Cellular topoisomerase I inhibition and antiproliferative activity by MJ-III-65 (NSC 706744), an indenoisoquinoline topoisomerase I poison.

To overcome camptothecin's (CPT) lactone instability, reversibility of the drug-target interaction, and drug resistance, attempts to synthesize compounds that are CPT-like in their specificity and potency yet display a unique profile have been underway. In this pursuit, we have identified one of the idenoisoquinoline derivatives, MJ-III-65 (NSC 706744; 6-[3-(2-hydroxyethyl)amino-1-propyl]-5,6-dihydro-2,3-dimethoxy-8,9-methylenedioxy-5,11-dioxo-11H-indeno[1,2-c]isoquinoline) with both similarities and differences from CPT. MJ-III-65 traps topoisomerase I (Top1) reversibly like CPT but with different DNA sequence preferences. Consistent with Top1 poisoning, protein-linked DNA breaks were detected in cells treated with MJ-III-65 at nanomolar concentrations. These MJ-III-65-induced protein-linked DNA breaks were resistant to reversal after an hour of drug removal, compared with CPT, which completely reversed. Studies in human cells in culture found MJ-III-65 to be cytotoxic. Furthermore, limited cross-resistance was observed in camptothecin-resistant cell lines. MJ-III-65 also exhibits antitumor activity in mouse tumor xenografts.

The insulin pump as murder weapon: a case report.

Microprocessor-controlled insulin pumps designed for continuous delivery of short-acting insulin analogs into subcutaneous tissues offer several important potential benefits for diabetic patients. The delivery of other substances using these systems is technically feasible. We present a case of homicide involving lethal doses of etomidate and atracurium injected via the victim's insulin pump. This unique situation could be encountered by homicide investigators more frequently as the popularity of these systems continues to grow.

Aminophylline reversal of antihypertensive agent toxicity.

Hypotension occurred following a combined beta blocker (atenolol), angiotensin converting enzyme inhibitor (quinapil) and selective serotonin reuptake inhibitor (fluvoxamine) overdose. In another instance heart block and hypotension was noted in association with a diltiazem and atenolol adverse interaction. Crystalloid infusion was ineffective in both cases, but toxicity was rapidly reversed with aminophylline administration. Aminophylline's recognized inotropic and chronotropic properties make it a potentially valuable therapeutic agent in the treatment of antihypertensive medication toxicity.

Possible relation of atypical parkinsonism in the French West Indies with consumption of tropical plants: a case-control study. Caribbean Parkinsonism Study Group.

BACKGROUND: In Europe and North America, Parkinson's disease is the major form of parkinsonism; less than 4% of cases are progressive supranuclear palsy (PSP) and about 20% are atypical parkinsonism. The distribution of these subgroups is different in the French West Indies. We aimed to define the clinical and demographic specificity of these disorders in Guadeloupe and to investigate a postulated link with consumption of herbal tea and fruits from the Annonaceae family (Annona muricata and Annona squamosa), which contain neurotoxic benzyltetrahydroisoquinoline alkaloids. METHODS: Between September, 1996, and August, 1998, 87 consecutive patients with parkinsonism were referred to the single neurological department in Guadeloupe. After detailed clinical, neurophysiological, cognitive, and neuroradiological assessment, they were classified by generally accepted criteria as having Parkinson's disease, PSP, or atypical parkinsonism. We compared the amount of tropical fruits and herbal tea consumed by the various parkinsonian subgroups and by frequency-matched controls (patients with benign symptoms and no neurodegenerative disease). FINDINGS: Of the 87 patients, 22 had Parkinson's disease, 31 had PSP, 30 had atypical parkinsonism, and four had atypical parkinsonism associated with motor neuron disease, 44 of the patients with PSP or atypical parkinsonism were male. The patients with atypical parkinsonism had symmetrical rigidity and bradykinesia, and no levodopa peak-dose dyskinesias. Patients with PSP differed from those with atypical parkinsonism because they had supranuclear vertical down-gaze palsy, severe gait and balance problems, and frontal-lobe syndrome. 29 patients with PSP reported regular consumption of pawpaw fruit, and 26 drank herbal tea. 30 patients with atypical parkinsonism reported regular consumption of pawpaw fruit, and 24 drank herbal tea. Both of these groups consumed significantly more fruit and herbal tea than patients with Parkinson's disease (fruit: odds ratio 23.6; herbal tea: 28.2); and controls (fruit: 20.7; herbal tea: 6.48). INTERPRETATION: Our study confirms the over-representation of atypical parkinsonism and PSP in patients with parkinsonism in the French West Indies. Chronic exposure to neurotoxic alkaloids could be an important aetiological factor because these compounds induce parkinsonism in animals. A larger epidemiological study, to clarify the link between these fruits with atypical parkinsonism and PSP, is proposed.