Phase I and pharmacokinetic study of rhizoxin.

Rhizoxin is a tubulin-binding cytotoxic compound, isolated from the fungus Rhizopus chinensis, with significant antineoplastic activity in several murine and human tumor models. In this Phase I study, the drug was administered by i.v. bolus injection at 3-wk intervals. Twenty-four patients with refractory solid tumors were treated; 60 courses of rhizoxin were given, at doses ranging from 0.8 to 2.6 mg/m2. Grade 3 mucositis, Grade 4 leukopenia, and Grade 3 diarrhea were dose limiting but reversible at 2.6 mg/m2, the maximum tolerated dose for both previously untreated and heavily pretreated patients. Alopecia and moderate discomfort at the injection site occurred at all doses. Other sequelae, including peripheral neuropathy, phlebitis, and nausea and vomiting, were sporadic and mild. Two heavily pretreated patients with recurrent breast cancer had minor responses to rhizoxin, one at 1.6 mg/m2 and the other at 2.6 mg/m2. Plasma concentrations of rhizoxin were measured by high-performance liquid chromatography. The drug was not detectable (less than 5 ng/ml) at doses of 0.8 mg/m2 and 1.6 mg/m2 and was not measurable 10 min after injection at 2.0 mg/m2. At 2.6 mg/m2, there was considerable intersubject variation in the plasma concentration-time profiles; the area under the curve ranged from 0.29 to 0.96 microgram/ml.min. Rhizoxin has shown some clinical activity in this Phase I study, and a dose of 2.0 mg/m2 is recommended for Phase II studies using this schedule.

Phase I and pharmacokinetic study of taxotere (RP 56976) administered as a 24-hour infusion.

N-Debenzoyl-N-tert-butoxycarbonyl-10-deacytyl taxol (Taxotere, RP 56976) is a semisynthetic analogue of taxol, prepared from a noncytotoxic precursor extracted from the needles of the European yew tree (Taxus baccata L.). It has a broad spectrum of antitumor activity against a variety of transplantable tumors in mice. In vitro cytotoxicity assays suggest that it is 2-5-fold more potent than taxol. In this phase I study Taxotere was administered by 24 h i.v. infusion at 3-week intervals. Thirty patients with solid tumors refractory to conventional therapy were treated; 70 courses of Taxotere were administered at doses ranging from 10 to 90 mg/m2. Grade 4 neutropenia and grade 3 mucositis were dose limiting but reversible at 90 mg/m2. The pattern and grade of toxicity at this dose were similar in 3 heavily pretreated patients compared with 7 patients who had received a maximum of one previous chemotherapy regimen. Alopecia occurred at 55 mg/m2 and above. Other mild toxicities included phlebitis, diarrhea, emesis, and sensory peripheral neuropathy, but these were neither dose-limiting nor clearly dose-related. One patient treated at 70 mg/m2 had an anaphylactoid reaction following the second dose of Taxotere. No cardiovascular toxicity was observed. No partial or complete responses were documented. Plasma concentrations of Taxotere were determined by high-performance liquid chromatography, and end-of-fusion levels at the maximum tolerated dose exceeded drug concentrations which are cytotoxic in vitro. The maximum tolerated dose for Taxotere administered as a 24-h infusion is 90 mg/m2.

Pneumocystis carinii pneumonia in a patient on etanercept for psoriatic arthritis.

BACKGROUND: Pneumocystis carinii pneumonia (PCP) is a rare form of pneumonia associated with immune-suppression. It is common in patients with AIDS and with a CD4 count of less than 200 cells/mm(3). We report a case of PCP secondary to immune-suppression in a 41-year-old man with psoriatic arthritis being treated with the immune-modulatory agent etanercept. METHODS: Diagnosis of PCP was made histologically using tissue obtained via transbronchial biopsy. RESULTS: There was a good response to standard treatment with high-dose co-trimoxazole. CONCLUSION: This report highlights a recognised but previously unreported complication of etanercept.

Changes in ventilation and its components in normal subjects during sleep.

Non-invasive measurements were made of ventilation, its derivatives, the contributions of abdomen and rib cage and arterial oxygen saturation in six healthy normal men whilst awake and during sleep. Minute ventilation fell significantly during slow wave (SW) sleep and rapid eye movement (REM) sleep (awake = 6.3 1 min-1, SW sleep = 5.7 1 min-1, REM sleep = 5.4 1 min-1; p less than 0.04). Mean inspiratory flow also fell significantly but timing was unchanged. The abdominal (diaphragmatic) contribution to ventilation fell very significantly during SW sleep but returned to awake levels during REM sleep (awake 54%, SW sleep 38%, REM sleep 56%; p less than 0.007). There were also significant falls in arterial oxygen saturation during SW and REM sleep (awake 97.3%, SW sleep 96.5%, REM sleep 96.2%; p less than 0.002). These falls represent reductions in arterial oxygen tension similar to those seen in patients with chronic airways obstruction and can be accounted for entirely by the associated reduction in ventilation.

Changes in blood gas levels after nebuhaler and nebulizer administration of terbutaline in severe chronic airway obstruction.

It has been suggested that patients with severe chronic airway obstruction might suffer dangerous hypoxia after administration of a beta-agonist through an air driven nebulizer. Twenty patients with severe chronic airway obstruction (12 male, mean age 71.1 (SEM 1.5) yr) were monitored with a Biox oximeter and Hewlett-Packard capnometer before and after 4 mg terbutaline was delivered through an air driven nebulizer or Nebuhaler. The eight patients with chronic hypoxia (mean PaO2 6.76 kPa, PaCO2 7.47 kPa. FEV1 0.53 l) experienced a 4.7% increase in oxygen saturation (SaO2) and 2.9% fall in transcutaneous carbon dioxide tension (PtcCO2) (p less than 0.05) during all treatments, followed by a return to initial levels. These changes were attributable to increased ventilation whilst breathing through a mouthpiece. A similar trend was seen in the SaO2 of the twelve normoxic patients (mean PaO2 9.32 kPa, PaCO2 5.34 kPa, FEV1 0.8 l), but there was a sustained fall in PtcCO2 of 3.7% (p less than 0.001) after administration of terbutaline. Inhaled terbutaline in the dosage given did not cause hypoxia in patients with severe chronic airflow obstruction, but nebulizer and Nebuhaler use was associated with a rise in SaO2 related to increased ventilation whilst breathing through a mouthpiece.

Experience with the Portacath.

Fifty Portacaths have been inserted in patients undergoing prolonged outpatient chemotherapy, most for haematological disease. Twenty-one are still working at a median duration of 12 months (range 1-27) and a further 15 were functioning normally at the time of the patients death (median survival 6 months). Four functioning Portacaths have been removed, three suspected of causing septicaemia and one believed erroneously to have occluded. Ten have ceased to function and nine of these have been removed. The causes of these failures are nearly all avoidable and are discussed in detail; many occurred early in our experience. With careful attention to detail and with management by trained and interested staff, the Portacath is a safe and reliable device for intermittent vascular access.

Respiratory inductance plethysmography: calibration techniques, their validation and the effects of posture.

Respiratory inductance plethysmography (RIP) is used to measure ventilation from two measurements of body surface movements (rib-cage and abdomen) via the application of volume-motion (V-M) coefficients. The correct derivation of both V-M coefficients (calibration) is necessary because there are considerable spontaneous variations in relative contributions from these two compartments even during resting breathing. In order to fully test a calibration, deliberate changes in rib-cage (RC) to abdominal (AB) contribution must be made. We used this approach to test two single-posture calibration techniques, multiple linear regression (MLR) and isovolume (ISV). Ten normal subjects and nine patients with chronic airway obstruction (CAWO) were studied using quiet breathing throughout. We also studied the effects of changing posture on the constancy of the V-M coefficients. MLR proved a little more accurate (p = 0.03) in deriving the V-M coefficients than ISV in normal subjects, and ISV consistently underestimated the AB V-M coefficient relative to RC. No difference between the two techniques existed in patients with CAWO. Both MLR and ISV calibrations failed to give acceptable calibrations in some patients. When MLR calibration was used, a deliberate 20% change in relative compartmental contribution (RC-AB) induced mean errors in RIP estimations of tidal volume of 3.5 and 9.5% in normal subjects and patients respectively. When there were no deliberate changes in relative contribution, the 95% confidence limits of individual tidal volume estimates were +/- 6.6 and +/- 12% in normal subjects and patients respectively. MLR calibration provides a statistical estimate of its quality at the time of V-M coefficient derivation.(ABSTRACT TRUNCATED AT 250 WORDS)

Obstructive sleep apnea following topical oropharyngeal anesthesia in loud snorers.

Previous studies support the presence of an upper airway reflex mechanism that contributes to the maintenance of upper airway patency during sleep. We investigated the possibility that interference with this reflex mechanism contributes to the development of obstructive sleep apnea. Eight otherwise asymptomatic snorers (seven male and one female), age 39 +/- 5.3 yr (mean +/- SEM), underwent overnight sleep studies on three successive nights. An acclimatization night was followed by two study nights randomly assigned to control (C) and oropharyngeal anesthesia (OPA). On the OPA night topical anesthesia was induced using 10% lidocaine spray and 0.25% bupivacaine gargle. A saline placebo was used on night C. All subjects slept well on both study nights (mean sleep duration was 6.2 h on both study nights), and sleep stage distribution was similar on both nights. Obstructive apneas and hypopneas (OAH) rose from 114 +/- 43 during C to 170 +/- 49 during OPA (p less than 0.02). Central apneas and hypopneas (CAH) were unchanged between the two nights (8 +/- 4.9 versus 7 +/- 3). The duration of OAH was similar on both study nights (20 +/- 1.9 s during C versus 20 +/- 1.5 s during OPA). The frequency of movement arousals terminating OAH tended to be higher during OPA (7 +/- 2.9/h) than during C (3 +/- 0.7); P = NS. The frequency of oxyhemoglobin desaturations was also higher during OPA (5 +/- 2.1/h) than during C (3 +/- 1.4), p less than 0.07.(ABSTRACT TRUNCATED AT 250 WORDS)