Oral metoclopramide as an adjunct to analgesics for the outpatient treatment of acute migraine.

OBJECTIVE: To compare the combination of oral metoclopramide plus an analgesic with oral triptan monotherapy in the treatment of migraine attacks in outpatients. DATA SOURCES: A search of PubMed (1966-October 2007), EMBASE (1974-October 2007), and International Pharmaceutical Abstracts (1970-October 2007) was conducted using the search terms metoclopramide, migraine, and oral. References of articles identified initially were also reviewed. STUDY SELECTION AND DATA EXTRACTION: Studies evaluating the efficacy and safety of oral metoclopramide compared with oral triptans for migraine treatment were included. Studies of non-oral forms of metoclopramide or studies that compared oral metoclopramide with placebo, analgesics, ergotamine, or other migraine therapies were excluded. Studies in which oral metoclopramide was combined with a triptan were also excluded. DATA SYNTHESIS: In the studies identified, oral metoclopramide was combined with aspirin or a similar analgesic. All of the studies assessed headache severity using a 4-point scale (0 = no pain, 1 = mild pain, 2 = moderate pain, 3 = severe pain). Headache relief was defined as a decrease in headache pain from grade 3 or 2 to grade 1 or 0 and was commonly assessed at 2 hours. For all primary and secondary efficacy outcomes-including migraine-associated nausea and vomiting-oral triptans were similar or superior to oral metoclopramide plus an analgesic. The combination was better tolerated, with no reports of serious metoclopramide adverse events such as extrapyramidal symptoms or tardive dyskinesia. CONCLUSIONS: Combinations containing oral metoclopramide plus an analgesic may be an option for patients in whom triptans are contraindicated or who experience intolerable adverse effects, or when cost is an issue. However, patients and physicians should be aware that the combination will likely be less effective than oral triptans in treatment of migraine and its associated symptoms. To determine the role of combination therapy that includes oral metoclopramide in mild-to-moderate migraines, further studies are warranted.

Linker length modulates DNA cross-linking reactivity and cytotoxic potency of C8/C8' ether-linked C2-exo-unsaturated pyrrolo[2,1-c][1,4]benzodiazepine (PBD) dimers.

A C2/C2'-exo-unsaturated pyrrolo[2,1-c][1,4]benzodiazepine (PBD) dimer 4b (DRG-16) with a C8-O(CH2)nO-C8' diether linkage (n = 5) has been synthesized that shows markedly superior in vitro cytotoxic potency (e.g., >3400-fold in IGROV1 ovarian cells) and interstrand DNA cross-linking reactivity (>10-fold) compared to the shorter homologue 4a (SJG-136; n = 3). In contrast, for the C-ring unsubstituted series, the corresponding n = 5 dimer (3c) is generally less cytotoxic and has a lower interstrand cross-linking reactivity compared to its shorter n = 3 homologue (3a). Dimer 4b cross-links DNA with >10-fold efficiency compared to 4a, and also inhibits the activity of the restriction endonuclease BamH1 more efficiently than either 3a or 4a. The C2-exo-unsaturated PBD dimers 4a,b are not only more effective than their C-ring saturated counterparts in terms of induced DeltaTm shift, but they also exert this effect more rapidly. Thus, while 3a and 3c exert 68 and 35% of their maximum effect immediately upon interaction with DNA, this level increases to 76 and 97% for 4a and 4b, respectively. Molecular modeling shows a rank order of 4b (n = 5) > 4a (n = 3) > 3a (n = 3) > 3c (n = 5) in terms of binding energy toward duplexes containing embedded target 5'-GAT(1-2)C cross-link sequences, reflecting the superior fit of the C2-exo-unsaturated rather than saturated C-rings of the PBD dimers. A novel synthesis of core synthetic building blocks for PBD dimers via stepwise Mitsunobu reaction and nitration with Cu(NO3)2 is also reported.