ABSTRACT
BACKGROUND: Pro re nata are frequent in psychiatry. The risks engendered by this treatment requires that their prescription and administration be made safer. The frequency of administration of pro re nata depends mainly on the nurse's clinical judgment. AIMS: Our first objective was to assess nurses' satisfaction about the quality of doctors' pro re nata prescriptions. Our second objective was to assess the nurses' self-reported practices for administering pro re nata treatments as written in the prescription. METHOD: Self-administered questionnaires were sent by the hospital's internal mail between November 13, 2014, and December 10, 2014 to all nurses in our psychiatric establishment in France. The questionnaire included multiple-choice questions and questions based on clinical vignettes. RESULTS: The response rate was 51.9% (124/239). Overall, 75.6% considered that the quality of the prescriptions in terms of dosage was satisfactory. However, regardless of the quality of the doctor's pro re nata prescription, nurses did not contact the doctor even when the prescription quality was poor. Unexpectedly, we found that 88.7% have administered medication "as needed" without a doctor's prescription and sometimes acted without consulting doctors. CONCLUSIONS: The nurses appeared globally satisfied with doctors' prescriptions of pro re nata medications. On the other hand, most administered some medications without any prescription, that is, illegally. Physicians must be rigorous in the quality of their PRN prescriptions. At the same time, nurses must comply with the medical prescription or contact the physician if the quality of the PRN prescription appears poor.
Subject(s)
Mental Disorders , Psychiatry , Humans , Mental Disorders/drug therapy , Mental Health , Surveys and Questionnaires , Self ReportABSTRACT
Cystemustine (N'-(2-chloroethyl)-N-(2-(methylsulphonyl)ethyl)-N'-nitrosourea) is a new chloroethylnitrosourea (CENU) being used in phase II clinical trials of disseminated melanoma. Clinical results show that tumour regression has only been observed in 25% of melanomas treated by CENUs. Tumour resistance to CENU is known to be mainly due to a DNA repair protein, O6-methylguanine-DNA methyltransferase (MGMT). The poor remission rate of melanoma with CENUs is attributed to the fact that metastases contain high MGMT levels. Previously, we have shown that O6-benzyl-N2-acetylguanosine (BNAG), an MGMT inhibitor, can be combined with cystemustine by intravenous administration, and increases the antitumour effect of cystemustine in resistant human melanoma. In the work presented here, we investigated the in vitro pharmacological effect of this combination on the DNA of human melanoma cells (M3Dau cells). A quantitative polymerase chain reaction (QPCR) assay was used to measure DNA damage in a fragment (2.7 kb) of the hprt gene. The results show that treatment with BNAG enhances the number of lesions in the DNA of cystemustine-treated resistant malignant melanocytes, which may account for the high tumour-cell toxicity of the combination of cystemustine and BNAG.
Subject(s)
Antineoplastic Agents/toxicity , Guanosine/analogs & derivatives , Nitrosourea Compounds/toxicity , O(6)-Methylguanine-DNA Methyltransferase/metabolism , Cell Survival/drug effects , DNA Damage , Drug Synergism , Enzyme Inhibitors/toxicity , Guanosine/toxicity , Humans , Melanocytes/enzymology , Melanoma , O(6)-Methylguanine-DNA Methyltransferase/antagonists & inhibitors , Polymerase Chain Reaction , Tumor Cells, CulturedABSTRACT
Cystemustine (N'-(2-chloroethyl)-N-(2-(methylsulphonyl)ethyl)-N'-nitrosourea), a new anticancer chloroethylnitrosourea (CENU) is being tested in a phase II clinical trial of disseminated melanoma. The antitumour effect of this drug is mainly due to DNA damage in malignant melanocytes. Recently, we have shown that this damage can induce apoptosis in some melanoma cell lines. In others, apoptosis is not clearly observed, although there is a strong cytostatic effect. In this paper, we have characterized the cytological effect of cystemustine on murine malignant melanocytes (B16 cell line) which are resistant to apoptosis induced by this CENU. The results show that 3 days after cystemustine treatment, these melanocytes had accumulated in phase G2 of the cell cycle. There was then a strong morphological modification during a long cytostatic phase up to 30 days after treatment. During this cytostatic phase, there was uncontrolled DNA synthesis and marked swelling. Also, tyrosinase activity, melanin content and the number of mature melanosomes were greatly increased. These results suggest that when malignant melanocytes are not able to undergo apoptosis after treatment with CENU, they accumulate in G2 and this is followed by enhancement of melanogenesis.
Subject(s)
Antineoplastic Agents/therapeutic use , G2 Phase , Melanins/biosynthesis , Melanoma, Experimental/drug therapy , Melanoma, Experimental/pathology , Nitrosourea Compounds/therapeutic use , Animals , Cell Survival/drug effects , Dose-Response Relationship, Drug , Flow Cytometry , Melanoma, Experimental/metabolism , Mice , Microscopy, Electron , Monophenol Monooxygenase/metabolism , Time Factors , Tumor Cells, CulturedABSTRACT
A series of O6-(alkyl/aralkyl)guanosines and 2'-deoxyguanosine analogs extended to peracetyl and N2-acetyl derivatives, potentially water soluble, was synthesized. Each was associated with N'-(2-chloroethyl)-N-[2-(methylsulfonyl)ethyl]-N'-nitrosourea for in vitro evaluation on M4Beu melanoma cells of their ability to enhance the cytotoxic effect of this chloroethylnitrosourea, which is frequently reduced by repairs performed by O6-alkylguanine-DNA-alkyltransferase. Structure-activity analysis revealed that (i) benzyl and 4-halobenzyl are the O6-substituents required to afford a significant activity, (ii) 2'-deoxyguanosine derivatives demonstrate greater potency than guanosine analogs, (iii) acetylation, especially at the N2 position, generally results in compounds with moderate ability but may prevent incorporation of such nucleosides into DNA. Accordingly, O6-(4-iodobenzyl)-N2-acetylguanosine (3b) and O6-benzylperacetyl-2'-deoxyguanosine (2a), as well as O6-benzyl-N2-acetylguanosine (1b) and O6-benzyl-N2-acetyl-2'-deoxyguanosine (2b), by far the most water soluble, exhibit a good profile for further in vivo trials by the intravenous route.
Subject(s)
Antimetabolites, Antineoplastic/toxicity , Antineoplastic Agents, Alkylating/toxicity , Deoxyguanosine/analogs & derivatives , Deoxyguanosine/toxicity , Ethylnitrosourea/analogs & derivatives , Guanosine/analogs & derivatives , Guanosine/toxicity , Animals , Antimetabolites, Antineoplastic/chemical synthesis , Antimetabolites, Antineoplastic/chemistry , Cell Survival/drug effects , Computer Simulation , Deoxyguanosine/chemical synthesis , Deoxyguanosine/chemistry , Drug Synergism , Ethylnitrosourea/toxicity , Guanosine/chemical synthesis , Guanosine/chemistry , Hydrogen Bonding , Indicators and Reagents , Magnetic Resonance Spectroscopy , Models, Molecular , Molecular Conformation , Molecular Structure , Static Electricity , Structure-Activity RelationshipABSTRACT
Bifunctional chloroethylating cytostatic agents produce lethal DNA lesions, as a result of the formation of O6-alkylguanines. These lesions can be repaired by O6-methylguanine-DNA methyltransferase (MGMT). This ubiquitous nuclear and cytosolic enzyme removes the alkyl group by accepting it to the cysteine residue of its active site, thus preventing the formation of DNA interstrand cross-links. The role of the circadian organization in cellular protection against such DNA insults was examined in male B6D2F1 mice, synchronized with an alternation of 12 h of light and 12 h of darkness (LD12:12). MGMT activity was determined in liver of mice obtained at eight different circadian times, located 3 h apart. MGMT activity varied 5-fold along the 24 h time-scale, from 7 +/- 1 pmol/g of tissue at 7 h after light onset (HALO), during the rest span, up to 32 +/- 9 pmol/g at 19 HALO (second mid to late activity span). This large amplitude circadian rhythm in MGMT activity may be an important determinant of the susceptibility rhythms to alkylating agents. The greatest DNA repair activity occurred at night when mice were active, eat and drink, and thus are at a higher risk of being exposed to chemical insults.
