Oral topotecan as single-agent second-line chemotherapy in patients with advanced ovarian cancer.

PURPOSE: To evaluate oral topotecan as single-agent, second-line therapy in patients with ovarian cancer previously treated with a platinum-based regimen. PATIENTS AND METHODS: Patients (N = 116) received oral topotecan 2.3 mg/m2 daily for 5 days every 21 days. Eligibility criteria included histologic diagnosis of International Federation of Gynecology and Obstetrics stage III or IV epithelial ovarian cancer, bidimensionally measurable disease, prior platinum-containing chemotherapy, age > or = 18 years, performance status < or = 2, and life expectancy > or = 12 weeks. RESULTS: Overall response rate was 21.6% (25 of 116 patients). Median duration of response was 25.0 weeks; median time to response was 8.4 weeks. Median time to progression was 14.1 weeks; median survival was 62.2 weeks. Grade 4 neutropenia was experienced by 50.4% of patients in 13.4% of courses administered. Grade 4 thrombocytopenia was experienced by 22.1% of patients in 5.1% of courses. Grade 3 or 4 anemia was experienced by 29.2% of patients in 8.5% of courses. Most frequent nonhematologic toxicities were predominantly (> 90%) grade 1 or 2 and included nausea, alopecia, diarrhea, and vomiting. CONCLUSION: Second-line oral topotecan administered at 2.3 mg/m2 for 5 days every 21 days demonstrated activity in patients with progressive or recurrent ovarian cancer after first-line platinum-based chemotherapy. This activity was comparable to that seen in previous studies with intravenous topotecan. Grade 4 neutropenia was less frequent with oral topotecan than previously reported for intravenous topotecan. Oral topotecan is an active, tolerable, and convenient formulation of an established agent for the second-line treatment of advanced epithelial ovarian cancer and may also facilitate exploring prolonged treatment schedules.

Trophic effects of essential fatty acids on pig skin.

The daily oral administration of 3 ml of two oils (So-5407 and So-1129) containing essential fatty acids (EFAs) for 16 weeks resulted in a transient increase in cell proliferative activity in the skin of female Large White pigs. The So-5407 oil contained 7% gamma-linolenic acid (GLA) whereas So-1129 was an oil of similar composition, but with no GLA. Hyperplasia of the epidermis was observed after the administration of both oils, and this was characterized by an increase in the size of the rete pegs. The maximum effect occurred at 4 weeks after the start of oil administration, at which time the number of viable cell layers had increased by a factor of approximately 1.5, and mean epidermal thickness (excluding the stratum corneum) was approximately 40% greater than that of the epidermis prior to oil administration. There was a marked increase in the labelling index (LI) of the basal cell layer of the epidermis in pigs receiving So-5407. Maximum LIs were quantified at 4 weeks after the start of administration and were 18.8 +/- 1.3% and 13.1 +/- 1.7% for pigs receiving So-5407 and So-1129, respectively. After this time the LI declined progressively and had returned to values within normal limits (P > 0.1) by 8 weeks after the start of administration of both oils. A similar pattern of change in the LI was seen in the follicular epithelium, although the peak values at 4 weeks after the start of oil administration of 12.2 +/- 1.8% and 10.8 +/- 0.9 for the groups receiving So-5407 and So-1129, respectively, were lower than in the epidermis. Labelled cells were also counted in the papillary dermis and maximum values were again seen at 4 weeks after the start of oil administration. Of the two oils, So-1129 had the greatest effect, with the number of labelled cells in the papillary dermis being a factor of three to four-fold higher than in skin prior to oil administration, between 2 and 12 weeks after the start of administration.

Modulation of the cell kinetics of pig skin by the topical application of evening primrose oil or Lioxasol.

The daily topical application of two compounds, a cream containing 10% evening primrose oil (EPO) and Lioxasol (a compound used clinically to treat radiation burns), resulted in increased cell proliferative activity in the skin of female Large White pigs. The effect was most pronounced in the case of the EPO based cream, and was comparable in magnitude with that observed in a previous study on pig skin using orally administered EPO. There was an increase in the size of the rete pegs in the epidermis by 6 weeks after the start of application of the EPO cream. However, this did not translate into an increase in the total thickness of the viable epidermis (excluding the stratum corneum) due to a reduction in the density of rete pegs, from 2 weeks after treatment. Lioxasol had no overall effect on the size of the rete pegs. The labelling index (LI) of cells in the basal layer of the epidermis of pigs receiving a daily topical application of EPO increased progressively with time from the start of application. The LI was maximal (17.9 +/- 2.4%) at the end of the observation period (8 weeks) at which time it was a factor of approximately 2 higher than in the basal layer prior to treatment. A considerably less marked increase in the LI of the basal layer was seen after the application of Lioxasol. The overall increase was approximately 20%, relative to the LI in the untreated epidermis. Labelled cell nuclei were also counted in the papillary dermis. After the application of the EPO cream, no significant increase in the number of labelled cells was observed until week 8, at which time values were approximately twice those in untreated skin. In Lioxasol treated skin the effect on the numbers of labelled cells in the papillary dermis was more immediate, with a approximately 60% increase at 2 weeks. This enhanced level of labelling was maintained until the end of the observation period of 10 weeks. Studies on the cell kinetics of the skin using the alcohol component of the Lioxasol preparation suggested that alcohol rather than Lioxasol was the most significant ingredient. It was concluded that the EPO cream merited further evaluation as a potential modulator of skin response to ionizing radiation.

Amelioration of both early and late radiation-induced damage to pig skin by essential fatty acids.

PURPOSE: To evaluate the possible role of essential fatty acids, specifically gamma-linolenic and eicosapentaenoic acid, in the amelioration of early and late radiation damage to the skin. METHODS AND MATERIALS: Skin sites on the flank of 22-25 kg female large white pigs were irradiated with either single or fractionated doses (20 F/28 days) of beta-rays from 22.5 mm diameter 90Sr/90Y plaques at a dose rate of approximately 3 Gy/min. Essential fatty acids were administered orally in the form of two 'active' oils, So-1100 and So-5407, which contained gamma-linolenic acid and a mixture of that oil with eicosapentaenoic acid, respectively. Oils (1.5-6.0 ml) were given daily for 4 weeks prior, both 4 weeks prior and 10-16 weeks after, or in the case of one single dose study, just for 10 weeks after irradiation. Control animals received a 'placebo' oil, So-1129, containing no gamma linolenic acid or eicosapentaenoic acid over similar time scales before and after irradiation. Acute and late skin reactions were assessed visually and the dose-related incidence of a specific reaction used to compare the effects of different treatment schedules. RESULTS: A reduction in the severity of both the early and late radiation reactions in the skin was only observed when 'active' oils were given over the time course of the expression of radiation damage. Prior treatment with oils did not modify the radiation reaction. A 3.0 ml daily dose of either So-1100 or So-5407 given prior to, but also after irradiation with single and fractionated doses of beta-rays produced the most significant modification to the radiation reactions, effects consistent with dose modification factors between 1.06-1.24 for the acute reactions of bright red erythema and/or moist desquamation, and of 1.14-1.35 for the late reactions of dusky/mauve erythema and dermal necrosis. There was the strong suggestion of an effect produced by the 'placebo' oil, So-1129, after higher daily doses of oil. CONCLUSIONS: Essential fatty acids can modulate normal tissue reactions when given over the time when radiation damage is normally expressed. Dose modification factors suggest that a > or = 10% higher dose is required to produce the same level of normal tissue injury. Clinical application of selected essential fatty acids at appropriate doses may lead to a significant increase in the therapeutic gain in patients treated for cancer by radiotherapy.

Stabilization of disease as an indicator of clinical benefit associated with chemotherapy in non-small cell lung cancer patients.

In Phase II oncology studies, response rate has traditionally been used to assess activity. However stabilization of disease (SD) may also provide patient benefit. To assess the value of SD (stabilization of measurable disease for at least 8 weeks) as a predictor of survival following chemotherapy in patients with non-small cell lung cancer (NSCLC), we have analyzed data from 198 NSCLC patients receiving topotecan i.v. or orally as first-line therapy either as single agent or in combination. Proportional hazards (Cox) regression models showed that responders [complete response (CR) + partial response (PR), 1.5% and 11.6% respectively] had an estimated risk of death that was 9.8% (95% CI: 4.2% to 22.7%) of that for progressive disease (PD) (60.1% of the patient population). Similarly, patients with SD (26.8% of the patient population) showed a potential benefit with a risk of death that was 27.7% of the one of patients with PD (95% CI: 17.8% to 43.1%). In conclusion SD may be a useful indicator of patient benefit from chemotherapy for NSCLC.

Comparative assessment of single-dose and fractionated boron neutron capture therapy.

The effects of fractionating boron neutron capture therapy (BNCT) were evaluated in the intracerebral rat 9L gliosarcoma and rat spinal cord models using the Brookhaven Medical Research Reactor (BMRR) thermal neutron beam. The amino acid analog p-boronophenylalanine (BPA) was administered prior to each exposure to the thermal neutron beam. The total physical absorbed dose to the tumor during BNCT using BPA was 91% high-linear energy transfer (LET) radiation. Two tumor doses of 5.1 Gy spaced 48 h apart (n = 14) or three tumor doses of 5.2 Gy, each separated by 48 h (n = 10), produced 43 and 70% long-term (> 1 year) survivors, respectively [corrected]. The outcome of neither the two nor the three fractions of radiation was statistically different from that of the corresponding single-fraction group. In the rat spinal cord, the ED50 for radiation myelopathy (as indicated by limb paralysis within 7 months) after exposure to the thermal beam alone was 13.6 +/- 0.4 Gy. Dividing the beam-only irradiation into two or four consecutive daily fractions increased the ED50 to 14.7 +/- 0.2 Gy and 15.5 +/- 0.4 Gy, respectively. Thermal neutron irradiation in the presence of BPA resulted in an ED50 for myelopathy of 13.8 +/- 0.6 Gy after a single fraction and 14.9 +/- 0.9 Gy after two fractions. An increase in the number of fractions to four resulted in an ED50 of 14.3 +/- 0.6 Gy. The total physical absorbed dose to the blood in the vasculature of the spinal cord during BNCT using BPA was 80% high-LET radiation.(ABSTRACT TRUNCATED AT 250 WORDS)

Rapid determination of drugs in biofluids by capillary electrophoresis. Measurement of antipyrine in saliva for pharmacokinetic studies.

A micellar electrokinetic capillary chromatography method was developed that permitted the resolution of antipyrine from endogenous compounds and its quantitation in neat saliva in as little as 1 min. Final conditions were: SpectraPhoresis 1000, 30(23) cm x 50 microns silica capillary, 50 mM sodium phosphate pH 9.6, 50 mM SDS, 10 s hydrodynamic load, detection scanning 200-300 nm or 260 nm, run 25 kV. To overcome the effects of Joule heating the capillary was cooled to 15 degrees C. Sensitivity was < 10 microM and linearity extended to 350 microM. Comparison with an HPLC assay demonstrated that hydrodynamic injection gave a loading bias unless samples and standards were of equal viscosity. For 75 samples from five subjects the correlation of CE vs. HPLC was then r = 0.99.

Modification of radiation-induced acute oral mucositis in the rat.

PURPOSE: A new non-toxic drug (compound A) consisting of curcumin, alpha-tocopherol and sunflower oil was developed and its efficacy tested in the treatment of radiation-induced oral mucositis in the rat. MATERIAL AND METHODS: Mature (12 weeks old, 200-225 g) female Sprague-Dawley rats were used. While under general anaesthesia, the tongues of the animals were slightly extended outside and a region of the underside of the tongue was irradiated in-situ with single doses of 2.27 MeV beta-rays from a 5-mm diameter 90Sr/90Y plaque. The dose-rate of the source was about 10 Gy min(-1) at the surface of the mucus membrane. Irradiations and subsequent assessment of the lesion were carried out under general anaesthesia maintained by a 1.5% halothane/oxygen mixture. Six groups of animals were irradiated with single doses of 13.5, 15.0, 16.5 or 18Gy. One subgroup (radiation only) received no further treatment, while the other five groups received 0.5 ml day(-1) of either compound A, sunflower oil, alpha-tocopherol, curcumin or water containing 10% ethanol by oral gavage until the end of experiments. Mucosal ulceration (erosion of mucosal epithelium) was considered as an end-point. From the day after irradiation until any acute radiation-induced oral mucosal lesion had healed, the tongues of the animals were assessed daily for the presence of radiation-induced mucositis (mucosal ulceration). Quantal data for the incidence of radiation-induced mucositis were analysed using logit analysis and a dose-modification factor was obtained. RESULTS: There was a modest increase in ED50, the dose expected to cause mucositis in 50% of the animals after both alpha-tocopherol and sunflower oil were administered. This resulted in dose-modification factors of 1.05. While curcumin treatment resulted in a dose-modification factor of 1.09. Compound A significantly reduced the incidence of radiation-induced mucositis with a statistically significant dose-modification factor of 1.2 +/- 0.1. CONCLUSIONS: Curcumin and other components of compound A appeared to be effective in the prevention of radiation-induced oral mucositis. However, the overall effect observed with the combination drug (compound A) appeared greater than additive.

Plasma and 24 h-urinary catecholamine concentrations in normal and patient populations.

Using a single HPLC-ECD methodology, plasma catecholamine data were compiled from 545 patients and 144 healthy subjects, and 24 h urinary free catecholamine data from 106 patients. From these data, normal reference ranges were derived for the clinical investigation of suspected phaeochromocytomas, specifically to address the question as to when a result is normal and when further investigation may be required. We have shown that noradrenaline and adrenaline concentrations in plasma and urine are not normally distributed, and basal plasma noradrenaline is significantly lower in normal volunteers than in hospital patients. We have also demonstrated that a reference range which does not take account of these factors will give a significant number of false-positive results. Age and sex did not appear to be significant variables for either plasma or urinary catecholamines. In the investigation of phaeochromocytoma, 95% confidence limits may be used as a warning to repeat sampling and 99% confidence limits as rendering the diagnosis extremely probable. In patients with phaeochromocytomas, urinary catecholamines had a 99.5% specificity and 100% sensitivity in the diagnosis, and thus provide for a rapid and efficient diagnostic screen.

Phase II trial of topotecan administered as a 21-day continuous infusion in previously untreated patients with stage IIIB and IV non-small-cell lung cancer.

Topotecan (9-dimethylaminoethyl-10-hydroxycamptothecin) is a topoisomerase I inhibitor. Twenty-six patients with stage IIIB or IV non-small-cell lung cancer (NSCLC) who had received no prior chemotherapy were treated in a multicenter study with topotecan 0.6 mg/m2/day for 21 days by continuous intravenous infusion every 28 days; this starting dose was decreased to 0.5 mg/m2/day in the last 23 patients because of myelosuppression. There was one partial response, for a response rate of 4% (95% confidence interval, 0.1%-19.6%). Median survival was 9 months. One-year survival was 39%. Of the 58 lung cancer symptoms at baseline, 40% were resolved by the end of best response (all in the partial response patient, 62% in stable disease patients, 26% in progressive disease patients). Catheter-related infections complicated 19% of courses. Red-cell transfusions were given in 50% of courses. Toxicity included grade 4 neutropenia (4%), grade 3-4 anemia (19%), grade 4 thrombocytopenia (8%), and catheter-related infections (19% courses). Although the major objective response rate was only 4%, patients treated with topotecan given as a 21-day continuous intravenous infusion experienced a decrease in cancer-related symptoms and a 1-year survival of 39%.

Evidence for humoral effects on the radiation response of rat foot skin.

The influence of perturbation of the physiologic state of the whole body on the outcome of radiation exposure has been examined in a rat foot model. Irradiation was carried out using 60Co gamma-rays. Moist desquamation was used as an endpoint. Rats were given a priming dose of 2 Gy, 4 Gy or 7 Gy to their whole body except their hind feet (partial body priming dose). After a variable time period both hind feet of these animals were irradiated with graded doses of 60Co gamma-rays. The incidence of moist desquamation in the irradiated feet of these animals was compared with the incidence of moist desquamation in animals that had not received the initial partial body priming dose. It was noticed that the incidence of moist desquamation in the rat foot skin of animals that received 7 Gy partial body priming dose 4 h prior to irradiation of their hind feet was significantly less than moist desquamation in control animals. The ED(50) value of 22.53+/-0.16 Gy for moist desquamation of the foot skin of control animals was significantly lower (p<0.01) than the value of 25.25+/-0.29 Gy obtained for animals that received a partial body priming dose of 7 Gy 4 h prior to irradiation of their hind feet. It was concluded that the response of rat foot skin to radiation was not purely the result of epidermal stem cell kill and that it can be modified by alterations in the overall physiological state of the animal's body brought about by a priming dose to the whole of the animal's body except the hind feet.

Sample introduction and separation in capillary electrophoresis, and combination with mass spectrometric detection.

Capillary-electrophoresis methods are attracting interest owing to the ability to yield rapid high-resolution separations, but many aspects, such as sample injection, separation conditions and detection, need further development. Effects related to sample injection and buffer composition have been investigated. Automated methods for electromigration injection of nl-size sample volumes are shown to give a precision of approximately +/-1%. Problems encountered with manual injection procedures have been examined by an electric field reversal technique. The effect of buffer pH on capillary zone-electrophoresis (CZE) separations can be attributed to changes in electro-osmotic flow velocities and to changes in the isoelectric points of analytes. The interfacing of capillary electrophoresis with mass spectrometry is described and demonstrated for a range of conditions, with a quaternary phosphonium salt mixture. Separations obtained by CZE and capillary isotachophoresis are compared and the relative advantages of the two techniques discussed.

A comparison of cardiac rate-pressure product and pressure-rate quotient with Holter monitoring in patients with hypertension and cardiovascular disease: a follow-up report.

OBJECTIVES: The purpose of this study was to evaluate patients with hypertension or cardiovascular disease, or both, for myocardial ischemia and cardiac arrhythmias while undergoing minor oral surgery. STUDY DESIGN: Sixteen patients were studied with noninvasive monitoring including heart rate, systolic, diastolic, and mean arterial blood pressure to calculate rate-pressure product (systolic blood pressure multiplied by heart rate) and pressure-rate quotient (mean arterial pressure divided by heart rate). These calculated measures were compared with the incidence of cardiac arrhythmias and ST segment depression recorded on a continuous Holter monitoring system. RESULTS: Nine of 16 (56%) developed supraventricular or ventricular ectopy during dental extractions or minor preprosthetic surgery performed with local anesthesia 2% xylocaine with 1/100,000 epinephrine dilution. Three of the nine patients who experienced these arrhythmias had coincident abnormal rate pressure product and pressure-rate quotient values. None of these patients exhibited ST-T wave changes suggestive of myocardial ischemia. Atrial or ventricular ectopy suggests that myocardial irritability was more likely to occur than ischemia as measured by Holter monitoring and compared with abnormal rate pressure product and pressure-rate quotient values recorded.

Comparison of oral chloral hydrate with intramuscular ketamine, meperidine, and promethazine for pediatric sedation--preliminary report.

Fifteen consecutive pediatric patients ranging from 3 to 5 years old were selected to receive one of three sedative/hypnotic techniques. Group 1 received oral chloral hydrate 50 mg/kg, and groups 2 and 3 received intramuscular ketamine 2 mg/kg and 3 mg/kg, respectively. In addition to ketamine, patients in groups 2 and 3 received transmucosal intramuscular injections of meperidine and promethazine into the masseter muscle. Sedation for the satisfactory completion of restorative dentistry was obtained for over 40 min on average in the chloral hydrate group, but completion of dental surgery longer than 40 min was achieved in groups 2 and 3 only by intravenous supplements of ketamine.

Extracellular adenosine initiates rapid arteriolar vasodilation induced by a single skeletal muscle contraction in hamster cremaster muscle.

AIM: Recent studies suggest that adenosine (ADO) can be produced extracellularly in response to skeletal muscle contraction. We tested the hypothesis that a single muscle contraction produces extracellular ADO rapidly enough and in physiologically relevant concentrations to be able to contribute to the rapid vasodilation that occurs at the onset of muscle contraction. METHODS: We stimulated four to five skeletal muscle fibres in the anaesthetized hamster cremaster preparation in situ and measured the change in diameter of arterioles at a site of overlap with the stimulated muscle fibres before and after a single contraction (stimulus frequencies: 4, 20 and 60 Hz; 250 ms train duration). Muscle fibres were stimulated in the absence and presence of non-specific ADO membrane receptor antagonists 8-phenyltheophylline (8-PT, 10(-6) M) or xanthine amine congener (XAC, 10(-6) M) or an inhibitor of an extracellular source of ADO, ecto-5'-nucleotidase inhibitor α,ß-methylene adenosine 5'-diphosphate (AMPCP, 10(-5) M). RESULTS: We observed that the dilatory event at 4 s following a single contraction was significantly inhibited at all stimulus frequencies by an average of 63.9 ± 2.6% by 8-PT. The 20-s dilatory event that occurred at 20 and 60 Hz was significantly inhibited by 53.6 ± 2.6 and 73.8 ± 2.3% by 8-PT and XAC respectively. Further, both the 4- and 20-s dilatory events were significantly inhibited by AMPCP by 78.6 ± 6.6 and 67.1 ± 1.5%, respectively, at each stimulus frequency tested. CONCLUSIONS: Our data show that ADO is produced extracellularly during a single muscle contraction and that it is produced rapidly enough and in physiologically relevant concentrations to contribute to the rapid vasodilation in response to muscle contraction.

Effects of fasting on villi along the small intestine: a stereological approach to the problem of quantifying villus 'shape'.

We present stereological methods for establishing the shapes of villi from simple measurements on histological sections. Villi at different intestinal locations are analyzed in control and fasted rats. Villus shape factors are sensitive indicators of the effects of fasting but estimates of villus height alone are not.