Subchronic effects following a single sarin exposure on blood-brain and blood-testes barrier permeability, acetylcholinesterase, and acetylcholine receptors in the central nervous system of rat: a dose-response study

Subchronic neurotoxic effects of sarin (O-isopropyl methylphosphonofluoridate) treatment at various doses in male Sprague Dawley rats were studied. The animals were treated with a single intramuscular (im) injection of 0.01, 0.1, 0.5, or 1 x LD50 (100 microg/kg). The animals were maintained for 90 d thereafter. [3H]Hexamethonium iodide was used to monitor the changes in blood-brain barrier (BBB) permeability in cortex, brainstem, midbrain, and cerebellum. Brainstem exhibited a significant decrease (approximately 58% of control) in uptake of [3H]hexamethonium iodide at 1 x LD50 dose. No significant changes were observed in BBB permeability in cortex, midbrain, and cerebellum at any dose. Plasma butyrylcholinesterase (BChE) activity remained unchanged, reflecting recovery of the enzyme activity from the initial inhibition following single exposure of 1 x LD50 sarin. Acetylcholinesterase (AChE) activity in the cortex remained inhibited (approximately 29%), whereas in the brainstem there was an increase (approximately 20%) at 1 x LD50 dose of sarin. The m2-selective muscarinic acetylcholine receptor (m2-mAChR) ligand binding was inhibited significantly at 1 x LD50 in the cortex, whereas brainstem showed significantly increased (approximately 45%) ligand binding at 1 x LD50 dose. Nicotinic acetylcholine receptor (nAChR), on the other hand, showed a biphasic response in ligand binding in the cortex with a decrease (approximately 30%) at 0.01 x LD50 but an increase (approximately 40%) at 1 x LD5O. Brainstem did not show any significant change in nAChR ligand binding. These results suggest that single exposure of sarin could lead to changes that may play an important role in neuropathological abnormalities in the central nervous system.     

Three novel monotetrahydrofuran annonaceous acetogenins from Annona montana

Three new monotetrahydrofuran (mono-THF) acetogenins, anmontanins A-C (1-3) were isolated from the leaves of Annona montana. Anmontanin C (3) is the first stereochemically pure acetogenin reported to have a gamma-hydroxymethyl-gamma-lactone moiety. Two known mono-THF acetogenins, murisolin and annonacin, were isolated from the seeds of the plant. The structures of compounds 1-3 were elucidated by spectral methods and chemical derivatization.     

Taraxacin, a new guaianolide from Taraxacum wallichii

A new guaianolide, taraxacin (1), and a known sesquiterpene ketolactone (2) have been isolated from an ethyl acetate-soluble part of a methanolic extract of Taraxacum wallichii. The structure of 1 was established using NMR, MS, and X-ray crystallographic methods. The (13)C NMR data of 2 is also being reported for the first time.     

Phase I and pharmacologic study of CT-2584 HMS, a modulator of phosphatidic acid, in adult patients with solid tumours

CT-2584 HMS, 1-(11-dodecylamino-10-hydroxyundecyl)-3, 7-dimethylxanthine-hydrogen methanesulphonate, is a modulator of intracellular phosphatidic acid. We treated 30 patients as part of a Phase I and pharmacokinetic study to determine the maximum-tolerated dose of CT-2584 HMS, toxicity profiles, pharmacokinetic profile and antitumour effects at escalating dose levels. CT-2584 HMS was given as a continuous infusion for 6 hours for 5 consecutive days every 3 weeks. Plasma samples for pharmacokinetic studies were analysed using a validated high-performance liquid chromatographic assay. Mean C(max)and AUC values for each dose group were similar on days 1 and 5 and increases in plasma concentration (C(max)and AUC) appeared proportional to the dose. CT-2584 HMS had a mean elimination half-life of 7.3 hours. Values of V(d)and clearance were independent of dose and duration of treatment. Dose escalation was halted at 585 mg/m(2)because of malaise and lethargy, which was sometimes accompanied by nausea and headache. 26 patients were evaluable for response, one patient with pleural mesothelioma achieved a partial response to treatment confirmed by CT scanning. A dose level of 520 mg/m(2)daily x 5 days would be suitable for Phase II testing. Alternative schedules of CT-2584 HMS to overcome the limiting toxicity of malaise would be worthy of examination.     

Cooperativity of Staphylococcal aureus enterotoxin B superantigen, major histocompatibility complex class II, and CD80 for immunotherapy of advanced spontaneous metastases in a clinically relevant postoperative mouse breast cancer model

One of the leading causes of death for women is metastatic breast cancer. Because most animal tumors do not accurately model clinical metastatic disease, the development of effective therapies has progressed slowly. In this study, we establish the poorly immunogenic mouse 4T1 mammary carcinoma as a postsurgical animal model. 4T1 growth characteristics parallel highly invasive human metastatic mammary carcinoma and, at the time of surgery, the extent of disease is comparable with human stage IV breast cancer. Progress in understanding the immune response has led to innovative immune-based anticancer therapies. Here, we test in this postsurgical model, a novel cell-based vaccine, combining MHC class II, CD80(B7.1), and SEB superantigen. Effective treatment of tumor-bearing mice with this immunotherapy requires expression of all three molecules. Mean survival time is extended from 5-7.5 weeks for control-treated mice to 6-10.5 weeks for therapy-treated mice. Increased survival is accompanied by a maximum of 100-fold decrease in clonogenic lung metastases. These therapeutic effects are particularly noteworthy because: (a) the postoperative model demonstrates that early metastases responsible for morbidity are established by 2 weeks after tumor inoculation with 7 x 10(3) parental 4T1 cells into the mammary gland; (b) the immunotherapy is started 4 weeks after tumor inoculation when the mice contain extensive, pre-established, disseminated metastases; and (c) CD4+ and CD8+ T cells are required for the effect.     

Sildenafil: a urologist's view

Erectile dysfunction (ED) is a common problem with a multifactorial aetiology. The treatment of ED has been revolutionised by the introduction of intracavernosal injections some two decades ago. However, the recent development of the orally-administered drug sildenafil (Viagra) has had a major impact on the treatment of ED. We discuss the trials with sildenafil with special reference to cardiovascular risk factors associated with ED.     

The treatment of hypertension in patients with erectile dysfunction

Hypertension is another predictor of erectile dysfunction (ED). This is further evidence supporting a link between the pathogenesis of atherosclerotic disease and ED. In one study (TOMHS) involving hypertensive patients, the incidence of ED was 14.4%. The drugs used to treat hypertension may cause ED. However, there is little trial-based evidence to indicate which drugs are more likely to cause this side effect. In general, thiazide diuretics and beta-blockers seem to cause ED more often. In contrast, the alpha-blocker, doxazosin, has not been associated with an increased incidence of ED as a side effect. Doxazosin also improves urinary flow in patients with benign prostatic hyperplasia (BPH). This condition is common in elderly men as is hypertension and ED. Therefore, doxazosin may present a special advantage among this group of patients. This alpha-blocker would also be a good choice in patients with impaired glucose tolerance/diabetes because it improves insulin sensitivity. Moreover, ED and hypertension are more prevalent among diabetics. On a more speculative note, doxazosin may potentiate the therapeutic impact of specific treatments for ED.