Comparison of patient simulation methods used in a physical assessment course.

OBJECTIVE: To determine whether there is a difference in student pharmacists' learning or satisfaction when standardized patients or manikins are used to teach physical assessment. DESIGN: Third-year student pharmacists were randomized to learn physical assessment (cardiac and pulmonary examinations) using either a standardized patient or a manikin. ASSESSMENT: Performance scores on the final examination and satisfaction with the learning method were compared between groups. Eighty and 74 student pharmacists completed the cardiac and pulmonary examinations, respectively. There was no difference in performance scores between student pharmacists who were trained using manikins vs standardized patients (93.8% vs. 93.5%, p=0.81). Student pharmacists who were trained using manikins indicated that they would have probably learned to perform cardiac and pulmonary examinations better had they been taught using standardized patients (p<0.001) and that they were less satisfied with their method of learning (p=0.04). CONCLUSIONS: Training using standardized patients and manikins are equally effective methods of learning physical assessment, but student pharmacists preferred using standardized patients.

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.

Design, synthesis, and biological evaluation of achiral analogs of duocarmycin SA.

The design, synthesis, as well as biochemical and biological evaluation of two novel achiral analogs of duocarmycin SA (DUMSA), 1 and 2, are described. Like CC-1065 and adozelesin, compounds 1 and 2 covalently reacted with adenine-N3 in AT-rich sequences and led to the formation of DNA strand breaks upon heating. The cytotoxicity of compounds 1 and 2 against human cancer cells (K562, LS174T) was determined using a MTT assay giving IC(50) values in the low nanomolar. Further cytotoxicity screening of compound 2 conducted by the NCI against a panel of 60 different human cancer cell lines indicated that it was particularly active against several solid tumor cells lines derived from the lung, colon, CNS, skin, and breast.

SJG-136 (NSC 694501), a novel rationally designed DNA minor groove interstrand cross-linking agent with potent and broad spectrum antitumor activity: part 1: cellular pharmacology, in vitro and initial in vivo antitumor activity.

SJG-136 (NSC 694501) is a rationally designed pyrrolobenzodiazepine dimer that binds in the minor groove of DNA. It spans 6 bp with a preference for binding to purine-GATC-pyrimidine sequences. The agent has potent activity in the National Cancer Institute (NCI) anticancer drug screen with 50% net growth inhibition conferred by 0.14 to 320 nmol/L (7.4 nmol/L mean). Sensitive cell lines exhibit total growth inhibition and 50% lethality after treatment with as little as 0.83 and 7.1 nmol/L SJG-136, respectively. COMPARE and molecular target analysis of SJG-136 data versus that of >60,000 compounds tested in the NCI 60 cell line screen shows that, although the agent has similarity to other DNA binding agents, the pattern of activity for SJG-136 does not fit within the clusters of any known agents, suggesting that SJG-136 possesses a distinct mechanism of action. Testing in the NCI standard hollow fiber assay produced prominent growth inhibition in 20 of 24 i.p. and 7 of 24 s.c. test combinations with 5 of 12 cell lines exhibiting cell kill. In addition, SJG-136 produced antitumor activity in mice bearing CH1 and CH1cisR xenografts, a cisplatin-resistant human ovarian tumor model, and also in mice bearing LS174T xenografts, a human colon tumor model. SJG-136 produces DNA interstrand cross-links between two N-2 guanine positions on opposite strands and separated by 2 bp. In human tumor cell lines, the cross-links form rapidly and persist compared with those produced by conventional cross-linking agents such as nitrogen mustards. In mice bearing the LS174T human colon xenograft, DNA interstrand cross-links can be detected in tumor cells using a modification of the single cell gel electrophoresis (comet) assay after administration of a therapeutic dose. Cross-links in the tumor increase with dose and are clearly detectable at 1 hour after i.v. administration. The level of cross-linking persists over a 24-hour period in this tumor in contrast to cross-links produced by conventional cross-linking agents observed over the same time period.

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.