Estimates of radiation absorbed dose for intraperitoneally administered iodine-131 radiolabeled B72.3 monoclonal antibody in patients with peritoneal carcinomatoses

Using a newly available model for determining estimates of radiation absorbed dose of radioisotopes administered intraperitoneally, we have calculated absorbed dose to tumor and normal tissues based on a surgically controlled study of radiolabeled antibody distribution. Ten patients with peritoneal carcinomatosis received intraperitoneal injections of the murine monoclonal antibody B72.3 radiolabeled with 131I. Biodistribution studies were performed using nuclear medicine methods until laparotomy at 4-14 days after injection. Surgical biopsies of normal tissues and tumor were obtained. The marrow was predicted to be the critical organ, with maximum tolerated dose [200 rad (2 Gy) to marrow] expected at about 200 mCi (7.4 GBq). In patients with large intraperitoneal tumor deposits, the tumor itself is an important source tissue for radiation exposure to normal tissues. Local "hot-spots" for tumor-absorbed dose were observed, with maximum tumor-absorbed dose calculated at 11,000 rad (11 Gy) per 100 mCi (3.7 GBq) administered intraperitoneal; however, tumor rad dose varied considerably. This may pose serious problems for curative therapy, especially in patients with large tumor burdens.     

Extending epidural blockade for emergency caesarean section. Evaluation of 2% lignocaine with adrenaline

Pre-existing epidural analgesia was rapidly extended in 36 consecutive patients presenting for emergency caesarean section by using 20 ml of 2% lignocaine + 1/200,000 adrenaline freshly prepared given by slow bolus injection. Despite a wide range of initial analgesic sensory levels the technique produced blocks that were dense with adequate anaesthesia for surgery in all patients within 12.5 min. The plasma local anaesthetic concentrations were well below the toxic range. Neonatal condition was good.     

Subarachnoid meperidine (Pethidine) causes significant nausea and vomiting during labor. The Duke Women's Anesthesia Research Group

BACKGROUND: The combined spinal-epidural (CSE) technique using bupivicaine-fentanyl has become an established method of pain control during parturition. One limitation is the relatively short duration of effective analgesia produced by bupivicaine-fentanyl. In contrast, subarachnoid meperidine has been shown to provide a long duration of anesthesia in nonobstetric patients. Therefore, the authors tested the hypothesis that subarachnoid meperidine produces a significant increase in the duration of analgesia compared with bupivicaine-fentanyl. METHODS: Based on a power analysis of preliminary data, the authors intended to recruit 90 patients for the study, randomized to three groups: 2.5 mg bupivicaine-25 microg fentanyl, 15 mg meperidine, or 25 mg meperidine. However, after enrolling 34 patients, the study was discontinued because of a significant increase in nausea or vomiting in the study patients. RESULTS: Nausea or vomiting was substantially increased in both meperidine groups compared with the bupivicaine-fentanyl group: 16 with nausea or vomiting in the meperidine groups (n = 21), compared with 1 in the bupivicaine-fentanyl group (n = 11), P = 0.0011. The mean duration of analgesia provided by 25 mg meperidine was 126 +/- 51 min, compared with 98 +/- 29 min for bupivicaine-fentanyl and 90 +/- 67 min for 15 mg meperidine. These data were not significant (P = 0.27). CONCLUSIONS: Although intrathecal meperidine could potentially prolong subarachnoid analgesia during labor, its use was associated with a significant incidence of nausea or vomiting. These data do not support the use of subarachnoid meperidine in doses of 15 or 25 mg for labor analgesia.     

High-throughput physicochemical and in vitro ADMET screening

During drug discovery, it is important to optimise the affinity for the biomolecular target and also the properties of molecules that influence absorption, distribution, metabolism, excretion, and toxicity (ADMET). The goal is to improve the properties of a lead compound and select highly ‘developable’ candidates. Efficient pharmaceutical property profiling operations are now run in parallel to potency screening during lead optimization and provide data for compound prioritization and for the selection of compounds for in vivo studies. The main components of a profiling strategy suitable for early discovery are the measurement of selected physicochemical properties together with in vitro screening for metabolic stability. In addition, enzyme or cellular assays may be deployed for investigation of cellular permeability (including active and passive transport), plasma protein binding, toxicity, and the potential for drug-drug interactions. The four principal physicochemical parameters measured are lipophilicity, dissociation constant, permeability through artificial membranes, and aqueous solubility. An objective of property-based design is the identification of structure property relationships for ADMET that can suggest structural modifications that will also promote or retain high affinity for the biomolecular target. Sometimes this is not possible and new lead molecules may need to be identified to provide new starting points. A sub-optimal in vitro profile may be acceptable as long as there is a reasonable probability of achieving an adequate in vivo profile for clinical studies. In these cases, the application of composite models that can relate in vitro to in vivo behavior is important. Full ‘physiologically based pharmacokinetic’ (PBPK) models can be used; however, there are also simpler approaches available that may be adequate and more easily applied for ranking compounds within a series. Reliable in vitro—in vivo correlation is still very difficult because of the multiplicity of mechanisms involved. For the future, there is a need to develop better criteria for making mechanistically based classifications to develop differentiated models that are appropriate for different types of compound. It is also difficult to correct models for non-specific binding of drugs to membranes and proteins and we need better lipophilicity measures for accurately estimating the affinity of drugs for tissues. PBPK modeling leads to the exciting concept of the ‘virtual human’; however, PBPK models suitable for drug discovery applications are still in their infancy and it will be some time before their promise is fulfilled.     

Bioethics as care work

German philosopher Martin Heidegger argued that humans are defined by care. The term he used, “Sorge,” picks out a wide range of caring relations, including sorrow, worry, the making of arrangements, and even fending for another. Since coming to The Hastings Center, I've been struck by the genuine care definitive of its scholars’ relationship to their work. Care about newborns, the elderly, and nonhuman animals. Care about doctors, nurses, and health care institutions. Care expressed in the panoply of ways biomedical knowledge and practices inform our havings, doings, and beings in the world. Perhaps in its better moments, bioethics just is care work. But care work is hard and messy.