Comparative pharmacokinetics of escalating doses of doxorubicin in patients with metastatic breast cancer

Summary Recombinant human granulocyte colony-stimulating factor (G-CSF) has been shown to reduce neutropenia following cytotoxic therapy, thereby enabling dose escalation to improve the response rate. It is important to know whether drug kinetics change as doses are increased. Doxorubicin was selected because of its broad spectrum of activity and its known efficacy in metastatic breast cancer. Doses of 75, 100, 125 and 150 mg/m² were given to 11 patients with metastatic breast cancer by infusion over 30 min. Serum concentrations of parent drug and metabolites were determined during the first 48 h following the infusion by high-performance liquid chromatography (HPLC). The serum concentration vs time curve decayed as a triple exponential function in four patients and as a double exponential function in seven. A four-compartment model, one central and three peripheral, would predict concentrations to within 1 SE of the observed values. Doxorubicinol was the principal metabolite, and doxorubicinone and 7-deoxydoxorubicinone were clearly identified. There was a linear increase in the AUC with dose. In addition, a small and transient increase in circulating levels of doxorubicinol and other important metabolites was observed 6 h following the administration of doxorubicin, which suggests the existence of an enterohepatic, or other, re-circulation mechanism. We conclude that in the dose range selected the kinetics of doxorubicin are linear and that the increase in toxicities seen with the higher doses of doxorubicin, following the second and third fortnightly administration, may be due to intracellular drug accumulation in tissues.     

Selective attenuation of neuropeptide-Y-mediated contractile responses in blood vessels from patients with diabetes mellitus

Vascular smooth muscle contractile responses to neuropeptide Y, ,ß-methyleneATP and noradrenaline were studied in circular segments of isolated vessels with intact endotheliumin vitro from 12 patients with diabetes mellitus type 2 (NIDDM) and 12 control subjects. The dilatory effect of acetylcholine was used to test the function of the endothelium. Subcutaneous arteries and veins (diameter 0.1–1.1 mm) were obtained during surgery. There was no difference in contractile responses to noradrenaline or ,ß-methyleneATP between diabetic and control vessels. The contractile response to neuropeptide Y, however, was markedly reduced in the diabetic group. The maximal contractile effect (46.0 ± 14.0%,p < 0.05) but not the sensitivity to neuropeptide Y was significantly less in diabetic veins compared to control (107.5 ± 19.6%). Thus, the attenuation of neuropeptide Y responses was present in humans as previously observed in alloxan-induced diabetes mellitus in rabbits. There was no difference in the dilator effect of acetylcholine between the diabetic and the control group in any of the vessel types, indicating that the difference in vascular reactivity to neuropeptide Y was not endothelium-dependent. In conclusion, the present study has shown that the postjunctional effects of neuropeptide Y, a co-transmitter of the peripheral sympathetic nervous system, is selectively attenuated in diabetes mellitus.     

Comparative study of laparoscopy vs. laparotomy for adnexal surgery: efficacy, safety, and cyst rupture

Operative laparoscopy is becoming routine in gynecologic surgery. This study was designed to compare the safety and efficacy of laparoscopy and laparotomy for ovarian cystectomy and adnexectomy. The medical records of 32 patients who underwent operative laparoscopy for adnexal masses (group L) were reviewed and compared with those of 32 patients who underwent surgical laparotomy (group S) for similar indications. All patients sustained either an ovarian cystectomy or adnexectomy. The group were matched for age, weight, and history of previous laparotomy. Median operating time for group L was 90 min and for group S was 85 min. Blood loss was significantly less in group L (33.4 +/- 22 mL) than in group S (84.6 +/- 22.2 mL), p < 0.0001. There were two intraoperative complications in group L and one in group S. Significantly less patients in group L had postoperative fevers (16%) as compared with those in group S (69%), p < 0.0001. There was a higher incidence of cyst rupture when cystectomy was performed in patients from group L (7 of 21) as compared with patients from group S (2 of 17). No such difference in cyst rupture was noted when an adnexectomy was affected in group L (1 of 11) and group S (1 of 15). Patients in group L remained in the hospital a shorter time period, 1.5 +/- 0.8 days, than patients in group S, 4.7 +/- 0.9 days, p < 0.0001. Patients in group L required a shorter postoperative recovery time before resuming normal activities, 9.1 +/- 6.6 days, than patients in group L, 27.5 +/- 9.2 days, p < 0.0001. Similarly, patients in group L required less time to become pain free, 10.1 +/- 7.4 days, than patients in group L, 17.7 +/- 6.1 days, p < 0.0005. This study demonstrates a statistically significant decrease in postoperative morbidity and faster recovery in patients undergoing laparoscopy for adnexal surgery as compared with patients undergoing laparotomy for the same procedure. When cystectomy is performed via the laparoscope, there is a higher incidence of cyst rupture than with laparotomy.     

Pharmacokinetics and pharmacodynamics of prolonged oral etoposide in women with metastatic breast cancer

The pharmacokinetics and pharmacodynamics of prolonged oral etoposide chemotherapy were investigated in 15 women with metastatic breast cancer who received oral etoposide 100 mg as a single daily dose for up to 15 days. There was considerable interpatient variability in the day 1 pharmacokinetic parameters: area under the plasma concentration time curve (AUC) (0–24 h) 1.95±0.87 mg/ml per min (mean ± SD), apparent oral clearance 60.9±21.7 ml/min per 1.73 m², peak plasma concentration 5.6±2.5 g/ml, time to peak concentration 73±35 min and half-life 220±83 min. However, intrapatient variability in systemic exposure to etoposide was much less with repeated doses. The intrapatient coefficient of variation (CV) of AUC for day 8 relative to day 1 was 20% and for day 15 relative to day 1 was 15%, compared to the day 1 interpatient CV of 45%. Neutropenia was the principal toxicity. Day 1 pharmacokinetic parameters were related to the percentage decrease in absolute neutrophil count using the sigmoidal E_max equation. A good fit was found between day 1 AUC and neutrophil toxicity (R ²=0.77). All patients who had a day 1 AUC>2.0 mg/ml per min had WHO grade III or IV neutropenia. The predictive performance of the models for neutrophil toxicity was better for AUC (percentage mean predictive error 5%, percentage root mean square error 18.1%) than apparent oral clearance, peak plasma concentration, or daily dose (mg/m²). A limited sampling strategy was developed to predict AUC using a linear regression model incorporating a patient effect. Data sets were divided into training and test sets. The AUC could be estimated using a model utilizing plasma etoposide concentration at only two time points, 4 h and 6 h after oral dosing (R ²=98.9%). The equation AUC_pr=–0.376+0.631×C_4h+0.336×C_6h was validated on the test set with a relative mean predictive error of –0.88% and relative root mean square error of 6.4%. These results suggest monitoring of AUC to predict subsequent myelosuppression as a strategy for future trials with oral etoposide.Division of Haematology and Medical Oncology, Peter MacCallum Cancer Institute, Locked Bag 1, A'Beckett St, Melbourne 3000, Australia     

Expression of MHC class I heavy chain and beta2-microglobulin in rat brainstem motoneurons and nigral dopaminergic neurons

We demonstrate here that motoneurons and nigral dopaminergic neurons in the brainstem of the adult rat, with the exception of motoneurons innervating ocular muscles, display high levels of both MHC class I heavy chain and beta2-microglobulin mRNAs. These neurons also display interferon-gamma receptor mRNA. We find it striking that these particular neurons are those which are vulnerable to neurodegeneration in diseases such as Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS).     

CG-clip expansive open-door laminoplasty: a technical note

The CG clip is a device designed for use in expansive open-door laminoplasty with both a spacer and means of attachment in a single unit. It provides an effective technique for open-door laminoplasty, which obviates the need for bone grafting or complex internal fixation by providing dynamic stabilization of the open laminae. A number of techniques for expansive open-door laminoplasty have been devised for the decompression of the spinal cord and nerve roots in cervical spondylotic myeloradiculopathy. Each of these techniques requires some degree of internal fixation and/or bone grafting. The CG clip is a single device which is composed of both a spacer and a spring clip for attachment. The spacer ensures a 4-5-mm sagittal expansion of the cervical spinal canal. The spacer is held in place along the lateral cut margin of the laminae by a spring-wound titanium clip, which folds over the central spinous process of the unilaterally elevated laminar block. In all respects except for grafting and internal fixation, the surgery is performed as for a standard expansive open-door laminoplasty. Sixteen of the first 24 patients to undergo this procedure improved at least one point on the Neurosurgical Cervical Spine Scale. Of the remaining eight patients, four remained the same and four deteriorated. The authors have found the CG-clip laminoplasty technique quick and easy to perform, with early results in the treatment of cervical spondylotic myeloradiculopathy consistent with those of other decompressive procedures.     

The GU-MACH study: the effect of 1-week omeprazole triple therapy on Helicobacter pylori infection in patients with gastric ulcer

AIMS: To study the efficacy of omeprazole triple therapy in the eradication of Helicobacter pylori in patients with active gastric ulcer, and to assess healing and relapse of gastric ulcer. METHODS: A double-blind, randomized study was carried out in 18 centres in Germany, Hungary and Poland. Patients (n = 160) with gastric ulcer and a positive H. pylori screening test were randomized to a 7-day twice daily treatment with omeprazole 20 mg, clarithromycin 500 mg and amoxycillin 1000 mg (OAC) or omeprazole 20 mg, clarithromycin 250 mg and metronidazole 400 mg (OMC), or with omeprazole 20 mg once daily (O). After completion of this 1-week treatment, patients were treated with omeprazole until healing (maximum 12 weeks), and followed for 6 months. H. pylori was assessed by urea breath test (UBT) and histology. RESULTS: Eradication rates ITT were OAC 79% (95% CI: 65-90%), OMC 86% (95% CI: 73-94%) and O 4% (95% CI: 0-14%). Eradication rates PP were OAC 83% (95% CI: 68-93%), OMC 93% (95% CI: 80-98%) and O 3% (95% CI: 0-13%). Gastric ulcer relapses occurred in 5, 0 and 11 patients in the groups, respectively. CONCLUSIONS: The results from the study demonstrate that OMC and OAC 1-week regimens are safe and effective for eradication of H. pylori in gastric ulcer patients, and that ulcer relapse is infrequent after successful eradication.     

Contact allergy to trimethylolpropane triacrylate (TMPTA) in an aziridine plastic hardener

4 workers developed hand and face dermatitis when exposed to a floor top coal. This contained a polyurethane arid a polyfunctional aziridine hardener and additives. The aziridine hardener was made by reacting propyleneimine with a polyfunctional acrylate, trimethylolpropane triacrylate (TMPTA). All 4 reacted to the hardener and to TMPTA, which is present in excess, 2 of them also reacted to pentacrythritol triacrylate (PETA), which can be used in the production of aziridine hardeners. TMPTA and PETA cross-react, and are known sensitizers in UV-hardening acrylates.
The present finding shows that well-known sensitizers can be found in hidden sources when used in a quite different chemical process.