Addressing the knowledge gap in the genomic landscape and tailored therapeutic approaches to adolescent and young adult cancers.

BACKGROUND: Adolescents and young adults (AYAs) represent a small proportion of patients with cancer. The genomic profiles of AYA patients with cancer are not well-studied, and outcomes of genome-matched therapies remain largely unknown. PATIENTS AND METHODS: We investigated differences between Japanese AYA and older adult (OA) patients in genomic alterations, therapeutic evidence levels, and genome-matched therapy usage by cancer type. We also assessed treatment outcomes. RESULTS: AYA patients accounted for 8.3% of 876 cases. Microsatellite instability-high and/or tumor mutation burden was less common in AYA patients (1.4% versus 7.7% in OA; P = 0.05). However, BRCA1 alterations were more common in AYA patients with breast cancer (27.3% versus 1.7% in OA; P = 0.01), as were MYC alterations in AYA patients with colorectal cancer (23.5% versus 5.8% in OA; P = 0.02) and sarcoma (31.3% versus 3.4% in OA; P = 0.01). Genome-matched therapy use was similar between groups, with overall survival tending to improve in both. However, in AYA patients, the small number of patients prevented statistical significance. Comprehensive genomic profiling-guided genome-matched therapy yielded encouraging results, with progression-free survival of 9.0 months in AYA versus 3.7 months in OA patients (P = 0.59). CONCLUSION: Our study suggests that tailored therapeutic approaches can benefit cancer patients regardless of age.

Gene expression profile of a newly established choriocarcinoma cell line, iC3-1, compared to existing choriocarcinoma cell lines and normal placenta.

Gestational choriocarcinoma is a malignant trophoblastic tumor that usually occurs in the uterus after pregnancy. The tumor is curable with advanced chemotherapy, but the molecular mechanism of choriocarcinoma tumorigenesis remains unclear. This is partly because the low incidence makes it difficult to obtain clinical samples for investigation and because an appropriate choriocarcinoma cell model to study the tumorigenesis has not been developed. We have established a new choriocarcinoma cell line, induced choriocarcinoma cell-1 (iC(3)-1), that possesses unique characteristics compared to other choriocarcinoma cell lines, including production of tumors that consist of the two types of cells commonly found in choriocarcinoma and mimicking of the clinical pathology. Existing trophoblast cell lines utilized in previous choriocarcinoma studies have had significantly dissimilar gene expression profiles. Therefore, it is important to choose an appropriate cell line for a particular study based on the characteristics of the cell line. In this study, to clarify the genetic characteristics of iC(3)-1 and to explore the tumorigenesis mechanism, we examined the gene profile of iC(3)-1 compared to those of existing cell lines and normal placental tissue. Bioinformatics analysis showed that several characteristic genes, IGF1R, CHFR, MUC3A, TAF7, PARK7, CDC123 and PSMD8, were significantly upregulated in iC(3)-1 compared to BeWo and JEG3 cells. Interestingly, HAS2, CD44 and S100P were significantly upregulated in iC(3)-1 compared to parental HTR8/SVneo cells and normal third trimester placenta. Choriocarcinoma samples also showed immunoreactivity to HAS2, CD44 and S100. In summary, the gene expression profile of iC(3)-1 suggests that studies using this cell line can make an important contribution to improved understanding of choriocarcinoma tumorigenesis.

An increased dose of insulin detemir improves glycaemic control and reduces body weight of Japanese patients with diabetes.

AIMS: The aim of study was to evaluate the safety and efficacy of insulin detemir as a basal insulin switching from neutral protamine Hagedorn insulin (NPH) and insulin glargine in patients with diabetes on an intensive insulin therapy regimen. METHODS: This 6-month multicentre, prospective, treat-to-target [glycosylated haemoglobin (HbA(1c) ) less than 6.5%] trial included 92 people with diabetes (61 type 1, 29 type 2 and two unknown diabetes types). Detemir was administered first with fixed dose and injection times and then adapted to optimal dose after 3 months. RESULTS: Mean HbA(1c) (%) of all the subjects at months 4 to 6 of the study was improved compared with month 0 (7.34 ± 0.87, 7.28 ± 0.88, 7.25 ± 0.93 vs. 7.55 ± 1.18; p < 0.05 paired t-test). However, significant improvement was seen only among the patients who had previously used NPH as a basal insulin. Twice-daily injection of basal insulin increased among people in the type 1 previously injected insulin glargine. Total insulin dose increased in the type 1 glargine group. The mean body weight change in the highest quartile body mass index (BMI) group was from 70.7 to 69.3 kg over the 6 months. Quality of life (QoL) relating to the patients' glycaemic control tended to improve without a change in frequency of hypoglycaemia. CONCLUSIONS: The results suggest that insulin detemir has a greater effect on glycaemic control in subjects with poor glycaemic control using NPH; can reduce or maintain body weight in obese patients; and obtains perceptive stability for patients with unstable glycaemic control.

Secretory IgA in saliva and academic stress.

Several reports have proposed that the concentration of secretory immunoglobulin A (S-IgA) in saliva is an indicator of psychological stress. With this in mind, we decided to examine it in 10 second year medical student volunteers at Kawasaki Medical School course between May 4 and July 13, 2000 and discussed the relationship between S-IbA and the stress from academic examinations. Saliva was collected three times (on rising, at forenoon, and at bedtime) every Thursday. During this period, sporadic academic examinations were held twice and term end examination occurred during the last two weeks. Results showed the concentration of S-IgA significantly higher at the on rising time-point than at the other two time-points. There was also a tendency for the S-IgA level in saliva to be higher on the day before academic examinations and during them and lower on the days between these examinations. In addition, daily variations in the S-IgA concentration sometimes seemed to be disturbed by other academic stress. Therefore it may be possible to use this measurement to monitor psychological stress in students and workers.

Nerve growth factor attenuates hippocampal cholinergic deficits and operant learning impairment in rats with entorhinal cortex lesions.

In the present study we investigated whether continuous intraventricular nerve growth factor (NGF) infusion could ameliorate hippocampal cholinergic deficits and learning impairment following entorhinal cortex lesions. Rats with such lesions received continuous intraventricular infusions of NGF or vehicle. Unlesioned rats with a sham operation were studied as controls. After learning sessions, a dialysis probe was implanted in the CA3 hippocampal region. In addition, brain sections were stained for synaptophysin immunoreactivity. In rats undergoing surgical procedures similar to those in the behavioral study, brains were processed for acetylcholinesterase (AChE) histochemistry. NGF-treated rats showed partial amelioration of lesion-associated hippocampal acetylcholine (ACh) efflux deficits and fixed-interval schedule learning impairment compared with vehicle-treated rats. Histochemical, immunohistologic, and microdensitometric analyses confirmed greater density of AChE-positive fibers and synaptophysin immunoreactivity in CA3, in NGF-treated rats relative to vehicle-treated rats, although not as great as in sham-operation rats, indicating partial recovery in NGF-treated rats. These results suggest that enhanced performance of the learning task with NGF treatment was related to improved hippocampal cholinergic function: specifically, increased cholinergic neurotransmission resulting from NGF effects on cholinergic neurons and presynaptic terminals.

Similarities and differences between Alzheimer's disease and vascular dementia from the viewpoint of nutrition.

Dietary habits were compared in patients with Alzheimer's disease (AD) and those with vascular dementia (VaD). Twenty-seven patients with AD, 15 patients with VaD, and 49 age-matched controls were enrolled. Nutritional status was assessed using a semiquantified food-frequency questionnaire. Dietary habits were very similar in male patients with AD and VaD. Both groups had significantly higher energy intake than their energy demands: +25% for AD and +35% for VaD, respectively. However, major sources of energy were different: grains and animal fats for AD versus only grains for VaD. Calculation of nutrients revealed excess intake of n-6 polyunsaturated fatty acids (PUFA) and relative deficiencies of multiple vitamins including antioxidants, vitamin C and carotene, and the vitamin B group. In contrast, dietary habits in female patients with AD differed significantly from those of male patients. Female patients consumed significantly lower amounts of fish and green vegetables. Calculation of nutrients showed absolute deficiencies of n-3 PUFA, multiple vitamins, and minerals. Our results show that AD and VaD are similar from the viewpoint of nutrition, except for the higher consumption of animal fats for AD patients, probably reflecting Westernization of dietary habits in recent years. Nutrition may be relevant to the pathogenesis of dementia through many processes. Higher intake of energy and lower intake of antioxidants may exaggerate the process of dementia through oxidative stress. Excessive amounts of n-6 PUFA or deficiency of n-3 PUFA may cause chronic inflammation, platelet aggregation, or endothelial dysfunction of microvasculature. Nutrition may be useful for preventing dementia, although gender-specific differences must be taken into account.

Intramolecular epitope spreading among anti-caspase-8 autoantibodies in patients with silicosis, systemic sclerosis and systemic lupus erythematosus, as well as in healthy individuals.

Dysregulation of apoptosis through the Fas-Fas ligand pathway is relevant in autoimmune disease onset. We recently reported elevated serum levels of sFas in patients with silicosis, systemic sclerosis (SSC) and systemic lupus erythematosus (SLE), and proposed a block of apoptosis in the pathogenesis. The disturbance of apoptosis in lymphocytes including autoreactive clones could induce autoantibody production. Since autoantibodies directed against unknown antigens are present in the sera of these patients, the sera samples were examined for the presence of autoantibodies directed to caspase-8. Using Western blotting, autoantibodies against caspase-8 were detected in healthy individuals and in over 60% of patients. Using epitope mapping employing 12 amino acid polypeptides with SPOTs system, a minimum of 4 epitopes and a maximum of 13 were found, which implied that epitope spreading was in progress. It is noteworthy that two important catalytic cystein residues were included within the epitopes; firstly the active site cystein Cys287, and secondly Cys360 located in the unique pentapeptide motif QACQG. Using recombinant human caspase-8 linked protein chip array, autoantibodies were identified and molecular weight determined. The antibodies were mainly IgG; 80% were subclass IgG1(lambda); 20% were IgG4(kappa). Despite the ratio of human light chain kappa:lambda = 2:1, the predominance of IgG1(lambda) is noticeable. Anti-caspase-8 autoantibodies are detectable in healthy individuals and in patients suffering silicosis, SSc or SLE. A few epitopes were detected in healthy individuals compared to those suffering autoimmune diseases, indicating the intramolecular epitope spreading. Relationship of autoantibodies and the clinical background of the patients requires clarification.

Anti-HER2-antibody enhances irradiation-induced growth inhibition in head and neck carcinoma.

To explore the antiproliferative effects of rhumAbHER2 on head and neck squamous carcinoma cell (HNSCC) lines and breast cancer cell lines (BCCLs) and to evaluate the combined effects with irradiation, 2 human HNSCC lines and 2 BCCLs were exposed to rhumAbHER2 with or without irradiation. The results showed that combined treatment enhanced the growth and colonization inhibitory effects of rhumAbHER2 or irradiation. Interestingly, the apoptotic cell fraction produced by irradiation disappeared on combined treatment. This disappearance was associated with repression of p53 and Bax upregulation induced by irradiation, but conservation of the upregulation of p27. Based on these results, rhumAbHER2 and irradiation may be a new strategy for treating HNSCC and breast cancers. In addition, the upregulation of cyclin-dependent kinase inhibitors by rhumAbHER2 may occur upstream of irradiation-induced p53 upregulation.

Long-term synaptic alteration in the rat hippocampal CA3 field following an entorhinal cortex lesion.

The entorhinal cortex is a key initial relay for cortical input to the hippocampus. To better understand hippocampal dysfunction resulting from early entorhinal cortex involvement in Alzheimer's disease, we stereotaxically injected ibotenic acid to produce unilateral entorhinal cortex lesions in rats. We then serially examined the CA3 hippocampal region by neuronal counts, histochemistry for acetylcholinesterase, and synaptophysin immunohistochemistry. Over 12 months, the neuronal counts did not change. Acetylcholinesterase-positive fibers were persistently but non-progressively beginning at 3 months. Synaptophysin immunoreactivity progressively declined over 12 months. Since much of the entorhinal cortex output proceeds to CA3 via the dentate gyrus, transsynaptic degeneration is suspected.

Establishment of CD7+ human myeloma sister cell lines, KMS-21-PE and KMS-21-BM, carrying t(11;14) and t(8;14).

Two new human myeloma cell lines were established from pleural effusion and bone marrow malignant cells derived from a single patient, who manifested hyperammonemia associated with multiple myeloma, and these were characterized. Both lines possess t(11;14)(q13;q32) and t(8;14)(q24;q32) reciprocal translocations and overexpress cyclin D1, but not c-myc. Human myeloma lines including these new lines produced and secreted excess ammonia into culture medium more than non-myelomatous hematological cell lines. In addition, these two lines were revealed to have high surface CD7 expression correlated with relatively high mRNA expression by MP-RT-PCR. Among 8 human myeloma lines, half of them revealed significant surface expression of CD7 and a positive correlation between expression levels of protein and message. CD7 message was also detected in surface negative lines. Consequently, there may be posttranslational regulation of the CD7 molecule, whose cellular biological role in expressing cells has not been elucidated.

Cell cycle analysis and expression of cell cycle regulator genes in myeloma cells overexpressing cyclin D1.

Among the recently discovered myeloma-specific gene alterations associated with chromosomal translocations, cyclin D1/PRAD1/Bcl-1 overexpression caused by t(11;14)(q13;q32) is considered to be the most frequent in myeloma patients and cell lines, and may be a prognostic factor clinically. To elucidate the cellular biological role of overexpressed cyclin D1 in myeloma cells, we examined the mRNA expression levels of cell cycle regulators including three cyclin Ds, cyclin-dependent kinase inhibitors (CDK-Is) and accelerators. Cyclin D1 overexpression was clearly demonstrated in the lines with abnormal 11q13 and associated with overexpression of S and G2 accelerator genes. The cyclin D1-overexpressing lines tended to have a shortened G1 phase compared with the non-expressing lines. In addition, artificial silencing using antisense oligonucleotides for cyclin D1 suppressed the growth rate of some but not all cyclin D1-overexpressing cells. These results indicate that overexpression of cyclin D1 caused by cytogenetic abnormalities may make cells progress through the cell cycle rapidly, but it seems that other factors such as cyclin D2 and translocation-related genes affect the cell cycle progression in myeloma cells.

Factors associated with mortality in patients with early-onset Alzheimer's disease: a five-year longitudinal study.

To identify neuropsychiatric and somatic factors related to survival in early-onset Alzheimer's disease, we longitudinally studied 108 patients (35 male, 73 female) with early-onset Alzheimer's disease who were 46 to 64 years old at onset and 50 to 69 years old when diagnosed at our institution. A five-year follow-up, 30 patients had died. Pneumonia was the most common cause (73%), followed by malignancy (20%) and heart disease (7%). Kaplan-Meier survival curves showed a lower survival rate in patients with early-onset Alzheimer's disease than in age- and sex-matched life-table data in Japan. In Cox proportional hazards analysis, male gender, early disease onset, concurrent physical illness at time of diagnosis, and a low mini-mental state examination score increased the likelihood of death in patients with early-onset Alzheimer's disease. Our study confirmed that these patients have considerable excess mortality and a different pattern of cause of death than in the general population. Gender, age at onset, physical illness, and cognitive function strongly influenced survival. These factors may be predictors of mortality in patients with early-onset Alzheimer's disease that are useful in counseling patients and their families.

Biological effects of asbestos fibers on human cells in vitro--especially on lymphocytes and neutrophils.

Biological effects of asbestos fibers were reviewed in relation to the polyclonal activation of human lymphocytes and to the release of free radicals from human neutrophils in vitro. Chrysotile, crocidolite, and amosite asbestos activate CD4+ T lymphocytes polyclonally, followed by activation-induced cell death (a type of apoptosis). The activation is HLA class II dependent, and certain Vbeta repertoire, e.g. Vbeta 5.3, are detected among the fractionated T cells with a high Ca++ level that had been stimulated by asbestos fibers. These observations support the possibility that asbestos acts as a superantigen, and that asbestos stimulate lymphocytes repeatedly in vivo. It has been reported that asbestos-induced cytotoxicity can be suppressed by the scavengers of superoxide or hydroxyl radical. Some of these scavengers such as dimethylsulfoxide (DMSO) or retinoic acid are known as inducers of cell differentiation. The biological functions of DMSO for cell differentiation of HL-60 cells to neutrophils are suppressed by co-culturing of crocidolite asbestos, because DMSO reacts with the hydroxyl radical released after the stimulation with crocidolite and spent itself. Superoxide dismutase (SOD) inhibited the effects of crocidolite, reacting rapidly with *O2- before the secondary release of *OH. It seems to be probable that asbestos fibers, especially crocidolite, suppress the tissue cell differentiation by releasing free radicals and by wasting inducers of cell differentiation as radical scavengers.

Autoantibodies detectable in the sera of silicosis patients. The relationship between the anti-topoisomerase I antibody response and HLA-DQB1*0402 allele in Japanese silicosis patients.

Eighty-one Japanese silicosis patients and 66 healthy volunteers were analyzed for autoantibodies by ELISA, and HLA-genotyping using the PCR-RFLP method was performed. Anti-topoisomerase I (anti-topo I) autoantibodies were detected in seven patients without any clinical features of autoimmune diseases such as progressive systemic sclerosis (PSS), although anti-topo I have been mostly reported in PSS patients. Antibodies directed to RNP, ssDNA, dsDNA and cent-B were not detected among the anti-topo I positive patients. The indirect immunofluorescent staining pattern of Hep-2 cells with the sera of anti-topo I positive silicosis patients demonstrated the typical mode of anti-topo I autoantibodies observed in the patients with PSS. The allelic frequency of HLA-DQB1*0402 was significantly higher in anti-topo I positive patients (28.6%) than in anti-topo I negative patients (1.5%, P < 0.001) or healthy controls (0.8%, P<0.001). HLA-DQB1*0301, DQB1*0601 and DPB1*1801 alleles were more frequently detected in anti-topo I positive patients than in the patients without anti-topo I or in healthy volunteers, but no significant difference was observed. DQB1 allele is associated with the induction of anti-topo I autoantibodies in Japanese silicosis patients, but the allele is not the same as in Caucasian PSS patients. Another allele (DQB1*0402) plays an important role in Japanese silicosis patients. The most important factor to induce anti-topo I autoantibodies seems not to be the type of alleles themselves, but the position of some specific amino acid residues in the DQ beta first domain. These findings will be useful for preventing occupational autoimmune diseases.

Expression and in vitro modification of parathyroid hormone-related protein (PTHrP) and PTH/PTHrP-receptor in human myeloma cells.

To elucidate the role of PTHrP in myeloma, we examined the expression levels of PTHrP and its receptor in human myeloma cell lines and clinical specimens from 13 myeloma cases. In vitro modification of PTHrP expression and production induced by TGF-beta and PMA in PTHrP expressing myeloma cell lines was also investigated. PTHrP expression was detected in six out of seven myeloma cell lines with an inverse correlation with the expression of its receptor, and in 10 out of 13 clinical specimens in varying degrees. The PTHrP expression and secretion into culture medium were enhanced by supplemental TGF-beta and PMA. PMA also seemed to affect PTHrP upregulation via TGF-beta activation. The fundamental role of PTHrP in bone lesions and hypercalcemia in myeloma may be important to consider even during the initial phase of the disease and particularly in the progression of bone complications with hypercalcemia.

Antidesmoglein autoantibodies in silicosis patients with no bullous diseases.

BACKGROUND: Pemphigus is an autoimmune bullous disease characterized by the presence of antidesmoglein autoantibodies. However, the mechanism of its autoantibody production remains unknown. In previous reports, we have described rare cases of pemphigus and pemphigoid associated with silicosis. It is well known that during long-term silicosis, some autoimmune diseases, such as systemic sclerosis, systemic lupus erythematosus or rheumatoid arthritis, can occur. OBJECTIVE: The aim of this study was to explore the presence of pemphigus or pemphigoid autoantibodies in silicosis patients without clinical bullous diseases or collagen diseases. METHOD: The presence of pemphigus antibodies was examined in 54 silicosis patients with no associated bullous diseases, using immunofluorescence, the enzyme-linked immunosorbent assay (ELISA) for desmoglein 1 and 3, and immunoblotting methods. In the antibody-positive cases, HLA genotyping of peripheral lymphocytes was performed with PCR-RFLP. RESULTS: Seven out of the 54 patients were found to be positive for pemphigus antibodies and 1 for bullous pemphigoid by immunofluorescence. In addition, by ELISA, 6 patients were found to be positive against the desmoglein 1 antigen, 2 against the desmoglein 3 antigen and 2 against both desmoglein 1 and desmoglein 3. CONCLUSION: The results of the present study strongly suggest the occurrence of pemphigus and pemphigoid autoantibodies in patients with silicosis. It remains unclear whether such patients will develop an autoimmune bullous disease in the future. Accordingly, long-term follow-up of antibody-positive patients is required.

A novel polymorphism of the brain-derived neurotrophic factor (BDNF) gene associated with late-onset Alzheimer's disease.

Several lines of evidence have suggested altered functions of the brain-derived neurotrophic factor (BDNF) in the pathogenesis of neurodegenerative diseases including Alzheimer's disease (AD). In the search for polymorphisms in the 5'-flanking and 5'-noncoding regions of the BDNF gene, we found a novel nucleotide substitution (C270T) in the noncoding region. We performed an association study between this polymorphism and AD in a Japanese sample of 170 patients with sporadic AD (51 early-onset and 119 late-onset) and 498 controls. The frequency of individuals who carried the mutated type (T270) was significantly more common in patients with late-onset AD than in controls (P = 0.00004, odds ratio: 3.8, 95% CI 1.9-7.4). However, there was no significant difference in the genotype distribution between the patients with early-onset AD and the controls, although this might be due to the small sample size of the early-onset group. Our results suggest that the C270T polymorphism of the BDNF gene or other unknown polymorphisms, which are in linkage disequilibrium, give susceptibility to late-onset AD. We obtained no evidence for the possible interactions between the BDNF and apolipoprotein E (APOE) genes, suggesting that the possible effect of the BDNF gene on the development of late-onset AD might be independent of the APOE genotype.

Different distribution of HLA class II alleles in anti-topoisomerase I autoantibody responders between silicosis and systemic sclerosis patients, with a common distinct amino acid sequence in the HLA-DQB1 domain.

Autoantibodies against DNA topoisomerase I (anti-topo I) have been reported to be specific to systemic sclerosis (SSc), however, anti-topo I was detected in patients with silicone breast implants, SLE without features of SSc, and rheumatic diseases. We detected anti-topo I positive silicosis patients without any symptoms of autoimmune diseases. The correlation between anti-topo I autoantibody responses and HLA class II has been established. HLA-DRB1*1502; DQB1*0601 has been reported to be the most frequent anti-topo I associated haplotype among Japanese SSc patients. In this study, haplotype HLA-DR15; DQ6 was detected in all 4 anti-topo I positive Asian Japanese SSc patients randomly selected. Furthermore, HLA-DQB1*0402 was identified in 3 of 4 anti-topo I positive silicosis patients. These findings coincide with the results of a previous study, in which all 4 Japanese patients with anti-topo I had the DQB1*04 alleles, whereas no studies among Caucasian-Americans, African-Americans and Choctaw Indians found the involvement of DQB1*04. We investigated common features among various DQB 1 alleles. HLA-DQB I with a distinct characteristic is clearly involved in the anti-topo I response irrespective of ethnic groups, the main disease, or silica exposure. A common positioning of distinct amino acids, (i.e. positions 14, 30, 57 and 77 of the DQbeta1 domain are methionine, tyrosine, aspartic acid and threonine, respectively,) seems to be associated with anti-topo I response. The above-mentioned amino acid sequence is detected in alleles *0301, *0303, *0306, *0401, *0402, *0601 and *0602.

[Malignant syndrome caused by a combination of bromperidol and donepezil hydrochloride in a patient with probable dementia with Lewy bodies].

The patient was a 68-year-old man with a 1-year history of delusions related to well-formed and detailed visual hallucinations. Bromperidol 12 mg was prescribed to treat his symptoms. After a diagnosis of dementia of Alzheimer's type was suspected, the patient received donepezil hydrochloride 5 mg. One week later, the patient's Parkinsonism deteriorated. One month later, the patient developed radical edema of the eyelids and the anterior neck, hypoproteinemia, and severe anteflexion of the body. One and a half months later, the patient developed malignant syndrome. His medication was discontinued and parenteral nutrition was started. The patient recovered from his malignant syndrome. However, 1 month later, his Parkinsonism had not improved. The patient received levodopa to treat his Parkinsonism and his symptoms subsequently improved. The hallucinations and systematized delusions returned. The patient's cognitive impairment deteriorated on one side. The aggravation of extrapyramidal symptoms and the development of malignant syndrome were believed to have been caused by the combination of bromperidol and donepezil hydrochloride and poor nutrition. Caution should be exercised when prescribing an antipsychotic drugs with donepezil hydrochloride.