Conformational studies of depurinating DNA adducts from syn-dibenzo(a,l)pyrene diolepoxide

One of the major DNA adducts from the extremely potent aromaticcarcinogen dibenzo(a,l)pyrene (DB(a,l)P) is the depurinatingadduct syn-DB(a,l)P diolepoxide-14-N7Ade. Low-temperature fluorescencespectra of this adduct (and related derivatives bound to N3-adenineand N7-guanine) showed two distinct (0, 0) origin bands withdifferent excited-state vibrational frequencies, as measuredby means of fluorescence line narrowing spectroscopy. The relativeintensity of the two origin bands was solvent dependent. Thehypothesis that this phenomenon could be due to a conformationalequilibrium was tested using molecular mechanics, dynamicalsimulations and semi-empirical quantum-mechanical calculations.The hydrolyzed metabolite DB(a,l)P tetraol was also studiedforcomparison. It was found that the syn-DB(a,l)P diolepoxide-14-N7Adeadduct is formed viatrans addition to the epoxide. Explorationof the conformational space indeed produced two potential energyminima; both corresponding to structures in which the aromaticring system is severely distorted. In conformation I theproximityof the distal ring forces the adenine base into a pseudo-axialposition and the cyclohexenyl ring adopts a half-boat structure.In conformation II the distal ring is bent in the opposite direction,allowing the cyclohexenyl ring to adopt a half-chair structurewith the base in a pseudo-equatorial position, partially stackedover the distal ring. The difference in (0, 0) transition energycalculated for the two conformers agrees very well with thespectroscopic data, and therelative orientations of the hydrogensbound to the cyclohexenyl ring in the major (half-boat) conformationI are in full agreement with the experimentally observed protonNMR coupling constants.     

Intracranial suppuration 1968-1982--a 15 year review

The CT scanner and the recognition of anaerobic organisms has altered the investigation and management of intracranial suppuration. Improved treatment of acute and chronic middle ear infection has also occurred. A 15 year retrospective review was undertaken to assess the effects of these changes. The ears and sinuses were confirmed as the major source of intracranial suppuration (69%) although initial presentation to ENT surgeons was less common (14%). Ear complications occur in childhood and in the fifth and sixth decades; sinus complications predominantly in the second and third decades. The incidence of sinus infection appears to be rising. With the introduction on the CT scanner cerebral abscess mortality declined from 27.5% to 6.5% and subdural abscess mortality halved. The introduction of metronidazole contributed to a drop in mortality. The use of the CT scanner and more accurate antibacterial treatment, including metronidazole, gives hope for a more successful outcome than was previously possible.     

Acetylcholinesterase is increased in mouse neuronal and astrocyte cultures after treatment with beta-amyloid peptides

The cellular origin of the acetylcholinesterase (AChE) associated with amyloid plaques in the Alzheimer's disease (AD) brain is unknown. In this study we report that amyloid beta-peptides (Abeta) increased AChE levels in both neuronal and astrocytic primary cultures, supporting the possibility that both neurons and glia may make a direct contribution to the pool of AChE seen around amyloid deposits in the AD brain.     

Osteoporosis in men treated with androgen deprivation therapy for prostate cancer

PURPOSE: We surveyed the growing literature on osteoporosis secondary to androgen deprivation therapy and provide suggestions regarding its identification and treatment. MATERIALS AND METHODS: We reviewed pertinent studies of male osteoporosis, osteoporotic fracture incidence or bone mineral density loss as a possible side effect of prostate cancer treatment and potential therapies for this side effect. RESULTS: Hypogonadism is a well-known cause of secondary osteoporosis in men. There is evidence of decreased bone mineral density with all types of androgen deprivation therapy, presumably due to its anti-testosterone effect. Bone mineral density loss is 3% to 5% yearly in the first few years of androgen deprivation therapy with an increase in osteoporotic fracture incidence. There are little data on potential treatments, although bisphosphonates and intermittent androgen deprivation therapy may have salutary effects. CONCLUSIONS: Osteoporosis is an important and debilitating side effect of androgen deprivation therapy, although precise estimates of its incidence, degree and cost are not completely elucidated. Until more data are available, it is prudent for all men beginning androgen deprivation therapy to receive calcium and vitamin D, and maintain a moderate exercise regimen. Baseline and at least 1 followup bone density measurement seem appropriate with bisphosphonate treatment a possibility in those in whom osteoporosis develops. More research is needed to explore the effect of bisphosphonates, calcium and vitamin D supplementation, exercise, calcitonin, selective estrogen re-uptake inhibitors, estrogens and intermittent androgen deprivation therapy on the course of androgen deprivation therapy induced osteoporosis. The osteoporotic fracture incidence and bone mineral density should be regularly incorporated into studies involving the hormonal treatment of prostate cancer.     

Low dose ketoconazole with replacement doses of hydrocortisone in patients with progressive androgen independent prostate cancer

PURPOSE: High-dose (400 mg.) oral ketoconazole 3 times daily with replacement doses of hydrocortisone has become a standard treatment option for patients with advanced prostate cancer which progresses after androgen deprivation. However, toxicity can hinder the ability to deliver treatment and the cost of the regimen can be substantial. Therefore, a prospective phase II study was conducted to assess the efficacy and safety of a regimen of low dose (200 mg.) oral ketoconazole 3 times daily with replacement doses of hydrocortisone in men with androgen independent prostate cancer. MATERIALS AND METHODS: The study included 28 patients with progressive prostate cancer despite anorchid levels of testosterone and ongoing testicular androgen suppression. Treatment consisted of low dose ketoconazole and replacement doses of oral hydrocortisone (20 mg. every morning and 10 mg. at bedtime). At the time of disease progression patients were treated with high dose ketoconazole and continued on the same dose of hydrocortisone. Adrenal androgen levels were measured, and baseline and followup levels correlated with clinical outcome. RESULTS: Overall, 13 (46%) of 28 patients had a prostate specific antigen decrease of more than 50% (95% confidence interval 27.5% to 66.1%). Median duration of prostate specific antigen decrease for all responders was 30+ weeks and 5 patients continue to exhibit a response, ranging from 36+ to 53+ weeks. In general, therapy was well tolerated. There were no grade 4 toxicities. Grade 3 toxicities included hepatotoxicity in 1 patient and depression in 2. The most common toxicities were nausea (29% grades 1 and 2), dry skin (18% grade 1) and fatigue (14% grade 1). Four (14%) patients discontinued low dose ketoconazole due to toxicities. Of the 16 patients who received high dose ketoconazole after disease progression with low dose ketoconazole, 3 were removed from treatment due to toxicity and no patient responded to high dose ketoconazole. There was no difference in the distribution of pretreatment endocrine values between responders and nonresponders, and the magnitude of change in adrenal androgen levels was not associated with response to therapy, although a potential association could easily have been missed due to small sample size. CONCLUSIONS: The regimen of low dose ketoconazole with replacement doses of hydrocortisone is well tolerated and has moderate activity in patients with progressive androgen independent prostate cancer.     

Cholinergic regulation of synaptic plasticity as a therapeutic target in Alzheimer's disease

There is increasing evidence for disturbances in nicotinic acetylcholine receptor (nAChR) function in Alzheimer's disease (AD). nAChRs are involved in the regulation of many processes, including synaptic plasticity and memory. Levels of nAChRs are altered in the Alzheimer brain and there is evidence that the amyloid betaprotein (Abeta) can directly bind to nAChRs. Nicotinic agonists may also protect cells from Abeta toxicity. Drugs which interact with the nAChR or which inhibit Abeta binding to nAChRs may be of value for the treatment of AD.