Changes in the oral streptococcal flora following irradiation/chemotherapy for bone marrow transplantation.
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Bacteria, Aerobic↗
Biomedical subjects
V S Lucas
Publications and source records attributed to V S Lucas.
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.
Bone Marrow Transplantation↗
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.
Administration, Oral↗
Post-insertion visits in medicated complete denture wearers.
The effect of systemic disease and medication on the number of post-insertion visits was investigated in 157 patients requiring new complete dentures, who were referred to a specialist prosthodontic practice. We found that the number of recall visits increased with age, particularly in patients medicated for central nervous system or psychiatric disorders, and more so with cardiovascular diseases treated with diuretics.
Adult↗
Fungal feeding-line infection.
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Equipment Contamination↗
Growth of the nasal septum in the Snell strain of hypopituitary dwarf mouse.
The literature relating to experimental investigation of growth of the nasal septum has been reviewed in detail. A total of 156 skulls from the Snell hypopituitary mouse, six controls and six dwarfs at each age group were radiographed in lateral view to enable measurement of the different components of the nasal septum. By 80 days of age, the snout of the nasal septum in the Snell strain of mice was 56 per cent the size of the snout in normal mice (n = 12, t = 8.07, P = 0.0005). It is concluded that the Snell strain of mouse is an example of a specific genetic defect causing severe growth retardation of cartilaginous tissues, particularly the nasal complex.
Animals↗
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.
Absorption↗
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.
Animals↗
Patterns of breast and bottle feeding and their association with dental caries in 1- to 4-year-old South African children. 2. A case control study of children with nursing caries.
In a case control study, 109 children with nursing caries (> or = 2 decayed, missing, or filled labial or palatal surfaces of primary incisor teeth) were matched for age, race, gender, and social class to 109 children without nursing caries from the same study areas. Mean dmfs and dmft scores were statistically higher in the nursing caries group but no statistically significant differences were found for feeding patterns between the groups in relation to the prevalence of nursing caries. In the present study nursing caries was found to be unrelated to the length of type of feeding (breast or bottle).
Bottle Feeding↗
Erythema migrans: an unusual presentation.
A case of erythema migrans affecting the attached gingivae and the upper and lower labial mucosa is described. No lesions were found on the tongue although this is the site most commonly affected.
Adult↗
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.
Adult↗
Diseases, medication, and postinsertion visits in complete denture wearers.
The records of 268 patients were used to assess the effects of five disease/drug complexes on the number of postinsertion visits in complete denture wearers. The data were analyzed with SAS and BMDP computer packages. The results showed a statistically significant increase in the number of postinsertion visits in patients who had central nervous system or psychiatric disorders. Practitioners are alerted to consider the ergonomic implications at the outset of treatment.
Adult↗
Association of psychotropic drugs, prevalence of denture-related stomatitis and oral candidosis.
The aims of this study were 1) to determine the association between the prevalence of denture-related stomatitis and oral candidosis in patients undergoing long-term treatment with psychotropic drugs and 2) to identify the relationships between an increased prevalence of oral candidosis, denture cleanliness, dietary habits and cigarette smoking in these patients. Clinical and laboratory investigation of psychiatric patients under treatment with psychotropic drugs and who were wearing complete maxillary dentures, compared with control (non-psychiatric) patients revealed that 1) the isolation frequency of candida was 64.7% compared with 33.3% in the controls; 2) palatal inflammation was present in 74.5% compared with 55% of the controls; 3) oral staphylococcus carriage was present in 56.9% compared with 17.6% of the controls; 4) cigarette smoking, sugar consumption and a poor standard of denture hygiene were more common in the psychiatric patients than in the controls.
Aged↗
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.
Adult↗
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.
Adult↗
Maxillary myxoma in a child of 11 months. A case report.
A myxoma of the maxilla in an infant is presented. It was initially treated as an inflammatory lesion. Failure to respond led to biopsy, which showed that the lesion was neoplastic; initially an incorrect diagnosis was made and totally inappropriate treatment was given. Reassessment of the biopsy material established the correct diagnosis and appropriate management was initiated.
Combined Modality Therapy↗
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.
Adult↗
Emesis as a critical problem in chemotherapy.
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Antiemetics↗