An inquiry-based exercise in medicinal chemistry: Synthesis of a molecular library and screening for potential antimalarial and anti-inflammatory compounds.

The development of new medicines holds particular fascination for chemistry, biochemistry, and biology students interested in a career in medicine or the life sciences. The identification and refinement of lead compounds to treat diseases requires researchers to be facile in a number of different disciplines including organic synthesis, biochemistry, cell biology, and molecular biology. We have developed an interdisciplinary, inquiry-based laboratory spanning both organic chemistry and biochemistry classes that acquaints students with research in medicinal chemistry. The first part of the exercise takes place in the second semester of organic chemistry, where pairs of students design and execute their own multistep synthesis of a novel compound with anti-inflammatory and/or antimalarial potential. Later, in first semester biochemistry, many of the same students then test these synthesized compounds for cytotoxicity, inhibition of the enzyme nitric oxide synthase, and inhibition of the transcription factor NF-kB. Learning outcomes, measured by the Classroom Undergraduate Research Experience (CURE) survey, suggest that students participating in both classes had higher gains than an average student. © 2018 International Union of Biochemistry and Molecular Biology, 46(5):424-434, 2018.

Mutans streptococci in xerostomic cancer patients after pilocarpine therapy: a pilot study.

OBJECTIVES: Opiod- and/or radiation-induced xerostomia in cancer patients is frequently associated with elevated levels of cariogenic mutans streptococci (MS). STUDY DESIGN: In a single-center, single blind 8-week clinical trial at The University of Texas M. D. Anderson Cancer Center, and from an initial sample of 32 patients, we evaluated MS counts in 28 cancer patients receiving chronic analgesic treatment for cancer pain. All patients received escalating doses of pilocarpine (Salagen) tablets, either 2.5 mg to 5 mg or 5 mg to 7.5 mg qid for 6 weeks, followed by placebo qid for a 2-week washout period. Whole resting saliva flow rates (g/5 min) and MS counts were evaluated at pretreatment, 3 weeks, 6 weeks, and 8 weeks. MS samples were obtained by 5-mL saline rinse (15 sec) at each visit prior to sialometry. RESULTS: In 19 patients (59%), MS counts exceeded 10(5) CFU/mL. At the end of the 6-week trial, 96% of patients showed a positive response to pilocarpine following a 30-minute postdosing evaluation (P=.001). MS counts were lower in 17 patients, higher in 6 patients, and nondetectable before and after pilocarpine in 5 patients (P=.03). CONCLUSION: The reduced MS counts associated with improved saliva flow rates following pilocarpine therapy in this short-term pilot study are encouraging, but further investigation in a larger group of patients over a longer study period is indicated.

Measuring chemotherapy-induced nausea and emesis.

BACKGROUND: Chemotherapy-induced nausea and emesis (CINE) is one of the most dreaded side effects of cancer therapy. To investigate the influence of these symptoms on a patient's quality of life (QOL), a validated tool measuring many domains is needed. METHODS: A QOL questionnaire consisting of scales from the European Organization for Research and Treatment of Cancer QLQ-C30, the Morrow Assessment of Nausea and Emesis, the Osoba Nausea and Emesis Module, and new items specific to nausea, emesis, and retching was constructed and administered daily for 7-9 days to outpatients receiving emetogenic chemotherapy. RESULTS: Test-retest and internal consistency reliabilities ranged from 0.44 to 0.84 and from 0.59 to 0.85, respectively. Item and scale correlations indicated good convergent and discriminant validity. Scales and items measuring similar factors (e.g., severity of emesis and severity of nausea) had strong correlations than did scales measuring dissimilar factors (e.g., cognitive functioning and physical functioning). The validity of known groups was demonstrated by significant differences (P < 0.01) in patients' QOL scores between days with no episodes of nausea, emesis, or retching, days with 1 or 2 episodes, and days with more than 3 episodes. Patients' QOL significantly decreased as the number of episodes per day increased (P < 0.001). CONCLUSIONS: A CINE QOL questionnaire that successfully measures the short-term impact of nausea, emesis, and retching on patients receiving emetogenic chemotherapy has been developed, largely as a battery of preexisting questionnaires. The psychometric properties of the new questionnaire show adequate reliability and validity to warrant its use in clinical trials and outcomes studies. CINE adversely affects many domains within a patient's QOL.

Cost of chemotherapy-induced thrombocytopenia among patients with lymphoma or solid tumors.

BACKGROUND: The purpose of this study was to estimate the mean incremental cost of chemotherapy-induced thrombocytopenia and the drivers of cost. Another goal was to estimate the impact of depth and duration of thrombocytopenia on the cost of thrombocytopenia. METHODS: A retrospective cohort, consisting of a random sample of 75 solid tumor or lymphoma patients who developed chemotherapy-induced thrombocytopenia (

The Bleeding Risk Index: a clinical prediction rule to guide the prophylactic use of platelet transfusions in patients with lymphoma or solid tumors.

BACKGROUND: The correlation between platelet count and bleeding has been well described, although no formal methods for applying this information to clinical decisions are available. The authors developed a clinical prediction rule to guide the prophylactic use of platelet transfusions among patients with lymphoma or solid tumors. METHODS: The Bleeding Risk Index (BRI) was developed from logistic regression analysis of a randomly selected 750-chemotherapy cycle derivation set using data from Day 1 of cycles. The sensitivity and specificity of a BRI-based prophylaxis strategy were compared in a 512-cycle validation set with two strategies based on initiation of prophylaxis when platelet counts fell below thresholds of 20,000 per microL or 10,000 per microL. RESULTS: Factors that were predictive of bleeding included any prior episode of bleeding (odds ratio [OR], 5.6; 95% confidence interval [95% CI], 2.2-14.0), treatment with a drug affecting platelet function (OR, 5.1; 95% CI, 2.0-12.6), bone marrow metastases (OR, 4.3; 95% CI, 1.7-10.8), a baseline platelet count < 75,000 per microL (OR, 3.5; 95% CI, 1.4-8.9), genitourinary or gynecologic malignancy (OR, 3.3; 95% CI, 1.3-8.2), a Zubrod performance status score > 2 (OR, 3.4; 95% CI, 1.4-8.5), and treatment with agents that were highly toxic to the bone marrow (OR, 2.2; 95% CI, 1.0-5.4). Compared with 20,000 and 10,000 platelet threshold strategies, the BRI-based strategy provided the best trade-off between sensitivity for major bleeding episodes (80%) and specificity for any bleeding (84%). CONCLUSIONS: Patients with lymphoma or solid tumors who are at high risk of bleeding can be identified reliably on Day 1 of a chemotherapy cycle. An individualized, BRI-based approach to bleeding prophylaxis provides a highly sensitive and specific alternative to traditional, nonindividualized platelet threshold strategies.