Indwelling pleural catheters: an overview and real-life experience.

BACKGROUND: Indwelling pleural catheters (IPCs) are most frequently used in those with malignant pleural effusions, although their use is expanding to patients with non-malignant diseases. AIM: To provide an overview of IPCs and highlight how, when and why they can be used including our own real-life experience. DESIGN: Data were collected retrospectively from a large tertiary centre for all individuals who received an IPC between June 2010 and February 2018 inclusive. The data collected included gender, age, origin of malignancy, number of drains prior to IPC, whether they had received pleurodesis prior to IPC, presence of a trapped lung, date of insertion, documented complications, overall outcome and date of death. RESULTS: A total of 68 patients received an IPC, the majority were female (n = 38, 57%) with an overall median age of 68 years (range 40-90 years). The most common site of cancer origin was lung (n = 33, 49%) followed by pleura (n = 10, 15%) and breast (n = 9, 13%). The median survival of all patients was 141 days (IQR 26-181). Sixteen percent (n = 11) of patients underwent a spontaneous pleurodesis resulting in their IPC being removed. Only three individuals had a complication (4.4%). CONCLUSIONS: IPC insertion is a safe procedure and represents an exciting and expanding field in the management of pleural disease. Further longitudinal studies are required to fully delineate their place in the management of both malignant and benign effusions.

Synthesis and in-vitro anticancer evaluation of bis-tacrine congeners.

In the search for potential new anticancer drugs, an efficient synthesis of bis-tetrahydroaminoacridine (bis-tacrine) and its congeners was accomplished by bis-amination of 9-chlorotetrahydroacridine and its congeners under heated conditions. The critical chlorides were efficiently prepared from o-aminoaromatic acids and cycloketones in-situ in the presence of phosphorus oxychloride. In-vitro cytotoxic evaluation of the compounds was carried out against a panel of 60 human cancer cell lines. Among them, butyl-linked bis-tacrine (5b) exhibited the strongest cytotoxic profile with GI50 (concentration causing 50% growth inhibition) values of approximately 0.04-0.08 microM against breast, colon, melanoma and non-small lung cancer cells. Congeners bearing a longer alkyl chain were on average 30- to 100-fold less cytotoxic against these cancer cells. Shorter connecting alkyl chains of bis-tacrine or its congeners dramatically decreased the cytotoxic effects. Compound 5b has been selected for further biological evaluation of its anticancer profile.

Synthesis and cytostatic properties of structure-simplified analogs of dolastatin 15.

The linear peptide dolastatin 15 (1), a potent antineoplastic constituent from the shell-less mollusk Dolabella auricularia, has been selected as the lead compound for developing novel antitumor drugs. Recently LU103793 (2), a synthetic and structure-simplified analog of dolastatin 15, has been demonstrated to be highly cytotoxic [IC50 = 0.1 nM; M. De Arruda, C.A. Cocchiaro, C.M. Nelson, C. M. Grinnel, B. Janssen, A. Haupt & T. Barlozzari (1995) Cancer Res. 55, 3085-3092]. Both compounds have been undergoing human cancer clinical trials in Europe and North America. Based on the novel structure of LU103793, a series of analogs modified at the N-terminal dolavalyl moiety and -Pro-Pro-benzylamide unit was developed. These synthesized analogs were tested using a sulforhodamine B (SRB) assay for the drug-screening program at NCI on a variety of human cancer cell lines. As expected, most analogs exhibited potent and selective growth inhibition against leukemia. Analog 18 was specifically active against HL-60 and K-562 cell lines (GI50s: 0.05 microM and 0.07 microM, respectively) while analogs 14 and 17 were selectively potent against prostate and breast cancer cell lines (GI50s at micromolar levels). However, all analogs were less potent than 2 as growth inhibitors of some breast and colon cancer cell lines (e.g. MDA-MB-435 and HT-29). We believe that modification of novel marine natural products as synthetic analogs might show particular promise for developing novel anticancer candidates with moderate specificity.

Inhibition of human immunodeficiency virus replication by nonimmunosuppressive analogs of cyclosporin A.

Analogs of the immunosuppressive cyclic undecapeptide cyclosporin A (CsA) with substitutions in positions 1, 4, 6, and/or 11 were rationally designed to possess substantially diminished or no immunosuppressive activity. When these compounds were assayed for their capacity to interfere with the replication of human immunodeficiency virus, some displayed a potent antiviral activity in newly infected cells. However, only CsA could interfere with virus replication in persistently infected cells. One CsA analog with antiviral activity costimulated the phytohemagglutinin-induced production of interleukin 2 by human lymphocytes. Human immunodeficiency virus particles from drug-exposed cells showed lower infectivity than virions from untreated cells. Thus, these nonimmunosuppressive analogs of CsA constitute a promising class of lead compounds to develop drugs for effective treatment of the acquired immunodeficiency syndrome.