liquid chromatography (HPLC) with ultraviolet (UV) detection, and etoposide protein binding by ultrafiltration of an etoposide-spiked, pretreatment serum sample, followed by HPLC analysis. Free etoposide area under the concentration-time curve (AUC) was derived from the total AUC and protein binding. RESULTS: Patients with renal impairment (serum creatinine level > 130 mumol/L) had a lower plasma etoposide clearance (13.6 v 18.5 mL/min/m2; P = .016), resulting in an increased total-drug and free-drug AUC (total etoposide AUC 615 v 452 micrograms/mL.hr; P = .016; free etoposide AUC 26.0 v 17.6 micrograms/mL.hr; P = .026) and increased hematologic toxicity (nadir neutrophil count 0.3 v 1.9 x 10(9)/L; P = .005). Patients with albumin levels less than 35 g/L had no change in total etoposide kinetics but had an increase in unbound etoposide (5.2% v 4.1%; P = .01), resulting in an increase in free etoposide AUC (27.5 v 16.5 micrograms/mL.hr; P = .003) and more profound toxicity (nadir neutrophil count 0.6 v 1.9 x 10(9)/L; P = .004). In patients with normal albumin and creatinine, increased toxicity in those older than 65 years was associated with a reduced drug clearance, and in those with increased liver enzymes by a trend toward an increase in free etoposide AUC. CONCLUSION: Increased hematologic toxicity after etoposide in patients with abnormal organ function is mediated by an increase in free etoposide AUC. A reduction in dose is clearly indicated in such patients.

Subcutaneous infusion of bleomycin--a practical alternative to intravenous infusion.

The phase specificity and short half-life of bleomycin make it likely that it would be more effective when administered by continuous infusion. This is supported by studies using cell lines, as well as by animal studies and clinical experience in humans. This study was conducted to compare the pharmacokinetics of intravenous (IV) and subcutaneous infusions of bleomycin. The serum concentrations of bleomycin were measured using a sensitive and specific radioimmunoassay. The results demonstrate similar plasma concentrations and area under the curve for both routes. The subcutaneous infusions were well tolerated, without local discomfort or excoriation. Subcutaneous infusion of bleomycin may thus offer a practical alternative to IV infusions and can be administered to patients who are ambulatory and out of hospital.

Effect of dose and schedule on pharmacokinetics of high-dose cytosine arabinoside in plasma and cerebrospinal fluid.

The pharmacokinetics of high-dose cytosine arabinoside (ara-C) were studied in 18 patients with acute leukemia and high-grade non-Hodgkin's lymphoma. The plasma concentrations of ara-C increased in proportion to the dose over a range of 1-3 g/m2. The initial and terminal half-lives were not influenced by the dose or schedule of administration and no accumulation of ara-C occurred with repeated dosage in the same patients. These data suggest that cytidine deaminase is not saturated within this dose range. The cerebrospinal fluid (CSF) concentrations of ara-C also rose linearly with the increase in dose and varied from 347 ng/mL (1 g/m2) to 1,070 ng/mL (3 g/m2). The mean CSF concentrations of ara-C following high-dose infusions over three hours were 6%-22% of simultaneous plasma concentrations. Three hours after completion of the intravenous infusion the CSF concentrations were greater than the corresponding plasma concentrations owing to the long half-life of ara-C in CSF compared to that in plasma. These data demonstrate that therapy with intravenous high-dose ara-C given twice daily provides continuous levels in the CSF at concentrations that are likely to be of value in the treatment of central nervous system leukemia.

A randomized trial of two etoposide schedules in small-cell lung cancer: the influence of pharmacokinetics on efficacy and toxicity.

PURPOSE: Etoposide is a schedule-dependent drug, as demonstrated by the superiority of 5 consecutive daily infusions over a continuous 24-hour infusion in patients with small-cell lung cancer. A randomized trial has therefore been conducted to compare an extended 8-day regimen with the 5-day schedule. PATIENTS AND METHODS: Ninety-four patients with small-cell lung cancer (35 limited disease, 59 extensive disease) were randomized to receive single-agent etoposide 500 mg/m2, either as 5 daily 2-hour infusions of 100 mg/m2 or as 8 daily 75-minute infusions of 62.5 mg/m2, both repeated every 3 weeks for six cycles. Single-agent carboplatin was administered at relapse in both arms of the study. Patients were stratified at randomization according to extent of disease and Karnofsky performance status (KPS). RESULTS: The overall response rate was 81% in the 5-day arm and 87% in the 8-day arm, with median survival durations of 7.1 and 9.4 months, respectively (no significant differences). The time over which plasma etoposide exceeded low plasma concentrations was significantly longer in patients who responded compared with patients who did not respond. This was most significant for time at concentrations greater than 1, 1.5, and 2 micrograms/mL. Hematologic toxicity was significantly worse in the 5-day arm of the study (cycle no. 1 nadir neutrophil count, 0.8 x 10(9)/L v 1.7 x 10(9)/L). Stepwise regression analysis found duration of exposure to plasma etoposide greater than 3 micrograms/mL to be predictive of nadir neutrophil count and duration of exposure to plasma etoposide greater than 2 micrograms/mL to be predictive of nadir WBC count. CONCLUSION: The 5-day and 8-day regimens had equivalent activity in small-cell lung cancer. A pharmacokinetic association between concentrations of etoposide and response and toxicity was found. Antitumor activity was associated with the maintenance of lower levels of etoposide than found to be associated with hematologic toxicity. This supports the hypothesis that the schedule of etoposide administration may affect efficacy and toxicity, and that prolonged exposure to low concentrations of etoposide may improve the therapeutic ratio for this drug.