Evaluation of coumarin derivatives as anti-fungal agents against soil-borne fungal pathogens.

Development of new and safer pesticides that are target-specific is backed by a strong Federal, public and commercial mandate. In order to generate a new generation of pesticides that are more ecologically friendly and safe, natural products are being evaluated for pesticidal activities. Many plant-derived chemicals have proven pesticidal properties, including compounds like sesamol (3,4-Methylenedioxyphenol), a lipid from sesame oil and coumarins (1,2-Benzopyrone) found in a variety of plants such as clover, sweet woodruff and grasses. Both of these plant-derived compounds have been shown to inhibit a range of fungi and bacteria and it is believed that these cyclic compounds behave as natural pesticidal defense molecules for plants. These compounds represent a starting point for the exploration of new derivative compounds possessing a range of antifungal activity and for use as seed protectants. Within this study, six derivatives of coumarin that resembled sesamol's structure were screened for their antifungal activity against a range of soil-bome plant pathogenic fungi. Fungi in this in vitro screen included Macrophomina phaseolina (causal agent of charcoal rot) and Pythium spp. (causal agent of seedling blight), two phylogenetically diverse and economically important plant pathogens. Preliminary studies indicate that many of these novel coumarin derivatives work very effectively in vitro to inhibit fungal growth and several coumarin derivatives have higher antifungal activity and stability as compared to either the original coumarin or sesamol compounds alone. Interestingly, several of these highly active coumarin derivatives are halogenated compounds with solubility in water, and they are relatively easy and inexpensive to synthesize. These halogenated coumarin derivatives remained active for extended periods of time displaying 100% inhibition of fungal growth for greater than 3 weeks in vitro. In addition to the in vitro fungal inhibition assays, preliminary phytotoxicity assays of these halogenated coumarin compounds show no obvious plant toxicity issues or interference in plant development. These results support additional research in this area of natural pesticide development.

Withdrawal phenomena in subjects with essential hypertension on clonidine or tiamenidine.

The incidence and pathogenesis of withdrawal phenomena with the centrally acting drugs clonidine (CLON) and tiamenidine (TIAM) were evaluated. Thirty subjects with hypertension on hydrochlorothiazide (HCTZ) were randomized to TIAM or CLON. Blood pressure and integrated plasma catecholamine levels fell equally in response to both drugs. On withdrawal, blood pressure and pulse rose in both groups with no difference between them. Three subjects had symptoms of withdrawal, four had blood pressure overshoot above pretreatment levels of 10 mm Hg or more, and eight had a rise in blood pressure of 30 mm Hg systolic or 20 mm Hg diastolic. There was no difference between TIAM and CLON in these effects. There was a direct correlation between blood pressure rise and increase in integrated plasma norepinephrine levels. We conclude that the incidence of withdrawal phenomena in subjects on TIAM or CLON is infrequent and that there is a direct relationship between the rise in blood pressure and the loss of suppression of catecholamines by these drugs.

Cardiac arrhythmias after abrupt clonidine withdrawal.

Abrupt clonidine withdrawal may be associated with sharp marked increases in catecholamine levels, heart rate, and blood pressure, which may induce nausea, vomiting, and palpitations. Relatively little information is available on the incidence of cardiac arrhythmias in this setting. With continuous ambulatory ECG recordings, we determined the incidence of arrhythmias in seven male hypertensive patients (without active heart disease) after abrupt clonidine withdrawal. Serious ventricular arrhythmias, including brief ventricular tachycardia, developed in two patients who had greater increases in mean systolic blood pressure (28 +/- 3 vs 10 +/- 8 mm Hg) and double product (552 +/- 681 vs 333 +/- 195) than the others. The differences were not significant. Ventricular arrhythmias were not related to age, dose, withdrawal symptoms, initial blood pressure, urinary norepinephrine levels, or ECG abnormalities. We conclude that serious ventricular arrhythmias may be relatively common but unpredictable during clonidine withdrawal, even in patients with no clinically apparent heart disease. The triggering of ventricular arrhythmias should be added to the list of components of clonidine withdrawal syndrome.

Application of alkaline sucrose gradient sedimentation to the study of DNA damage and its repair in mammalian cells treated with methylmethanesulfonate and 4-nitroquinoline-1-oxide.

KB cells and L cells were treated with methylmethanesulfonate (MMS) or 4-nitroquinoline-1-oxide (4 NQO) and the resulting damage to DNA and its repair were examined by sedimentation in an alkaline sucrose gradient. The sedimentation profiles obtained were found to be the resultant of a complex interrelationship between drug dosage, duration of the lysis period and the repair capacity of the cells. A systematic study of these variables was made which led to a plausible and useful interpretation of the sedimentation profiles. Both drugs produce two kinds of DNA modifications which show up as a single-strand breaks but affect the sedimentation profile in characteristic ways. One of these modifications which is quite alkali-labile can be studied using a 30-min lysis period. The other modification is less alkali-labile and can be studied using a long lysis period. Both KB cells and L cells can repair the former type of damage but only KB cells can repair the latter type of damage.