BackgroundAntipsychotic medication reduces the severity of serious mental illness (SMI) and improves patient outcomes only when medicines were taken as prescribed. Nonadherence to the treatment of SMI increases the risk of relapse and hospitalization and reduces the quality of life. It is necessary to understand the factors influencing nonadherence to medication in order to identify appropriate interventions. This systematic review assessed the published evidence on modifiable reasons for nonadherence to antipsychotic medication in patients with SMI.MethodsArticles published between January 1, 2005, and September 10, 2015, were searched on MEDLINE through PubMed. Abstracts were independently screened by 2 randomly assigned authors for inclusion, and disagreement was resolved by another author. Selected full-text articles were divided among all authors for review.ResultsA qualitative analysis of data from 36 articles identified 11 categories of reasons for nonadherence. Poor insight was identified as a reason for nonadherence in 55.6% (20/36) of studies, followed by substance abuse (36.1%, 13/36), a negative attitude toward medication (30.5%, 11/36), medication side effects (27.8%, 10/36), and cognitive impairments (13.4%, 7/36). A key reason directly associated with intentional nonadherence was a negative attitude toward medication, a mediator of effects of insight and therapeutic alliance. Substance abuse was the only reason consistently associated with unintentional nonadherence, regardless of type and stage of SMI.DiscussionAlthough adherence research is inherently biased because of numerous methodological limitations and specific reasons under investigation, reasons for nonadherence consistently identified as significant across studies likely reflect valid existing associations with important clinical implications.ConclusionThis systematic review suggests that a negative attitude toward medication and substance abuse are consistent reasons for nonadherence to antipsychotic medication among people with SMI. Adherence enhancement approaches that specifically target these reasons may improve adherence in a high-risk group. However, it is also important to identify drivers of poor adherence specific to each patient in selecting and implementing intervention strategies.

Treatment of SKH-1 hairless mice with UVB (30 mJ/cm 2 ) twice a week for 20 weeks results in the formation of cellular patches, long before the appearance of tumors, that are visualized in epidermal sheets with an antibody (PAb240) recognizing mutated p53 protein. Direct sequencing analysis of the whole coding region of the p53 gene (exons 2-11) detected one or two mutations in 64.4% of 104 analyzed patches and no mutations in nonstained adjacent normal controls. Homozygous mutation was detected in 22.4% of the mutant patches. Except for two nonsense mutations, all others were missense (exons 4-9) and mostly (95.5%) at the DNA-binding domain. Primer extension analysis of cloned PCR fragments found three of four double-mutated patches harboring different mutations in separate alleles. All mutation hotspots reported earlier in UVB-induced mouse squamous cell carcinomas (SCC) at codons 270 (Arg ! Cys), 149 (Pro ! Ser), 275 (Pro ! Leu and Pro ! Ser), and 176 (His ! Tyr) with a frequency of 32.1%, 7.1%, 14.7%, and 3.2% were detected in epidermal patches at a frequency 47.7%, 9.1%, 4.5%, and 2.3%, respectively. Mutations at codons 210 and 191 found in patches at respective frequencies of 8.0% and 4.5% were not previously detected in UVB-induced mouse SCC. In summary, (a) the p53 mutation profile of UVB-induced skin patches and SCC was very similar suggesting that patches are precursor lesions for SCC, (b) a small number of patches harbored mutations that were not before observed in SCC from UVB-treated mice, and (c) about 36% of the patches did not harbor a p53 mutation. (Cancer Res 2005; 65(9): 3577-85)

PMEG (9-(2-phosphonylmethoxyethyl)guanine) is an acyclic nucleotide analog being evaluated for its antiproliferative activity. We examined the inhibitory effects of PMEG diphosphate (PMEGpp) toward DNA polymerases (pol) ␦ and ⑀ and found it to be a competitive inhibitor of both these enzymes. The apparent K i values for PMEGpp were 3-4 times lower than the K m values for dGTP. The analog was shown to function as a substrate and to be incorporated into DNA by both enzymes. Examination of the ability of pol ␦ and pol ⑀ to repair the incorporated PMEG revealed that pol ⑀ could elongate PMEG-terminated primers in both matched and mismatched positions with an efficiency equal to 27 and 85% that observed for dGMP-terminated control templateprimers. Because PMEG acts as an absolute DNA chain terminator, the elongation of PMEG-terminated primers is possible only by cooperation of the 3-5-exonuclease and DNA polymerase activities of the enzyme. In contrast to pol ⑀, pol ␦ exhibited negligible activity on these template-primers, indicating that pol ⑀, but not pol ␦, can repair the incorporated analog. PMEG1 (9-(2-phosphonylmethoxyethyl)guanine) ( Fig. 1) is a member of a new class of acyclic nucleotide analogs characterized as phosphonylmethyl ethers. Several analogs in this class have demonstrated broad spectrum antiviral activity (1). PMEG is being evaluated as an antitumor agent for cancer treatment. Its anti-proliferative activity has been demonstrated in vitro against human leukemic cells (2) as well as a number of solid tumor cell lines (3). PMEG also showed antitumor activity in two types of mouse transplantable tumors, P388 lymphocytic leukemia and B16 melanoma (4). In addition, the analog suppressed the growth of papillomavirus-induced condylomas on human foreskin xenografts in mice (5).Once inside the cells, cellular enzymes phosphorylate the analog to PMEG mono-and diphosphate (6). The diphosphate form (PMEGpp) is an analog of dGTP. Although the mechanism of action of PMEG has not yet been determined, PMEG diphosphate has been shown to be a potent inhibitor of rat DNA polymerase ␣ and ⑀ (7) and to be incorporated into DNA in vitro by human DNA polymerase ␣ and ␦ (8, 9). Therefore, it can potentially inhibit cellular DNA synthesis.DNA polymerases ␣, ␦, and ⑀ are the enzymes cooperating in chromosomal DNA replication (10). Pol ␣, associated with DNA primase activity, synthesizes RNA-DNA primers for initiation of DNA replication at ori sites and for priming of Okazaki fragments on the lagging strand of DNA. Pol ␦, in cooperation with proliferating cell nuclear antigen (PCNA) and other protein factors, synthesizes the leading strand of DNA. Pol ⑀, which is dispensable for SV40 DNA replication (11) but not for cellular DNA replication (12), may be required as a second DNA polymerase on the lagging DNA strand (13). In contrast to pol ␣, both pol ␦ and pol ⑀ have intrinsic 3Ј-5Ј-exonuclease activity associated with a proofreading function (14). Both enzymes are necessary for the repair of cellular DNA damage after UV ...

Oral administration of green tea or caffeine to SKH-1 mice during UVB irradiation for several months inhibited the formation of skin cancer. Similar effects were observed when green tea or caffeine was given to tumor-free UVB-initiated mice with a high risk of developing skin tumors in the absence of further UVB irradiation (high risk mice). Mechanistic studies indicated that topical application of caffeine stimulated UVB-induced apoptosis as well as apoptosis in UVB-induced focal hyperplasia and tumors in tumor-bearing mice. Oral or topical administration of caffeine enhanced the removal of patches of epidermal cells with a mutant form of p53 protein that appeared early during the course of UVB-induced carcinogenesis, and oral administration of caffeine altered the profile of p53 mutations in the patches. In additional studies, topical application of caffeine was shown to have a sunscreen effect, and topical application of caffeine sodium benzoate was more active than caffeine as a sunscreen and for stimulating UVB-induced apoptosis. Caffeine sodium benzoate was also highly active in inhibiting carcinogenesis in UVB-pretreated high risk mice. Our studies indicate that caffeine and caffeine sodium benzoate may be useful as novel inhibitors of sunlight-induced skin cancer.

Incubation of CEM cells for 24 h with the guanine, 2,6-diaminopurine, and adenine nucleotide analogs of the 9-(2-phosphonylmethoxyethyl) series, 9-(2-phosphonylmethoxyethyl)guanine (PMEG), 9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine (PMEDAP), and 9-(2-phosphonylmethoxyethyl)adenine (PMEA), was found to inhibit DNA synthesis 50% at concentrations of 1, 6, and 25 microM, respectively. Possible reasons for the marked differences were investigated, including cellular transport of the analogs, different efficiencies of intracellular phosphorylation, differential effects on 2'-deoxynucleotide (dNTP) pools, and differences in the affinities of the cellular DNA polymerases for the diphosphate derivatives of the drugs. No significant differences in cellular uptake were found among the analogs; however, they did differ in the efficiency of phosphorylation, i.e., CEM cells were found to accumulate higher levels of PMEG-diphosphate (PMEGpp) than PMEDAP-diphosphate (PMEDAPpp) or PMEA-diphosphate (PMEApp). Treatment of cells with any of the nucleotide analogs resulted in increased dNTP pools, with PMEG producing the greatest increase. All three analogs had the greatest effect on the dATP pool size, whereas the dGTP pool size was not significantly affected. Comparison of the ratios of nucleotide analog diphosphates to their corresponding dNTPs under conditions where DNA synthesis is inhibited 50% suggested that cellular DNA polymerases were approximately twice as sensitive to PMEGpp than to PMEDAPpp and 5-fold more sensitive to PMEGpp than to PMEApp. Consistent with this hypothesis, examination of the efficiencies with which the replicative DNA polymerases alpha, delta, and epsilon incorporated the analogs showed that DNA polymerase delta, the most sensitive of the DNA polymerases, incorporated PMEGpp twice as efficiently as PMEDAPpp and 7-fold more efficiently than PMEApp.