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AimsThe feasibility, morbidity and toxicity of an intensified surgical treatment strategy consisting of aggressive cytoreductive surgery, intra-operative intraperitoneal perfusion of cisplatin and hyperthermia were evaluated in women with recurrent ovarian cancer. MethodsFive heavily pre-treated patients with extensive abdominal tumour bulk entered this pilot study. In all cases aggressive cytoreduction leaving tumour remnants <5 mm in diameter could be performed. This was followed intra-operatively by perfusion of the abdominal cavity with hyperthermic cisplatin 50–70 mg/m2for 90 min. During perfusion the intra-abdominal temperature was maintained at 40°C. The median duration of surgery was 10 hours (range 9–11 hours). ResultsNo major intra- or post-operative complications emerged. Median post-operative ileus (resuming of soft diet) was 11 days (9–13 days). The mean period of hospitalization was 25 days (range 17–42). Toxicity due to i.p. cisplatin was mainly metabolic and of grade 1–2, while no nephrotoxicity was observed. The pharmacokinetics of cisplatin indicated that the maximum concentration of cisplatin measured in the perfusate was 15 times higher than in plasma. ConclusionsWe conclude that aggressive cytoreduction combined with hyperthermic intra-operative intraperitoneal cisplatin was feasible in a small group of heavily pre-treated ovarian cancer patients with extensive tumour bulk with acceptable morbidity and toxicity. Further studies are required in larger groups of patients to further establish the feasibility of this intensified treatment strategy. We stress that OVHIPEC is not a treatment modality on its own for advanced ovarian cancer. The effectiveness of OVHIPEC is likely to be dependent on the effectiveness of post-operative adjuvant chemotherapeutic regimens.

The purpose of this study was to investigate the influence of hyperthermia on cisplatin pharmaco-kinetics and DNA adduct formation. The latter was investigated both in tumour cell lines in vitroand in tumour cells and buccal cells from cancer patients. The patients had advanced ovarian carcinoma and were entered into a phase I study for cytoreductive surgery followed by hyperthermia in combination with intraperitoneal cisplatin administration. The cisplatin–DNA modifications in vivoand in vitrowere studied by an immunocytochemical method with the polyclonal antiserum NKI-A59. The patient samples for pharmacokinetic determinations were analysed by flameless atomic absorption spectrometry. In vitro, the combination of hyperthermia and cisplatin enhanced cell killing compared with either treatment alone, such that the cisplatin-resistant ovarian cell line A2780/DDP became almost as sensitive as the parent A2780 cell line (resistance factor reduced from 30 to 2 at the IC50). In addition, increased cisplatin–DNA adducts were observed in the resistant cell line after the combined treatment compared with cisplatin alone. A good correlation was found between nuclear staining density and surviving fraction for all groups, indicating that the DNA adducts generated are an important determinant of toxicity and that the mechanism by which hyperthermia enhances kill is by increasing adduct levels. In the patients, the ratio of drug concentration in the peritoneal perfusate compared with that in plasma was found to be approximately 15, indicating a favourable pharmacokinetic ratio. Cisplatin–DNA adduct formation in tumour cells from patients was higher than in buccal cells, reflecting this higher drug exposure, i.e. local plus systemic versus systemic only. In addition, the tumour cells but not buccal cells were exposed to hyperthermia. The higher number of tumour adducts also suggests that a favourable therapeutic ratio could be achieved. Platinum–DNA adduct formation was found to decrease with distance from the surface of the tumour nodules. However, at a distance of 3–5mm, the nuclear staining density levels were still measurable and higher than in buccal cells. In conclusion, the combined pharmacokinetic and adduct data in patients support the advantages of the intraperitoneal route for drug administration, and the addition of heat.

A standardtlc procedure was tested for its applicability in the qualitative analysis of several creams. It was found that in creams of known composition the presence of almost all of the active cream components as well as the excipients can be confirmed. An additional eluent, spray reagent, or a liquid extraction clean-up step sometimes appeared to be necessary. If the cream base composition is not known, a ‘fingerprint’ of the various types of excipients is obtained with the described procedure.

The possibilities of applying reversed-phase high performance liquid chromatography to the analysis of o/w emulsion type creams without preceding sample clean-up were investigated. The Chromatographic behaviour of cream base components and active compounds in reversed phase systems consisting of methanol-water mixtures as the mobile phase and a chemically bonded octadecyl stationary phase, was studied. A number of active compounds and the preservative (sorbic acid) could be determined — often in one Chromatographic run — without complications, by simply dissolving the sample in a suitable solvent mixture and injecting an aliquot of the solution into the Chromatograph. Separation was achieved by the proper choice of methanol content, pH and ionic strength of the eluent. The compounds were detected by uv absorption. Some of the lipophilic cream base components could easily be determined in the same manner, with methanol as the eluent and with refraction index detection. The developed procedure was applied to the analysis of a number of creams. Some of the results are presented as examples, demonstrating the suitability of the method for quality control purposes.

Abstract: The uv absorbing properties of the components of the cream bases as described in the Formulary of the Dutch Pharmacists were investigated. Directuv spectrophotometric determinations without any clean-up steps appeared to be possible for a number of drugs (e.g. tripelennamine HCl, tretinoin, salicylic acid, methyl salicylate, resorcinol, clioquinol), with the help of a solvent mixture in which the cream samples dissolved completely to yield clear solutions. Correcting for the contribution to theuv absorbance by the preservative is sometimes necessary and can be achieved by measuring the absorbance at two wavelengths. The determination of chlorhexidine, as an example of a basic drug withuv absorbing properties which prevent direct measurements of the solution of the cream samples, could be achieved after removal of the interfering compounds by a simple liquid-liquid extraction.

Two elettrooptic materials, deuterated cesium dihydrogen arsenate (D-CDA, CsD_2AsO_4) and lithium tantalate (LiTaO_3), are examined for the application of a traveling wave-type coherent light modulator. The main design goals are (a) low drive power of 4 W for 10% linear amplitude modulation; (b) ±3-dB bandwidth of 1 GHz; and (c) 50-Ω impedance. Experimental performance based on theoretical expectations are presented for both materials. Using a microwave network analyzer, the results indicate that the D-CDA modulator gives better performance with a VSWR of 1.06 as compared with the LiTaO_3 modulator figure of 1.23. Direct Current contrast ratio measurements for D-CDA and LiTaO_3 were 50:1 and 20:1, respectively.

Two interesting representatives of a new generation of platinum-based cytostatic drugs that are currently being tested in clinical trials are lobaplatin [1,2-diaminomethylcyclobutane platinum(II) lactate] and oxaliplatin [1,2-diaminocyclohexane platinum (II) oxalate]. Since little is known about the DNA adduct formation of these compounds, we studied their formation in DNA in vitro in calf thymus DNA and in cells. The major adducts formed in vitro were the Pt-GG and Pt-AG intrastrand crosslinks. The latter adducts could be detected using a recently developed 32P-postlabelling method. Using both this assay and atomic absorption spectroscopy, it was shown that there is a substantially higher rate of the in vitro adduct formation by cisplatin, compared with lobaplatin and oxaliplatin. Platinum concentrations required to obtain 90% cell kill during a 2 h incubation of A2780 cells were 15 microM for cisplatin and oxaliplatin and 22 microM for lobaplatin. Using an antiserum originally raised against cisplatin-treated DNA, we were also able to detect platinum-DNA adducts induced by lobaplatin and oxaliplatin. Maximal nuclear staining for all three compounds was observed after a 4 h post-incubation period. The nuclear staining level induced by cisplatin was about 10-fold higher than after lobaplatin and oxaliplatin treatment. GG and AG adducts, measured by 32P-postlabelling, also showed maximum levels at about 4 h after treatment. Relative GG peak levels were 4:1:3 for cisplatin, lobaplatin and oxaliplatin, respectively. The ratios of GG over AG intrastrand crosslinks in the A2780 cells were not significantly different for the various compounds. In conclusion, the 32P-postlabelling technique has been shown to be appropriate for adduct analysis, not only for the classical Pt compounds cisplatin and carboplatin but also for novel platinum compounds like lobaplatin and oxaliplatin. Results indicated large differences in reactivity of the latter compounds to DNA in vitro, compared with cisplatin. This difference was smaller in cells, suggesting enhancement of adduct formation by certain cellular mechanisms and/or compounds. From these studies, no conclusions can be drawn with respect to the cytotoxicity of the different Pt-GG and Pt-AG intrastrand crosslinks formed by these compounds.