Age-related accumulation of B-1 cell progenitors in mice reflects changes in miR15a/16-1 expression and radioresistance capacity.

Hyperproliferative diseases such as Chronic Lymphocytic Leukemia (CLL) and Systemic Lupus Erythematosus (SLE) are potentially related to some disturbance in the apoptosis pathway, specifically in B-1a cells (CD5+). Accumulation of B-1a cells in lymphoid organs, bone marrow or periphery is observed in some leukemia experimental murine models along aging. It is known that aging also increases the healthy B-1 cell population. However, it is not yet clear if it happens due to self-renewal of mature cells or proliferation of progenitor cells. Herein we demonstrated that the B-1 cell precursor population (B-1p) from bone marrow of middle-aged mice is higher than from young mice. Also, these aged cells are more resistant to irradiation and have downregulation of microRNA15a/16. Alterations in these microRNAs expression and in Bcl-2 regulation were already described in human hematological malignancies and new therapeutically approaches focus on that axis. This finding could explain the early events related to cell transformation during aging and correlate with beginning of symptoms in hyperproliferative diseases. Moreover, studies have already reported these pro-B-1 as a contributor to the origin of other leukemia (Acute Myeloid Leukemia - AML). Our results point to a possible relation between B-1 cell precursors and hyperproliferation during aging. We hypothesized that this population could be maintained until the mature status of the cell or reveal changes that result in re-activation of precursor in adult bone marrow, culminating in accumulation of B-1 cells later. Based on this, B-1 cell progenitor could represent an origin for B cell malignancies and a new candidate target to diagnose and treatments in the future.

Esterification of p-Coumaric Acid Improves the Control over Melanoma Cell Growth.

Previous studies reported that p-coumaric acid modulates melanoma growth. Because the esterification of p-coumaric acid (p-CA) enhanced its activity as an antimelanogenic agent, we aimed to determine the antitumor potential of two derivatives, the ethyl and butyl esters, against the murine B16-F10 and the human SK-MEL-25 melanoma cells. Cell viability was determined in vitro by the lactate dehydrogenase release and violet crystal absorption assays. The cell proliferation rate and cell cycle behavior were determined by the colony formation assay and flow cytometry analysis. Although p-CA, at the concentration of 1 mM, failed to exert a significant antitumor activity, the ethyl and butyl ester derivatives caused substantial tumor cell death at doses < 1 mM. Despite a reduction in their direct cytotoxicity at minor doses, both products controlled the melanoma growth by arresting the cell cycle at the G0/G1 (B16-F10) or S/G2 (SK-MEL-25). Furthermore, the in vivo experiments showed that the butyl ester derivative suppressed the lung B16-F10 burden, compared to the p-CA-treated mice. Thus, the esterification of p-coumaric acid improved the control over the proliferation of murine and human melanoma cells and can be considered an approach for designing novel anticancer agents.

Prevalence, intensity and identity of bacteraemia following conservative dental procedures in children.

INTRODUCTION: The aim of this study was to investigate the prevalence, intensity and microbial identity of bacteraemia following conservative dental procedures. The procedures were placement of rubber dam, use of the fast drill, use of the slow drill and placement of a matrix band and wedge. METHOD: Two hundred and five children and adolescents undergoing general anaesthesia for dental treatment at the Eastman Dental Hospital were recruited. Each subject was randomly allocated to one of the procedure groups. A baseline blood sample was taken before any dental treatment was carried out. A second blood sample was taken 30 s after a single conservative procedure. The blood samples were processed using lysis filtration. All bacterial isolates were identified using comparative 16 S ribosomal RNA gene sequencing. Oral Streptococcus spp. and coagulase-negative Staphylococcus spp. were further identified by comparative sodA gene sequencing. RESULTS: The prevalence of bacteraemia was significantly greater following placement of rubber dam (P = 0.01) and placement of matrix band and wedge, compared with baseline. The intensity of bacteraemia was significantly greater following placement of rubber dam (P = 0.001) and placement of matrix band and wedge (P = 0.0001). The most frequently isolated bacteria were Streptococcus spp. (56%), Actinomyces spp. (15%) and coagulase-negative Staphylococcus spp. (15%). CONCLUSION: Conservative dental procedures are a significant cause of bacteraemia.

The transcriptome of Cryptosporidium oocysts and intracellular stages.

Human cryptosporidiosis is caused primarily by two species of apicomplexan parasites, Cryptosporidium parvum and C. hominis. Although infection of cell monolayers with sporozoites does not support the complete parasite life cycle, the in vitro system is used to study the asexual phase of multiplication, which consists of two generations of merogony. To better understand host-parasite interaction and to gain insight into gene regulatory processes driving the complex life cycle of Cryptosporidium parasites, we analyzed the transcriptome of C. parvum in oocysts, sporozoites and infected cell monolayers 2-48 h post-infection. Analysis of RNA-Seq data from replicate oocyst, sporozoite and intracellular samples revealed significant differences between transcriptomes expressed outside and inside the host cell. Compared to the transcriptome found in the host cell, the oocyst transcriptome is less diverse. Biological processes significantly over-represented intracellularly relate to biosynthetic processes. Genes significantly overexpressed in oocysts show evidence of specialized functions not found in other Apicomplexa. A more comprehensive view of gene regulation during the Cryptosporidium life cycle will require the analysis of later time points during the infection, particularly of the poorly studied sexual phase of the life cycle.

Periodontal Ligament Visibility (PLV): validation of PLV to determine adult status.

BACKGROUND: Gradual obliteration of the Periodontal Ligament Visibility (PLV) of lower third molars indicates increasing age. This is used to help determine whether or not an age disputed subject is above or below the 18 year threshold. AIM: The main focus was to determine, in test subjects of known age, whether the PLV system used 'blind' is able to reliably indicate whether the subject was a child (age < 18 years) or adult (age > 18). MATERIALS AND METHODS: A total of 250 normal subjects in the age range 16 to 26 years, from the archives of Guy's Hospital in London, UK, were used to validate the system of PLV. The radiographic assessment of PLV1 was used to categorize four grades of PLV. RESULTS: It was found that for both females and males PLV-C and PLV-D gave very high probabilities (p = 1.000) of the test subjects being of adult status. CONCLUSION: Periodontal Ligament Visibility has the potential to play an important part in the assessment of age disputed asylum seekers who look adult and claim to be children.

In our opinion.

The misleading statements made in the British Dental Journal in the December 2016 issue relating to dental age assessment are assessed for inaccuracies and negligent omission of the issue of Child Protection. It is emphasised that there is a need for the approach of objective knowledge viz. not influenced by personal feelings or opinions in considering and representing facts. The article by the Chair of the Education, Ethics, and Team Working Group implies that unsatisfactory consent procedures are followed. The DARLInG (Dental Age Research London Information Group) have followed a carefully prescribed procedure that fulfils all the requirements of the advice given by the Consent Committee at King's College Hospital. In addition, the active support in the form of independent support workers and lawyers assisted by interpreters is described. The issue of the lawful use of ionising radiation is described with correct information about where this information can be obtained. The seriously misleading statements made by the Chair of the Education, Ethics and Education Working Group are identified. An unacceptable oversight is the failure of the BDA representatives to draw attention to the need for child protection. The potential benefit of dental age estimation in terms of appropriately providing support for asylum seekers is described.The failure of the BDA Ethics group to be up to date with recent research which shows a high level of certainty in assigning age disputed subjects to above (or below) the 18-year threshold is discussed and the importance of this in reliably determining, in an objective way, the age status of asylum seekers. The incorrect and salacious use of the term 'X-rated' is highlighted and a formal request for its withdrawal has been made.

Phase I and clinical pharmacology trial of crisnatol (BWA770U mesylate) using a monthly single-dose schedule.

Crisnatol is a novel lipophilic arylmethylaminopropanediol with significant antineoplastic activity in a variety of murine and human tumor models which functions as a DNA intercalator. In this Phase I trial, a 6-h infusion of the drug was administered i.v. in 700 to 1500 ml of 5% dextrose in water every 28 days. Eighty-five courses at doses of 7.5 to 516 mg/m2 were administered to 43 patients with refractory solid tumors. Reversible neurological toxicity was dose limiting at 516 mg/m2 and was manifested as somnolence, dizziness, blurred vision, unsteady gait, and alpha-slowing on electroencephalogram at the end of infusion. All neurological signs and symptoms were reversible. No hematological toxicity was observed. Other toxicities included phlebitis, mild to moderate nausea and vomiting, reversible sinus node arrest in one patient, and hypertension. Crisnatol plasma concentrations were determined by high-pressure liquid chromatography. After infusion, plasma concentrations declined biexponentially with a terminal t1/2 of 2.9 h. Using a two-compartment model, the mean apparent volume of distribution at steady state and total-body clearance were 58.8 liters/m2 and 18.3 liters/h/m2, respectively, indicative of extensive tissue distribution and rapid hepatic clearance. Peak plasma levels occurred at the end of infusion and correlated with the onset of neurological toxicity. The recommended Phase II dose for this schedule is 388 mg/m2.

Phase I and clinical pharmacology trial of 502U83 using a monthly single dose schedule.

502U83 is an arylmethylaminopropanediol derivative exhibiting significant antineoplastic activity in a number of murine and human tumor models. In this Phase I trial, a 1-h or 4-h infusion of the agent was administered i.v. in 250 ml of 5% dextrose in water every 28 days. Fifty-three courses at doses of 25 to 2000 mg/m2 were administered to 36 patients with refractory solid tumors. Prolongation of the PR, QRS, and QT intervals on electrocardiograms was dose limiting at 2000 mg/m2. This prolongation appeared dose related and was reversible upon discontinuation of the infusion. No hematological toxicity was observed. Other toxicities included only sporadic and mild to moderate nausea and vomiting. No tumor responses were noted. 502U83 plasma concentrations were determined by high-pressure liquid chromatography. Complete pharmacokinetic profiles were obtained for 21 of the 36 patients. After infusion, plasma concentrations declined in a biexponential or in a triexponential manner with a harmonic mean terminal t 1/2 of 8.83 h. Using a three-compartment model, the mean apparent volume of distribution at steady state and total-body clearance were 195 liters/m2 and 42.5 liters/h/m2, respectively, indicative of extensive tissue distribution. No correlation could be found between the pharmacokinetic parameters and prolongation of the cardiac conduction intervals. Because of the cardiac effects with the drug, the schedule of administration of 502U83 used in this study cannot be recommended.

Phase I study of pharmacological and immunological effects of human lymphoblastoid interferon given to patients with cancer.

An extensive Phase I evaluation of human lymphoblastoid interferon has been completed which, in addition to describing its clinical and pharmacological effects, emphasized a broad-scale evaluation of the immune response as a function of interferon dosage. Dose-limiting toxicity was generally due to constitutional symptoms which are remarkably similar to those produced by influenza, although transient peripheral and central neurotoxicity (including deterioration in cognitive and behavioral functions) is observed at higher doses. It is difficult to establish "clean" dose-response effects except for fever and bone marrow suppression, neither of which is a major dose limitation. Enhancement of the immune system was limited to natural killer cells which had a complex dose-response relationship, whereby low interferon concentrations were less stimulatory (than were high doses) following a single dose but gave more sustained stimulation over a 5-week course of 3 times per week i.m. administration. The effects on various measures of monocyte function and of nonspecific immunity (hypersensitivity, immunoglobulins, complement) were negative. We suspect that in practice it may be difficult to exploit the narrow dosage window of immunostimulation, but it is important to note that the nontoxic lower doses were more stimulatory than were the very high doses which are being used in numerous clinical trials.

Phase I clinical and pharmacologic study of eniluracil plus fluorouracil in patients with advanced cancer.

PURPOSE: To determine the highest dose of fluorouracil (5-FU) that could be safely administered with Eniluracil (776C85; Glaxo Wellcome Inc, Research Triangle Park, NC), an inactivator of dihydropyrimidine dehydrogenase (DPD), on a daily schedule for 5 days, and to define the toxicities of the combination and the pharmacokinetics of 5-FU when administered with 776C85. PATIENTS AND METHODS: Patients with advanced solid tumors refractory to standard therapy were enrolled at two institutions. The study consisted of three periods designed to evaluate the safety, pharmacokinetics, and pharmacodynamics of 776C85 alone (period 1); the effects of 776C85 on the pharmacokinetics of 5-FU (period 2); and the maximum-tolerated dose (MTD) of 5-FU, with or without leucovorin, that could be safely administered with 776C85 (period 3). Cohorts of at least three patients each received oral 776C85 alone at doses of 3.7 mg/m2/d, 18.5 mg/m2/d and 0.74 mg/m2/d. After a 14-day washout period, each patient then received 776C85 daily for 3 days, with a single intravenous (i.v.) bolus dose of 5-FU 10 mg/m2 on day 2. After a second washout period, patients were treated with 776C85 daily for 7 days and 5-FU i.v. bolus on days 2 through 6. The starting dose of 5-FU 10 mg/m2/d was escalated until the MTD was determined. After determination of the MTD of 5-FU given with 776C85, oral leucovorin 50 mg/d on days 2 through 6 was added to determine the MTD of 5-FU with leucovorin in the presence of 776C85. Near the completion of the study, additional cohorts of patients were treated with 776C85 at 50 mg/d and oral 5-FU with or without leucovorin. RESULTS: Sixty-five patients were enrolled onto the study and 60 were assessable for toxicity and response. Bone marrow suppression was the primary and dose-limiting toxicity of this regimen. Other toxicities included diarrhea, mucositis, anemia, anorexia, nausea, vomiting, and fatigue. 776C85 suppressed DPD activity in peripheral-blood mononuclear cells (PBMCs) by at least 90% for at least 24 hours at all dose levels tested. In the presence of 776C85, 5-FU half-life was prolonged, clearance was reduced, and the drug displayed linear pharmacokinetics. Recommended doses for further testing on a daily for 5-day schedule are 776C85 10 mg/d with i.v. 5-FU 25 mg/m2/d; 776C85 10 mg/d with i.v. 5-FU 20 mg/m2/d plus leucovorin 50 mg/d; 776C85 50 mg/d with 5-FU given orally at 15 mg/m2/d with leucovorin at 50 mg/d. CONCLUSION: 5-FU can be safely administered with 776C85; however, the MTDs are considerably lower than those conventionally used, caused, at least in part, by marked alterations in 5-FU plasma pharmacokinetics.

Pharmacokinetic, bioavailability, and feasibility study of oral vinorelbine in patients with solid tumors.

PURPOSE: The feasibility of administering vinorelbine (Navelbine, Burroughs Wellcome Co, Research Triangle Park, NC), a semisynthetic vinca alkaloid with broad activity, as a liquid-filled gelatin capsule was evaluated in a bioavailability (F) and pharmacokinetic study. PATIENTS AND METHODS: Each of 17 cancer patients had pharmacokinetic studies performed after receiving vinorelbine 30 mg/m2 intravenously (IV), which is the maximum-tolerated dose (MTD) for weekly IV administration, and twice after receiving the oral formulation at a nominal dose of 100 mg/m2. Subsequently, these patients and 10 other subjects received the oral formulation at a dose of 100 mg/m2/wk to evaluate the feasibility of chronic oral administration. RESULTS: Plasma drug disposition was well described by a triphasic model. Mean central volume of distribution and steady-state volume of distribution (Vss) were large (0.66 +/- 0.46 L/kg and 20.02 +/- 8.55 L/kg, respectively); the mean harmonic terminal half-life (t1/2) was long (18 hours); and the high mean clearance (CI) rate (0.80 +/- 0.68 L/h/kg) approached hepatic blood flow. F was low (0.27 +/- 12), and absorption was rapid (mean time of maximum plasma concentration [Tmax], 0.91 +/- 0.22 hours). Absorption parameters after the first and second oral doses were similar, with mean F values of 0.27 +/- 0.14 and 0.25 +/- 0.11, respectively. Coefficients of variability (CVs) for F, maximum plasma concentration (Cmax), and Tmax were 32%, 42%, and 78%, respectively, indicating moderate intraindividual variability. The pharmacologic profile of this oral formulation indicates that there is a large first-pass effect. Neutropenia was the principal toxicity of oral vinorelbine. Grade 3 or 4 neutropenia occurred in 63% of patients, but only 11% developed neutropenia and infection. Nausea, vomiting, and diarrhea were also common with oral administration, but these effects were rarely severe and could be ameliorated by using a divided-dose schedule and/or prophylactic antiemetic and antidiarrheal agents. The mean nominal oral dose was 82 mg/m2, and the mean percentage of intended dose that was received was 92%. Although dose escalations were permitted for negligible toxicity, doses were not escalated to greater than 100 mg/m2/wk in any patient. Vinorelbine given as a liquid-filled gelatin capsule at 100 mg/m2 provided equivalent pharmacologic exposure as 30 mg/m2 IV. CONCLUSION: The oral administration of vinorelbine, specifically as a liquid-filled, soft gelatin capsule, is a feasible route of administration. Weekly oral dosing at 100 mg/m2 induces a consistent degree of myelosuppression, but the high frequency of grade 3 or 4 neutropenia, albeit brief and uncomplicated, warrants the recommendation of a slightly lower starting dose, ie, 80 mg/m2/d, for subsequent phase II evaluations, especially in heavily pretreated patients.

Phase I and pharmacologic study of oral fluorouracil on a chronic daily schedule in combination with the dihydropyrimidine dehydrogenase inactivator eniluracil.

PURPOSE: To determine the maximum-tolerated dose (MTD), toxicities, and pharmacokinetics of oral fluorouracil (5-FU) administered twice daily in combination with oral eniluracil, an inactivator of dihydropyrimidine dehydrogenase, administered for 28 days every 35 days. PATIENTS AND METHODS: Oral 5-FU 1.35 mg/m(2) twice daily was administered with oral eniluracil 10 mg daily for 14 to 28 days, followed by a 1-week rest period. Eniluracil was started 1 day before 5-FU. Patients then received escalated doses of oral 5-FU 1. 35 to 1.8 mg/m(2) twice daily with an increased dose of eniluracil 10 mg twice daily for 28 days. A reduced dose of 5-FU 1.0 mg/m(2) with eniluracil 20 mg twice daily was evaluated. RESULTS: Thirty-six patients with solid malignancies were enrolled onto the study. Diarrhea was the principal dose-limiting toxicity of oral 5-FU and eniluracil given on this chronic schedule. The recommended phase II dose is 5-FU 1.0 mg/m(2) twice daily with eniluracil 20 mg twice daily. Mean (SD) values for terminal half-life, apparent volume of distribution, and systemic clearance of 4.5 hours (0.83 hours), 19 L/m(2) (3.0 L/m(2)), and 51 mL/min/m(2) (13 mL/min/m(2)), respectively. An average of 77% of 5-FU was excreted unchanged in urine after 28 days of treatment. The mean (range) 5-FU C(SS,min) values achieved at the 1.0 mg/m(2) dose level were 22 ng/mL (8 to 38 ng/mL). CONCLUSION: Chronic oral administration of 5-FU with oral eniluracil is tolerable and produces 5-FU steady-state concentrations similar to those achieved with protracted intravenous administration of 5-FU on clinically relevant dose schedules. Eniluracil provides an attractive means of administering 5-FU on protracted schedules.

The clinical pharmacokinetics of vinorelbine (Navelbine).

Vinorelbine (Navelbine; Burroughs Wellcome Co, Research Triangle Park, NC; Pierre Fabre Médicament, Paris, France) is a semisynthetic vinca alkaloid agent that has been structurally modified on the catharanthine nucleus to impart increased lipophilicity. As a result, vinorelbine appears to possess a higher therapeutic index and different pharmacokinetic properties from other marketed vinca alkaloids. Vinorelbine has been quantified in biologic matrices by measurement of total radioactivity, radioimmunoassay, and high-performance liquid chromatography. Because it is specific for the parent drug, high-performance liquid chromatography has generated the most reliable pharmacokinetic data. Vinorelbine is highly bound to platelets and lymphocytes, and is also bound to alpha 1-acid glycoprotein, albumin, and lipoproteins. The drug undergoes significant metabolism and elimination via the liver and metabolites are excreted primarily in the bile. Two likely vinorelbine metabolites, vinorelbine N-oxide and deacetylvinorelbine, have been isolated and identified in human urine and very low concentrations appeared in plasma. Urinary excretion of unchanged drug accounts for less than 20% of an intravenous dose, with fecal elimination accounting for an additional 30% to 60%. The pharmacokinetic profile of vinorelbine after intravenous bolus or infusion is characterized by triexponential decay. Initial rapid decay is due primarily to distribution into tissues in the peripheral compartments. There is a prolonged terminal phase due to relatively slow efflux of the drug from peripheral compartments, which results in a long terminal phase half-life, with average values ranging from 27.7 to 43.6 hours. Plasma clearance of vinorelbine is high, approaching hepatic blood flow in humans, and its volume of distribution is large, indicating extensive extravascular distribution. In comparison to vinblastine or vincristine, vinorelbine has a higher clearance and a larger volume of distribution than either drug, and a half-life shorter than vinblastine but longer than vincristine. There is no relationship between the age of the patient and the pharmacokinetic parameters of vinorelbine, and coadministration of cisplatin does not appear to influence the pharmacokinetics of vinorelbine. Vinorelbine is the first vinca alkaloid to show promising efficacy following oral administration, and this has led to the development of a liquid-filled, soft-gelatin capsule dosage form. The absolute bioavailability of vinorelbine from this dosage form was 27% when intravenous doses of 30 mg/m2 were compared with oral doses of 100 mg/m2.

Oral health of children undergoing allogeneic bone marrow transplantation.

The objective of this study was to investigate changes in the oral health of children undergoing allogeneic bone marrow transplantation. The study group comprised 23 children undergoing allogeneic bone marrow transplantation and their matched controls. The study group comprised 23 children undergoing allogeneic bone marrow transplantation and their matched controls. Measurements were taken of the mean decayed, missing and filled surfaces and the mean decayed, missing and filled teeth in both deciduous and permanent dentition at baseline, the mean bacterial plaque and gingival inflammation indices and mucositis at specific event-related times during the transplantation period, were measured. The number of decayed, missing and filled surfaces in deciduous teeth was significantly greater in the transplant children than the matched controls (P < 0.05) at baseline. There was a significant increase in both the mean bacterial plaque score for the deciduous teeth (P < 0.003) and the permanent teeth (P < 0.001) and the mean gingival inflammation score for the deciduous (P < 0.001) and the permanent teeth (P < 0.001), at 7 days post-transplantation. At 4 months post-transplantation the plaque and gingival inflammation score had returned to baseline levels. There were significantly increased mean bacterial plaque and gingival inflammation scores during the period of intense immunosuppression following allogeneic bone marrow transplantation.

Antiemetic effect of intramuscular levonantradol in patients receiving anticancer chemotherapy.

Positive results of investigations of the antiemetic activity of delta-9-tetrahydrocannabinol (THC) in patients receiving cancer chemotherapy have led to the development of levonantradol, a synthetic derivative of THC. We assessed both the antiemetic activity and toxicity of intramuscular levonantradol in patients receiving cancer chemotherapy who were refractory to conventional antiemetic therapy. An open dose-finding study was conducted using initial doses of 0.5 mg. Doses were escalated by 0.5 mg when an incomplete response with no toxicity was observed. Of the 28 patients initially treated, 25/28 (89 per cent) achieved a complete or partial antiemetic response at doses ranging from 0.5 to 1.5 mg. There was no difference in response rate with respect to age or patient size. Of the 31 patients evaluable for toxicity, six reported none. Dysphoria, the dose-limiting toxicity, occurred in five patients (16 per cent) at 1.0 to 1.5-mg doses. The most commonly reported side effects were somnolence (48 per cent) and dry mouth (32 per cent). We conclude that intramuscular levonantradol is an effective antiemetic at doses as low as 0.5 mg.

Levonantradol for chemotherapy-induced emesis: phase I-II oral administration.

Thirty five patients were enrolled into a Phase I-II study of oral levonantradol being tested as an antiemetic for chemotherapy patients who were refractory to the aggressive use of standard antiemetic agents. Sixty-nine total courses were given. Dysphoric reactions (fear, anxiety, hallucinations) were the most serious side effects, and were most prevalent at the highest dose tested (2.0 mg q4h). Somnolence, a "high" feeling, hypotension were also noted. Antiemetic responses were seen at 0.5, 1.0, 1.5 and 2.0 mg dose levels: the two intermediate doses gave responses comparable to those previously reported for oral THC. It is suggested that a combination of oral and parenteral levonantradol may prove to be a very effective program to relieve the otherwise disabling problems of persistent nausea and vomiting.

The effects of food and divided dosing on the bioavailability of oral vinorelbine.

The effects of food and divided dosing on the bioavailability of a liquid-filled gelatin capsule formulation of vinorelbine (Navelbine), a semisynthetic vinca alkaloid with broad clinical activity, was evaluated in patients with advanced solid tumors. A group of 13 patients were randomized to treatment with the oral formulation at the recommended phase II dose of 80 mg/m2 per week either in the fasting state or after ingestion of a standard meal. Patients were treated 1 week later in the alternate state relative to their first dose. The effects of divided dosing were assessed during the 3rd week, at which time vinorelbine was administered in two divided doses. After the completion of pharmacokinetic and bioavailability studies, patients received the oral formulation at a dose of 80 mg/m2 per week in two divided doses to evaluate the feasibility of chronic oral drug administration. Both manipulations resulted in small, albeit statistically significant, reductions in the relative bioavailability of this oral formulation. The relative bioavailability decreased by 22 +/- 28% when treatment followed the ingestion of a standard meal, possibly due to a delay in gastrointestinal transit time. The mean time of maximum plasma concentration (Tmax) increased from 1.3 +/- 1.6 h in the fasting state to 2.5 +/- 1.6 h in the fed state, although this difference was not statistically significant. Similarly, the relative bioavailability declined by 16 +/- 51% when vinorelbine was administered in two divided doses. An analysis of dose proportionality revealed disproportionate increases in dose-normalized Cmax and AUC values with single oral doses above 120 mg, which may account for this phenomenon. The high clearance of vinorelbine, which approaches hepatic blood flow, and the lack of dose proportionality after oral administration, indicate that there is a large first-pass effect which may be saturable, or nonlinear, above single doses of 120 mg. In addition, the toxicological and pharmacological characteristics of oral vinorelbine indicate that treatment after a standard meal or on a divided dosing schedule is safe. Chronic oral administration of the agent in two divided doses was also well tolerated. However, the small reduction in the relative bioavailability following the ingestion of a standard meal and with divided dosing suggest the need for further pharmacodynamic studies to determine if reductions in drug exposure of this magnitude may portend diminished antitumor activity.

Phase I clinical and pharmacology study of 502U83 given as a 24-h continuous intravenous infusion.

502U83 is an arylmethylaminopropanediol that displays significant antitumor activity in a number of murine and human tumor-model systems. In the present phase I study, a 24-h continuous intravenous infusion of this agent was given every 28 days to patients with advanced or refractory solid tumors. In all, 46 patients received a total of 96 cycles of 502U83 at doses ranging from 25 to 8,000 mg/m2. No significant hematologic, gastrointestinal, or neurologic toxicity was observed. At doses of 2,000 mg/m2 and higher, prolongation of the corrected QT interval on ECG was evident in most patients but was completely reversible, was not associated with arrhythmias, and was not dose-limiting. Dose-limiting pulmonary toxicity characterized by acute onset of dyspnea, severe hypoxemia, interstitial pulmonary edema, and death occurred in three patients treated at the highest dose levels. Plasma concentrations of 502U83 and its metabolites were measured by high-performance liquid chromatography. The 502U83 maximal concentration (Cmax) and area under the concentration-time curve (AUC) were proportional to the delivered dose; however, substantial interpatient variability in total body clearance was noted at all dose levels. Significant conversion of 502U83 to two glucuronide metabolites was detected. Metabolite concentrations were highest in the three patients who succumbed to pulmonary toxicity, although the precise contribution of these metabolites to the observed toxic effects is unknown. In view of the unfavorable clinical profile of QTc prolongation and pulmonary toxicity produced by 502U83, further clinical development of this agent has been suspended.

Changes in the oral streptococcal flora of children undergoing allogeneic bone marrow transplantation.

The changes in the oral streptococcal flora of twenty children undergoing allogeneic bone marrow transplant are described. Saliva was collected from each child on four separate occasions: (i) before the conditioning regimen; (ii) 7 days post-transplantation; (iii) when the neutrophil count had risen above 0.5 x 10(9)/l; (iv) 119 days post-transplantation. Indices for dental caries, plaque, gingivitis, herpetic stomatitis and mucositis were also recorded. There was a significant decrease in the total aerobic (P<0.001) and anaerobic counts (P<0.0002) between baseline and 7 days post-transplantation. The proportion of the 'Streptococcus oralis group' (Streptococcus mitis and S. oralis) increased significantly from baseline 12.1% to 48.4% at 7 days post-transplantation (P<0.003). The plaque and gingivitis indices increased significantly from baseline to 7 days post-transplantation (P<0.001). Twenty percent of the children had either positive blood cultures or Hickman line cultures for the 'S. oralis group', and it is possible that the inflamed gingival tissues are a further site of entry for these streptococci. There were no differences in the total anaerobic counts or the proportion of the 'S. oralis group' between baseline and the end of the study in the transplant children, or between the transplant and control children.