A novel group of racemic isopropyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-pyridinylpyridine-5-carboxylate isomers [(+/-)-12-14] were prepared using a modified Hantzsch reaction that involved the condensation of nitroacetone with isopropyl 3-aminocrotonate and 2-, 3-, or 4-pyridinecarboxaldehyde. Determination of their in vitro calcium channel-modulating activities using guinea pig ileum longitudinal smooth muscle (GPILSM) and guinea pig left atrium (GPLA) assays showed that the 2-pyridinyl isomer (+/-)-12 acted as a dual cardioselective calcium channel agonist (GPLA)/smooth muscle selective calcium channel antagonist (GPILSM). In contrast, the 3-pyridinyl [(+/-)-13] and 4-pyridinyl [(+/-)-14] isomers acted as calcium channel agonists on both GPLA and GPILSM. The agonist effect exhibited by (+/-)-12 on GPLA was inhibited by nifedipine and partially reversed by addition of extracellular Ca2+. In anesthetized rabbits, the 4-pyridinyl isomer (+/-)-14 exhibited a hypertensive effect that was qualitatively similar to that exhibited by the nonselective agonist Bay K 8644 and the 3-pyridinyl isomer (+/)-13, whereas the 2-pyridinyl isomer (+/-)-12 induced a hypotensive effect similar to that of the calcium channel antagonist nifedipine. Similar results were obtained in a spontaneously hypertensive rat model. In vitro studies showed that the (+)-2-pyridinyl enantiomer (+)-12A exhibited agonist activity on both GPILSM and GPLA, but that the (-)-2-pyridinyl enantiomer (-)-12B exhibited agonist activity on GPLA and antagonist activity on GPILSM. Whole-cell voltage-clamp studies using isolated guinea pig ventricular myocytes indicated that (-)-12B inhibited the calcium current (ICa), that (+)-12A increased slightly ICa, and that (+/-)-12 inhibited ICa but the latter inhibition was less than that for (-)-12B. (-)-12B effectively inhibited ICa at all membrane potentials examined (-40-50 mV), whereas (+)-12A exhibited a weak agonist effect near the peak of the I-V curve. The 2-pyridinyl isomers (enantiomers) 12 represent a novel type of 1,4-dihydropyridine calcium channel modulator that could provide a potentially new approach to drug discovery targeted toward the treatment of congestive heart failure and probes to study the structure-function relationships of calcium channels.

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The influence of caffeine (60 mg) was studied on the pharmacokinetic characteristics of acetaminophen (500 mg single dose) in ten healthy male human volunteers in a complete cross-over design. A high-performance liquid chromatography (HPLC) method was used to analyse serum drug concentrations. Caffeine caused a highly significant (p < 0.01) increase in AUC and AUMC, a significant (p < 0.05) increase in Cmax, and a significant (p < 0.05) decrease in clearance (C1/F) of acetaminophen. We conclude that caffeine taken in doses commonly available commercially or in a cup of coffee can significantly potentiate the therapeutic potential of acetaminophen in man.

Sorghum halepense (L.) Pers. is ranked among the worst and extensively disseminated weed species. It is emerging as a potential menace for agroecosystems in 53 different countries across the world. This weed is adapted to warmer regions and is native to Mediterranean areas of Africa, Asia, and Europe. In the mid-1900s, cultivation of this weed species as a potential forage crop resulted in its escape from crop fields and invasion of agricultural and natural areas, but in some European countries, it has been introduced deliberately (e.g., as contamination of seeds and soil). S. halepense interferes with economically important agronomic and horticultural crops and cause 57-88% yield losses. Herbicide tolerance, diverse propagation mechanisms, rapid development, and strong competitiveness are key attributes in its invasion. Conventional management approaches are limited in their scope to control this weed due to its rapid vegetative growth and increasing herbicidal tolerance. Integration of chemical methods with cultural or mechanical approaches is important for restricting its future spread to non-infested areas. This review provides insights into the invasion mechanisms of S. halepense, which will help in its

Annual ryegrass (Lolium rigidum Gaud.), traditionally utilised as a pasture species, has become the most problematic and difficult-to-control weed across grain production regions in Australia. Annual ryegrass has been favoured by the adoption of conservation tillage systems due to its genetic diversity, prolific seed production, widespread dispersal, flexible germination requirements and competitive growth habit. The widespread evolution of herbicide resistance in annual ryegrass has made its management within these systems extremely difficult. The negative impacts of this weed on grain production systems result in annual revenue losses exceeding $93 million (AUD) for Australian grain growers. No single method of management provides effective and enduring control hence the need of integrated weed management programs is widely accepted and practiced in Australian cropping. Although annual ryegrass is an extensively researched weed, a comprehensive review of the biology and management of this weed in conservation cropping systems has not been conducted. This review presents an up-to-date account of knowledge on the biology, ecology and management of annual ryegrass in an Australian context. This comprehensive account provides pragmatic information for further research and suitable management of annual ryegrass.

A group of racemic alkyl and 2-phenethyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(3- or 6-substituted-2-pyridyl)-5-pyridinecarboxylates (13a-q) was prepared using a modified Hantzsch reaction that involved the condensation of a 3- or 6-substituted-2-pyridinecarboxaldehyde (7a-j) with an alkyl or 2-phenethyl 3-aminocrotonate (11a-d) and nitroacetone (12). Nuclear Overhauser (NOE) studies indicated there is a significant rotamer fraction in solution where the pyridyl nitrogen is oriented above the 1,4-dihydropyridine ring, irrespective of whether a substituent is located at the 3- or 6-position. A potential H-bonding interaction between the pyridyl nitrogen free electron pair and the suitably positioned 1,4-dihydropyridine NH moiety may stablize this rotamer orientation. In vitro calcium channel antagonist and agonist activities were determined using guinea pig ileum longitudinal smooth muscle (GPILSM) and guinea pig left atrium (GPLA) assays, respectively. Compounds having an i-Pr ester substituent acted as dual cardioselective calcium channel agonists (GPLA)/smooth muscle-selective calcium channel antagonists (GPILSM), except for the C-4 3-nitro-2-pyridyl compound which exhibited an antagonist effect on both GPLA and GPILSM. In contrast, the compounds with a phenethyl ester group, which exhibited antagonist activity (IC50 = 10(-5)-10(-7) M range) on GPILSM, were devoid of cardiac agonist activity on GPLA. Structure-activity relationships showing the effect of a substituent (Me, CF3, Cl, NO2, Ph) at the 3- or 6-position of a C-4 2-pyridyl moiety and a variety of ester substituents (Me, Et, i-Pr, PhCH2CH2-) upon calcium channel modulation are described. Compounds possessing a 3- or 6-substituted-2-pyridyl moiety, in conjuction with an i-Pr ester substituent, are novel 1,4-dihydropyridine calcium channel modulators that offer a new drug design approach directed to the treatment of congestive heart failure and may also be useful as probes to study the structure-function relationships of calcium channels.

Avena fatua and Avena ludoviciana are closely related grass weed species infesting a large number of crops around the world. These species are widely distributed in diverse agro-ecosystems from temperate to sub-tropical regions due to their unique seed traits, successful germination ecology, high competitive ability, and allelopathic potential. A. fatua is more widespread, adaptable, and problematic than A. ludoviciana. Both these species infest major winter and spring crops, including wheat, oat, barley, canola, maize, alfalfa, and sunflower, causing up to 70% yield losses depending on crop species and weed density. Chemical control has been challenged by large-scale herbicide resistance evolution in these weed species. A. fatua is the most widespread herbicide-resistant weed in the world, infesting about 5 million hectares in 13 countries. The use of alternative herbicides with different modes of action has proved effective. Several cultural practices, including diverse crop rotations, cover crops, improved crop competition (using competitive cultivars, high seed rates, narrow row spacing, altered crop geometry), and allelopathic suppression, have shown promise for controlling A. fatua and A. ludoviciana. The integrated use of these cultural methods can reduce the herbicide dose required, and lower dependency on herbicides to control these grasses. Moreover, integrated management may successfully control herbicide-resistant populations of these weed species. The use of integrated approaches based on the knowledge of biology and ecology of A. fatua and A. ludoviciana may help to manage them sustainably in the future.

A group of racemic 3-[2-nitrooxyethyl (1,3-dinitrooxy-2-propyl or 4-nitrophenylethyl)] 5-isopropyl 1,4-dihydro-2,6-dimethyl-4-[2- trifluoromethylphenyl (2-nitrophenyl or 3-nitrophenyl)]-3,5-pyridinedicarboxylates 13-15 were prepared using the Hantzsch reaction that involved the condensation of 2-nitrooxyethyl 9a, 1,3-dinitrooxy-2-propyl 9b or 4-nitrophenylethyl 9c acetoacetate with isopropyl 3-aminocrotonate 11 and 2-trifluoromethyl 12a, 2-nitro 12b or 3-nitro 12c benzaldehyde. In vitro calcium channel antagonist activities were determined using a guinea pig ileum longitudinal smooth muscle assay. Compounds 13-15 exhibited superior, or equipotent, calcium channel antagonist activity (10(-8) to 10(-10) M range) relative to the reference drug nifedipine (IC50 = 1.43 x 10(-8) M). The R1 C-3 ester substituent was a determinant of calcium channel antagonist activity where the potency order was CH2CH2ONO2 > CH2CH2-C6H4-4-NO2 > or = CH(CH2ONO2)2. In contrast, the C-4 R2-aryl substituent (2-CF3-C6H4-, 2-O2N-C6H4- or 3-O2N-C6H4-) was not a major determinant of activity. Compounds 13a-15a, which possess a 3-(2-nitrooxyethyl) ester substituent exhibit superior calcium channel antagonist smooth muscle relaxant activity (IC50 = 10(-10) M range) relative to nifedipine, could serve as potential probes to investigate the in vivo release of nitric oxide (NO) which induces vascular muscle relaxation.