Discovery of a proneurogenic, neuroprotective chemical.

An in vivo screen was performed in search of chemicals capable of enhancing neuron formation in the hippocampus of adult mice. Eight of 1000 small molecules tested enhanced neuron formation in the subgranular zone of the dentate gyrus. Among these was an aminopropyl carbazole, designated P7C3, endowed with favorable pharmacological properties. In vivo studies gave evidence that P7C3 exerts its proneurogenic activity by protecting newborn neurons from apoptosis. Mice missing the gene encoding neuronal PAS domain protein 3 (NPAS3) are devoid of hippocampal neurogenesis and display malformation and electrophysiological dysfunction of the dentate gyrus. Prolonged administration of P7C3 to npas3(-/-) mice corrected these deficits by normalizing levels of apoptosis of newborn hippocampal neurons. Prolonged administration of P7C3 to aged rats also enhanced neurogenesis in the dentate gyrus, impeded neuron death, and preserved cognitive capacity as a function of terminal aging. PAPERCLIP:

Novel orexin receptor agonists based on arene- or pyridine-fused 1,3-dihydro-2H-imidazole-2-imines.

A structurally novel class of benzo- or pyrido-fused 1,3-dihydro-2H-imidazole-2-imines was designed and evaluated in an inositol phosphate accumulation assay for Gq signaling to measure agonistic activation of the orexin receptor type 2 (OX2R). These compounds were synthesized in 4-9 steps overall from readily available starting materials. Analogs that contain a stereogenic methyl or cyclopropyl substituent at the benzylic center, and a correctly configured alkyl ether, alkoxyalkyl ether, cyanoalkyl ether, or α-hydroxyacetamido substituted homobenzylic sidechain were identified as the most potent activators of OX2R coupled Gq signaling. Our results also indicate that agonistic activity was stereospecific at both the benzylic and homobenzylic stereogenic centra. We identified methoxyethoxy-substituted pyrido-fused dihydroimidazolimine analog 63c containing a stereogenic benzylic methyl group was the most potent agonist, registering a respectable EC50 of 339 nM and a maximal response (Emax) of 96 % in this assay. In vivo pharmacokinetic analysis indicated good brain exposure for several analogs. Our combined results provide important information towards a structurally novel class of orexin receptor agonists distinct from current chemotypes.

The structure of importin α and the nuclear localization peptide of ChREBP, and small compound inhibitors of ChREBP-importin α interactions.

The carbohydrate response element binding protein (ChREBP) is a glucose-responsive transcription factor that plays a critical role in glucose-mediated induction of genes involved in hepatic glycolysis and lipogenesis. In response to fluctuating blood glucose levels ChREBP activity is regulated mainly by nucleocytoplasmic shuttling of ChREBP. Under high glucose ChREBP binds to importin α and importin ß and translocates into the nucleus to initiate transcription. We have previously shown that the nuclear localization signal site (NLS) for ChREBP is bipartite with the NLS extending from Arg158 to Lys190. Here, we report the 2.5 Šcrystal structure of the ChREBP-NLS peptide bound to importin α. The structure revealed that the NLS binding is monopartite, with the amino acid residues K171RRI174 from the ChREBP-NLS interacting with ARM2-ARM5 on importin α. We discovered that importin α also binds to the primary binding site of the 14-3-3 proteins with high affinity, which suggests that both importin α and 14-3-3 are each competing with the other for this broad-binding region (residues 117-196) on ChREBP. We screened a small compound library and identified two novel compounds that inhibit the ChREBP-NLS/importin α interaction, nuclear localization, and transcription activities of ChREBP. These candidate molecules support developing inhibitors of ChREBP that may be useful in treatment of obesity and the associated diseases.

Synthesis and evaluation of analogs of 5'-(((Z)-4-amino-2-butenyl)methylamino)-5'-deoxyadenosine (MDL 73811, or AbeAdo) - An inhibitor of S-adenosylmethionine decarboxylase with antitrypanosomal activity.

We describe our efforts to improve the pharmacokinetic properties of a mechanism-based suicide inhibitor of the polyamine biosynthetic enzyme S-adenosylmethionine decarboxylase (AdoMetDC), essential for the survival of the eukaryotic parasite Trypanosoma brucei responsible for Human African Trypanosomiasis (HAT). The lead compound, 5'-(((Z)-4-amino-2-butenyl)methylamino)-5'-deoxyadenosine (1, also known as MDL 73811, or AbeAdo), has curative efficacy at a low dosage in a hemolymphatic model of HAT but displayed no demonstrable effect in a mouse model of the CNS stage of HAT due to poor blood-brain barrier permeation. Therefore, we prepared and evaluated an extensive set of analogs with modifications in the aminobutenyl side chain, the 5'-amine, the ribose, and the purine fragments. Although we gained valuable structure-activity insights from this comprehensive dataset, we did not gain traction on improving the prospects for CNS penetration while retaining the potent antiparasitic activity and metabolic stability of the lead compound 1.

Development of proneurogenic, neuroprotective small molecules.

Degeneration of the hippocampus is associated with Alzheimer's disease and occurs very early in the progression of the disease. Current options for treating the cognitive symptoms associated with Alzheimer's are inadequate, giving urgency to the search for novel therapeutic strategies. Pharmacologic agents that safely enhance hippocampal neurogenesis may provide new therapeutic approaches. We discovered the first synthetic molecule, named P7C3, which protects newborn neurons from apoptotic cell death, and thus promotes neurogenesis in mice and rats in the subgranular zone of the hippocampal dentate gyrus, the site of normal neurogenesis in adult mammals. We describe the results of a medicinal chemistry campaign to optimize the potency, toxicity profile, and stability of P7C3. Systematic variation of nearly every position of the lead compound revealed elements conducive toward increases in activity and regions subject to modification. We have discovered compounds that are orally available, nontoxic, stable in mice, rats, and cell culture, and capable of penetrating the blood-brain barrier. The most potent compounds are active at nanomolar concentrations. Finally, we have identified derivatives that may facilitate mode-of-action studies through affinity chromatography or photo-cross-linking.

Synthesis and evaluation of duocarmycin SA analogs incorporating the methyl 1,2,8,8a-tetrahydrocyclopropa[c]oxazolo[2,3-e]indol-4-one-6-carboxylate (COI) alkylation subunit.

The design, synthesis and evaluation of methyl 1,2,8,8a-tetrahydrocyclopropa[c]oxazolo[2,3-e]indol-4-one-6-carboxylate (COI) derivatives are detailed representing analogs of duocarmycin SA containing an oxazole replacement for the fused pyrrole found in the alkylation subunit.

Total synthesis and evaluation of iso-duocarmycin SA and iso-yatakemycin.

The total synthesis and evaluation of iso-duocarmycin SA (5) and iso-yatakemycin (6), representing key analogues of the corresponding natural products incorporating an isomeric alkylation subunit, are detailed. This pyrrole isomer of the natural alkylation subunit displayed an enhanced reaction regioselectivity and a 2-fold diminished stability. Although still exceptionally potent, the iso-duocarmycin SA derivatives and natural product analogues exhibited a corresponding approximate 3-5-fold reduction in cytotoxic activity [L1210 IC(50) for (+)-iso-duocarmycin SA = 50 pM and for (+)-iso-yatakemycin = 15 pM] consistent with their placement on a parabolic relationship correlating activity with reactivity. The DNA alkylation selectivity of the resulting key natural product analogues was unaltered by the structure modification in spite of the minor-groove presentation of a potential H-bond donor. Additionally, a unique ortho-spirocyclization with such derivatives was explored via the preparation, characterization, and evaluation of 34 that is incapable of the more conventional para-spirocyclization. Although 34 proved sufficiently stable for isolation and characterization, it displayed little stability in protic solvents (t(1/2) = 0.19 h at pH 3, t(1/2) = 0.20 h at pH 7), a pH-independent (H(+) independent) solvolysis rate profile at pH 3/4-7, and a much reduced cytotoxic potency, but a DNA alkylation selectivity and efficiency comparable to those of duocarmycin SA and iso-duocarmycin SA. The implications of these observations on the source of the DNA alkylation selectivity and catalysis for this class of natural products are discussed.

Synthesis and evaluation of a thio analogue of duocarmycin SA.

The design, synthesis, and preliminary evaluation of methyl 1,2,8,8a-tetrahydrocyclopropa[c]thieno[3,2-e]indol-4-one-6-carboxylate (CTI) derivatives are detailed representing a single atom change (N to S) embedded in the duocarmycin SA alkylation subunit.

Synthesis and Preliminary Evaluation of Duocarmycin Analogues Incorporating the 1,2,11,11a-Tetrahydrocyclopropa[c]naphtho[2,3-e]indol-4-one (CNI) and 1,2,11,11a-Tetrahydrocyclopropa[c]naphtho[1,2-e]indol-4-one (iso-CNI) Alkylation Subunits.

Efficient syntheses and a preliminary evaluation of 1,2,11,11a-tetrahydrocyclopropa[c]-naphtho[2,3-e]indole (CNI) and 1,2,11,11a-tetrahydrocyclopropa[c]naphtho[1,2-e]indole (iso-CNI), and their derivatives containing an anthracene and phenanthrene variant of the CC-1065 or duocarmycin alkylation subunit are detailed.

Prevalence and correlates of pain in the Canadian National Palliative Care Survey.

BACKGROUND: Pain is a common problem for people with cancer who are nearing the ends of their lives. OBJECTIVE: In the present multicentre Canadian study of palliative cancer care, the prevalence of pain, its perceived severity and its correlates across a range of physical, social, psychological, and existential symptoms and concerns were examined. METHODS: Semistructured interviews were conducted with 381 patients. In addition to inquiring about pain, the interview also assessed 21 other symptoms and concerns, and collected information about demographic characteristics, functional status and medication use. RESULTS: Pain of any intensity was reported by 268 (70.3%) participants, although for 139 (36.5%), the severity was rated as minimal or mild. For 129 (33.9%) individuals, pain was reported as moderate to extreme, and considered by the respondents to be an important ongoing problem. Patients who reported moderate to extreme pain were younger than other participants, but had lower functional status and a shorter median survival duration. They were more likely than other participants to be treated with opioid medications (P<0.001) and, less reliably, with benzodiazepines (P=0.079). Compared with participants with no, minimal or mild pain, those with moderate to extreme pain had a higher prevalence of distressing problems on 11 of 21 other symptoms and concerns. The strongest correlations were with general malaise (rho = 0.44), suffering (rho = 0.40), nausea (rho = 0.34), weakness (rho = 0.31), drowsiness (rho = 0.29) and anxiety (rho = 0.29). CONCLUSIONS: Pain continues to be a difficult problem for many patients who are receiving palliative cancer care, particularly younger individuals who are nearing death.

Pathways to competence: parental adversity and the roles of parenting quality and social support.

The authors studied a representative Canadian cohort from the National Longitudinal Study of Children and Youth at 3 points in time, when the participants were aged 10-11 years (n = 2,147), 12-13 years (n = 1,976), and 14-15 years (n = 1,762). The presence of parent-related adversity appeared detrimental to young people's emotional and behavioral competence. Parents' self-reports of adversity predicted children's self-reports of their own behavioral functioning 2 years later. The authors identified parenting quality and social support as independent resource variables for young people's competence, rather than protective variables in the face of parent-related adversity. Latent variable path analyses suggested the increasing value of both resource variables over time for all young people.

Desire for euthanasia or physician-assisted suicide in palliative cancer care.

OBJECTIVE: To investigate the attitudes of terminally ill individuals toward the legalization of euthanasia or physician-assisted suicide (PAS) and to identify those who would personally desire such a death. DESIGN: In the Canadian National Palliative Care Survey, semistructured interviews were administered to 379 patients who were receiving palliative care for cancer. Patients who expressed a desire for physician-hastened death were followed prospectively. MAIN OUTCOME MEASURES: Attitudes toward the legalization of euthanasia or PAS were determined, as was the personal interest in receiving a hastened death. Demographic and clinical characteristics were also recorded, including a 22-item structured interview of symptoms and concerns. RESULTS: There were 238 participants (62.8%) who believed that euthanasia and/or PAS should be legalized, and 151 (39.8%) who would consider making a future request for a physician-hastened death. However, only 22 (5.8%) reported that, if legally permissible, they would initiate such a request right away, in their current situations. This desire for hastened death was associated with lower religiosity (p=.010), reduced functional status (p=.024), a diagnosis of major depression (p<.001), and greater distress on 12 of 22 individual symptoms and concerns (p<.025). In follow-up interviews with 17 participants, 2 (11.8%) showed instability in their expressed desire. CONCLUSION: Among patients receiving palliative care for cancer, the desire to receive euthanasia or PAS is associated with religious beliefs; functional status; and physical, social, and psychological symptoms and concerns. Although this desire is sometimes transitory, once firmly established, it can be enduring.

Depression and anxiety disorders in palliative cancer care.

Depression and anxiety disorders are thought to be common in palliative cancer care, but there is inconsistent evidence regarding their relevance for other aspects of quality of life. In the Canadian National Palliative Care Survey, semi-structured interviews assessing depression and anxiety disorders were administered to 381 patients who were receiving palliative care for cancer. There were 212 women and 169 men, with a median survival of 63 days. We found that 93 participants (24.4%, 95% confidence interval=20.2-29.0) fulfilled Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnostic criteria for at least one anxiety or depressive disorder (20.7% prevalence of depressive disorders, 13.9% prevalence of anxiety disorders). The most frequent individual diagnosis was major depression (13.1%, 95% confidence interval=9.9-16.9). Comorbidity was common, with 10.2% of participants meeting criteria for more than one disorder. Those diagnosed with a disorder were significantly younger than other participants (P=0.002). They also had lower performance status (P=0.017), smaller social networks (P=0.008), and less participation in organized religious services (P=0.007). In addition, they reported more severe distress on 14 of 18 physical symptoms, social concerns, and existential issues. Of those with a disorder, 39.8% were being treated with antidepressant medication, and 66.7% had been prescribed a benzodiazepine. In conclusion, it appears that depression and anxiety disorders are indeed common among patients receiving palliative care. These disorders contribute to a greatly diminished quality of life among people who are dying of cancer.

Palliative care nurses' perceptions of the Edmonton Symptom Assessment Scale: a pilot survey.

AIM: to evaluate, at a pilot level, palliative care nurses' perceptions of the Edmonton Symptom Assessment Scale's (ESAS's) feasibility and usefulness. METHODS: all nurses working within the Edmonton Palliative Care Programme were provided with a one-page document containing five statements about the benefits and feasibility of the ESAS, and invited to rate each statement on a five-point Likert scale (1=strongly agree; 5=strongly disagree). RESULTS: of the 74 nursing staff employed in the programme, 48 (64.9%) chose to participate in this study. Perceptions of the ESAS were most favourable among the 22 registered nurses: 21 (95.4%) believed the ESAS helped staff care for patients; and 17 (77.3%) believed patients benefited from implementation of the instrument. Most registered nurses found that the ESAS took little time and effort to complete. Licensed practical nurses and nursing attendants had a less favourable perception of the ESAS. CONCLUSION: the results of this pilot study demonstrate that palliative care nurses' perceptions of the ESAS are favourable generally, although they vary according to level of professional training. A full-scale study will be necessary to attain a more in-depth evaluation.

Mental disorders and the desire for death in patients receiving palliative care for cancer.

OBJECTIVES: The desire for death in terminally ill patients is associated with depression and anxiety, but not all patients who report it meet criteria for mental disorders. We examined the characteristics of subgroups of palliative cancer patients who expressed a desire for death that occurred either with or without a concurrent depressive or anxiety disorder. DESIGN: Cross-sectional survey. SETTING: Eight Canadian palliative care programs. PARTICIPANTS: 377 patients with cancer. MAIN OUTCOME MEASURES: Desire for Death Rating Scale; Structured Interview of Symptoms and Concerns. RESULTS: Most participants (69.5%) had no desire for death. Of the remainder, 69 (18.3%) acknowledged occasional transient thoughts, and 46 (12.2%) reported an apparently genuine desire to die. In the latter group, 24 individuals (52.2%) were diagnosed with a mental disorder and 22 (44.8%) were not. Individuals with no serious desire for death and no mental disorder reported the least distress in physical, social, existential, and psychological symptoms and concerns; those with a mental disorder and a significant desire for death reported the most. The subgroup of patients with a serious desire for death but no concurrent mental disorders still reported increased distress due to physical symptoms and social concerns, as well as a higher prevalence of global suffering. CONCLUSIONS: The expression of a desire for death by a terminally ill patient should raise a suspicion about mental health problems, but is not in itself clearly indicative of one. Nevertheless, it may serve as a catalyst to review the individual's physical symptom management and interpersonal concerns, and overall sense of suffering.

The Edmonton injector: a simple device for patient-controlled subcutaneous analgesia.

In a prospective open study we tested the Edmonton injector (EI), a device designed by our group for subcutaneous injection of narcotics. In 25 patients, the EI was used for patient-controlled analgesia (PCA); mean duration of treatment was 28 +/- 10 days. Mean equivalent daily dose of morphine was 160 +/- 85 mg. All patients found the EI safe and simple to operate. The main reason for discontinuation was death (10 cases) or return to oral narcotics (8 cases). In 20 patients who were admitted to the hospital and were too ill to learn PCA, the EI was used for regular s.c. administration by nurses. Narcotics were administered every 4 h and extra doses were administered on a 'PRN' basis. Waiting time for a 'PRN' dose in 8 patients before starting the EI was 18 +/- 7 min; after the EI was started, it was 3 +/- 4 min (P less than 0.01). We conclude that the EI is safe, effective and inexpensive, and that it will be particularly useful in smaller hospitals and developing countries.

Neuropsychological effects of methylphenidate in patients receiving a continuous infusion of narcotics for cancer pain.

Twenty consecutive patients with cancer pain receiving a continuous subcutaneous infusion of narcotics were admitted to a double-blind, crossover trial designed to assess the effects of methylphenidate on neuropsychological functions. After a baseline assessment, patients were randomized to receive methylphenidate orally at 08.00 h for 2 consecutive days or placebo. During day 3, a crossover took place and patients received the alternate treatment for 2 more days. At the end of the trial, both patients and investigators were asked to choose blindly the most effective treatment. Cognitive tests (finger tapping, FT 10 and 30 sec; arithmetics, A; reverse memory of digits, RM; and visual memory, VM) were performed in all patients before and 45 min after their morning dose of narcotics for 2 consecutive days. Mean percentual change in FT 10 sec, FT 30 sec, A, RM, and VM after the narcotic dose were 89 +/- 12%, 98 +/- 15%, 108 +/- 17%, 101 +/- 17%, and 97 +/- 21% in the placebo group versus 119 +/- 16 (P less than 0.001), 130 +/- 19 (P less than 0.001), 78 +/- 21 (P less than 0.001), 125 +/- 28 (P less than 0.01), and 128 +/- 26 (P less than 0.001) in the methylphenidate group, respectively. After completion of the trial, methylphenidate was chosen blindly by the patient and investigator in 13 and 14 cases, placebo in 3 and 2 cases, a "no choice" in 3 and 3 cases, respectively (P less than 0.01). Our results suggest that methylphenidate is capable of improving cognitive function in patients receiving high doses of opiates subcutaneously. More research is necessary in order to determine the duration of cognitive improvement after each dose of methylphenidate as well as the best type and dose of amphetamine.

Decreased local toxicity with subcutaneous diamorphine (heroin): a preliminary report.

We report the cases of 5 patients who developed severe local toxicity during the subcutaneous administration of morphine sulphate and hydromorphone hydrochloride. All patients required site changes more frequently than once every 24 h due to redness, swelling, or pain while receiving morphine or hydromorphone. All patients showed prolongation in the duration of sites of infusion once an equianalgesic dose of diamorphine hydrochloride (heroin) was started. No change in pain control or systemic toxicity was detected with diamorphine. These findings suggest that diamorphine could be a useful alternative for patients who develop severe toxicity to subcutaneous morphine or hydromorphone.

The cognitive effects of the administration of narcotic analgesics in patients with cancer pain.

Forty patients with cancer pain receiving intermittent narcotics were admitted to a prospective study designed to assess the cognitive effects of narcotics. Twenty patients had undergone no change in narcotic dose or type greater than or equal to 7 days (stable dose, SD, group), and 20 patients had undergone an increase of greater than or equal to 30% in dose less than or equal to 3 days before (increased dose, ID, group). Age, primary tumor, type, dose and route of narcotic were not different between the SD and ID group. Cognitive tests (finger tapping, FT, 10 and 30 sec, arithmetic, A, reverse memory of digits, RM, and visual memory, VM) were performed in all patients before and 45 min after their morning dose of narcotics for 2 consecutive days. Mean percentual change in FT 10 sec, FT 30 sec, A, RM, and VM after the narcotic dose were 97 +/- 9%, 100 +/- 14%, 100 +/- 13%, 100 +/- 15%, 98 +/- 19%, in the SD group, vs. 77 +/- 14% (P less than 0.001), 83 +/- 13% (P less than 0.001), 124 +/- 21% (P less than 0.001), 60 +/- 21% (P less than 0.001) and 68 +/- 21% (P less than 0.001) in the ID group, respectively. Our results suggest that patients who undergo a significant increase in the dose of intermittent narcotics experience significant cognitive impairment, that disappears after 1 week of the increase. More research is needed to better characterize the cognitive toxicity of intermittent narcotics, and to determine the cognitive effects of long acting narcotics, continuous infusions, or of the addition of amphetamines.

Circadian distribution of extra doses of narcotic analgesics in patients with cancer pain: a preliminary report.

In this open study we reviewed the circadian distribution of extra doses of narcotic analgesics in 61 bed-ridden patients with cancer pain. The information was collected prospectively and retrospectively in 34 and 27 cases, respectively. All patients were receiving parenteral narcotics using the Edmonton Injector, and none had incidental pain or cognitive impairment. A total of 1322 extra doses of narcotics (each dose = 10% of the daily dose) were administered during 610 patient days (average of 2.17 +/- 1.6 doses/patient/day). The mean daily number of extra doses during each interval was as follows: 02.00-06.00 h (0.24 +/- 0.27), 06.00-10.00 h (0.26 +/- 0.31), 10.00-14.00 h (0.43 +/- 0.44), 14.00-18.00 h (0.44 +/- 0.41), 18.00-22.00 h (0.40 +/- 0.36), and 22.00-02.00 h (0.40 +/- 0.36) (02.00-06.00 h and 06.00-10.00 h vs. 10.00-02.00 h: P less than 0.01). Forty-five of 61 patients (76%) received most of their extra doses of narcotics between 10.00 and 22.00 h. The data suggest that our patients require a larger number of extra doses during day time. Our design cannot establish the reason for this circadian variation.