Malaria epidemics in the highlands of Ethiopia.

OBJECTIVE: To confirm the occurrence and describe the patterns of the 2003 malaria epidemics reported in the highlands of Ethiopia. DESIGN: A retrospective descriptive study. SETTINGS: Fifty epidemic affected districts between altitude ranges of 1500 and 2500 m in three regions in Ethiopia. RESULTS: Exaggerated seasonal transmission was observed in 25 districts, 16 in Oromia region and 9 in SNNPR. A sustained upward trend with 3-4 consecutive abnormal seasonal transmissions, which has started since 2002, has been identified in 22 districts. True explosive epidemic malaria was recorded at exceptionally high altitude (around 2500m) in at least one of the health facilities in seven districts. The incidence of malaria in 2003 epidemic has showed a six fold increase on average (range 2-20) from the threshold level. CONCLUSION: Occurrence of a malaria epidemic was confirmed in all studied districts showing that the level of malaria endemicity and magnitude of the problem is increasing. The findings suggest the strategic importance of taking well-timed and appropriately targeted preventive and control interventions.

Further definition of the D1 dopamine receptor pharmacophore: synthesis of trans-6,6a,7,8,9,13b-hexahydro-5H-benzo[d]naphth[2,1-b]azepines as rigid analogues of beta-phenyldopamine.

In an effort to define further the active geometry of the beta-phenyldopamine pharmacophore of certain dopamine D1 agonists, the title compounds have been synthesized as conformationally restricted homologues of the potent benzophenanthridine dopamine D1 agonist dihydrexidine 4a. The dihydroxy secondary amine 5b was evaluated as a potential agonist, whereas the N-methyl compounds 5a and 5c were hypothesized to be antagonists. Surprisingly, none of the three compounds had high affinity for dopamine D1 or D2 receptors. A comparison of the low-energy conformations of these molecules shows that the pendant phenyl ring of 5b is twisted about 28 degrees relative to that of the corresponding ring of 4a. Further, the additional methylene used to expand the C ring of 5b projects toward the alpha face of the molecule, perhaps suggesting that steric protrusion in this region of the molecule is not tolerated. Finally, the phenethylamine fragment incorporated into these molecules deviates about 30 degrees from the antiperiplanar conformation postulated to be necessary for agonist activity. On the other hand, the potential antagonist molecules 5a and 5c were compared with the dopamine D1 antagonist SCH 39166 2. The conformations of the former two structures differ quite dramatically from that of 2. The most notable differences lie in the relative orientations of the pendant phenyl rings in the two series, as well as the fact that the ethylamine fragment in 2 approximates a gauche conformation, while the comparable orientation in 5a and 5c more nearly approaches an antiperiplanar conformation. These findings will be used to refine further the model of the dopamine D1 agonist receptor that we have previously developed.