The reversal of profound mivacurium-induced neuromuscular blockade

Purpose

Mivacurium is metabolized by plasma cholinesterase catalyzed ester hydrolysis. Acetylcholinesterase antagonists used in the reversal of muscle relaxation may also inhibit plasma cholinesterase and, therefore, delay the hydrolysis of mivacurium. The clinical interaction between acetylcholinesterase antagonists and mivacurium induced neuromuscular blockade was studied.

Method

Intraoperative muscle relaxation was maintained with a mivacurium infusion to achieve a constant intense block (first twitch, T¹, 2–3% of control). Patients were randomly divided into three groups. Patients in Group 1 received no anticholinesterase, in Group 2 neostigmine 0.07 mg · kg^?1, and in Group 3 edrophonium 1 mg · kg^?1. The times between termination of the mivacurium infusion (Group 1) or the administration of the anticholinesterase (Groups 2 and 3) to 25%, 50%, 75% and 95% T₁ recovery, and to 50%, 70% and 90% recovery in the ratio, T₄/T₁ (TR) were recorded.

Result

In the neostigmine Group, T₁ recovery to 25%, 50% and 75% ( 2.32 ± 1.41, 3.90 ± 1.85 and 6.88 ± 2.66 min) was accelerated compared with control (3.36 ± 1.34, 5.78 ± 2.22, and 8.58 ± 3.60, and), but recovery to 95% (18.53 ± 9.09 vs 13.29 ± 5.24 min) was delayed. Also, TR recovery to 50%, 70%, and 90% was slower (14.47 ± 8.73, 21.25 ± 11.06 and 31.37 ± 12.11 min vs 11.75 ± 3.74, 13.78 ± 4.39 and 17.86 ± 6.44 min). However, all T₁ and TR recovery times were decreased in the edrophonium group (0.88 ± 0.51, 2.00 ± 1.50, 4.97 ± 2.96, and 9.35 ± 5.24 min for T₁ and 6.86 ± 3.93, 9.05 ± 4.51 and 12.24 ± 6.66 min for TR).

Conclusion

Neostigmine reversal of intense mivacurium neuromuscular block should be avoided, as this may result in prolongation of the block.     

Accuracy of a rapid 10-minute carbon-14 urea breath test for the diagnosis of Helicobacter pylori-associated peptic ulcer disease

Urease in the human gastric mucosa is a marker for infection with Helicobacter pylori (HP), an organism which is associated with peptic ulcer disease. To detect gastric urease, we examined 184 patients (144 males, 40 females; mean age: 49.8±15.6 years) with suspected peptic ulcer disease. Fasting patients were given orally 5 Ci of carbon-14 labelled urea. From each patient only one breath sample was collected in hyamine at 10 min. The amount of ¹⁴C collected at 10 min was expressed as follows: [(DPM/mmol CO₂ collected)/(DPM administered)] × 100 × body weight (kg). The presence of HP colonization was determined by examination of multiple endoscopic prepyloric antral biopsy specimens subjected to culture or a rapid urease test. For the purpose of this study, HP-positive patients were defined as those with characteristic bacteria as indicated by a positive result of either the culture or the rapid urease test; HP-negative patients were defined as those with negative findings on both the culture and the rapid urease test. Of the 184 cases, 99 (53.8%) were positive for HP infection, and 85 (46.2%), negative. The sensitivity and specificity of the rapid 10 min ¹⁴C-urea breath test for the diagnosis of HP-associated peptic ulcer disease were evaluated by a receiver operating characteristic (ROC) curve with a variable cut-off value from 1.5 to 4.5. When a cut-off value of 1.5 was selected, the sensitivity was 100% and the specificity, 83.5%; when a cut-off value of 4.5 was selected, the sensitivity was 54.5% and the specificity, 97.6%. Correspondence to: Chia-Hung Kao     

Time course of satisfaction of search

"Satisfaction of search" (SOS) refers to the effect in which a second lesion remains undetected after detection of another lesion on the same radiograph. The objective of this study was to clarify our understanding of SOS by relating it to total time of inspection and time intervals before, between, and after discovery of lesions. Detection accuracy of native lesions in chest radiographs, before and after the addition of a simulated nodular lesion, was measured for ten observers. Analysis of data from this and a previous experiment showed that average perceptual accuracy of individual receiver operating characteristic curves was significantly reduced with the addition of the nodules. Plots and analyses of search time revealed that, on average, during a typical 46-second inspection of a case, simulated nodules were found at 18 seconds, native abnormalities at 25 seconds, and false positives occurred at 33 seconds. Time needed to find nodules did not depend on whether native lesions were present; time to find native lesions did not change with addition of nodules; and total search time was the same for images with one, two, or no lesions. The detection results show that the SOS effect was obtained, but that interrupting search in order to measure it also diminishes accuracy. Analysis of the time course data relates SOS to perceptual capture and strategic halting of search.     

Dopamine distribution and behavioral alterations resulting from dopamine infusion into the brain of the lesioned rat

In an effort to verify the "dopamine secretion hypothesis" as the mechanism responsible for the antiparkinsonian efficacy of adrenal medullary transplants into the brain, the effects of dopamine infusion into the brains of rats with unilateral substantia nigra lesions were examined. The apomorphine-induced rotation, characteristic of this animal model, was diminished after 7 days of continuous dopamine infusion (10 micrograms/hr) into the ipsilateral striatum, whereas intraventricular infusion was without effect. Chromatographic analysis of the dopamine distribution after 10 days of infusion into either region revealed that ipsilateral delivery of dopamine did not result in contralateral increases in dopamine content. Examination of the adjacent striatum following ipsilateral intraventricular delivery indicated that dopamine had only penetrated 1 mm. Even with intrastriatal delivery, there were still parts of the infused striatum which had below-normal levels of dopamine. The fact that striatal tissue presents a significant barrier to the penetration of dopamine is discussed in relation to adrenal medullary and fetal nigral transplants.     

The conduct of in vitro and in vivo drug-drug interaction studies: a Pharmaceutical Research and Manufacturers of America (PhRMA) perspective.

Current regulatory guidances do not address specific study designs for in vitro and in vivo drug-drug interaction studies. There is a common desire by regulatory authorities and by industry sponsors to harmonize approaches, to allow for a better assessment of the significance of findings across different studies and drugs. There is also a growing consensus for the standardization of cytochrome P450 (P450) probe substrates, inhibitors and inducers and for the development of classification systems to improve the communication of risk to health care providers and to patients. While existing guidances cover mainly P450-mediated drug interactions, the importance of other mechanisms, such as transporters, has been recognized more recently, and should also be addressed. This article was prepared by the Pharmaceutical Research and Manufacturers of America (PhRMA) Drug Metabolism and Clinical Pharmacology Technical Working Groups and represents the current industry position. The intent is to define a minimal best practice for in vitro and in vivo pharmacokinetic drug-drug interaction studies targeted to development (not discovery support) and to define a data package that can be expected by regulatory agencies in compound registration dossiers.     

Phase II trial of gefitinib in recurrent glioblastoma.

PURPOSE: To evaluate the efficacy and tolerability of gefitinib (ZD1839, Iressa; AstraZeneca, Wilmington, DE), a novel epidermal growth factor receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma. PATIENTS AND METHODS: This was an open-label, single-center phase II trial. Fifty-seven patients with first recurrence of a glioblastoma who were previously treated with surgical resection, radiation, and usually chemotherapy underwent an open biopsy or resection at evaluation for confirmation of tumor recurrence. Each patient initially received 500 mg of gefitinib orally once daily; dose escalation to 750 mg then 1,000 mg, if a patient received enzyme-inducing antiepileptic drugs or dexamethasone, was allowed within each patient. RESULTS: Although no objective tumor responses were seen among the 53 assessable patients, only 21% of patients (11 of 53 patients) had measurable disease at treatment initiation. Seventeen percent of patients (nine of 53 patients) underwent at least six 4-week cycles, and the 6-month event-free survival (EFS) was 13% (seven of 53 patients). The median EFS time was 8.1 weeks, and the median overall survival (OS) time from treatment initiation was 39.4 weeks. Adverse events were generally mild (grade 1 or 2) and consisted mainly of skin reactions and diarrhea. Drug-related toxicities were more frequent at higher doses. Withdrawal caused by drug-related adverse events occurred in 6% of patients (three of 53 patients). Although the presence of diarrhea positively predicted favorable OS from treatment initiation, epidermal growth factor receptor expression did not correlate with either EFS or OS. CONCLUSION: Gefitinib is well tolerated and has activity in patients with recurrent glioblastoma. Further study of this agent at higher doses is warranted.     

Technetium-99m tetrofosmin SPECT predicts chemotherapy response in small cell lung cancer.

The multidrug resistance gene 1 encoding human P-glycoprotein (Pgp) is thought to play an important role in the multidrug resistance of lung cancer. The purpose of this study was to predict chemotherapy response by technetium-99m tetrofosmin (Tc-99m TF) lung single photon emission computed tomography (SPECT) and compare Pgp expression in patients with untreated small cell lung cancer (SCLC). Forty patients with untreated SCLC received Tc-99m TF lung SPECT prior to chemotherapy. The chemotherapy response was evaluated in the 3rd month after completion of treatment. Immunohistochemical staining of Pgp expression was performed on multiple nonconsecutive sections of biopsy specimens. By quantitative analyses, tumor to background ratios were 1.86 +/- 0.27 and 1.17 +/- 0.26 for patients with a good and poor response, respectively (p < 0.05). All of the 20 patients with a good chemotherapy response also had a positive Tc-99m TF lung SPECT and negative Pgp expression. In contrast, only 4 of the 20 patients with a poor chemotherapy response had a positive Tc-99m TF lung SPECT. Moreover, 10 of the 20 patients with a poor chemotherapy response also had negative Pgp expression (p < 0.05). Therefore, we concluded that Tc-99m TF lung SPECT can accurately predict the chemotherapy response, and Tc-99m TF lung SPECT findings can be partially compatible with Pgp expression in patients with untreated SCLC.     

A fully human antimelanoma cellular adhesion molecule/MUC18 antibody inhibits spontaneous pulmonary metastasis of osteosarcoma cells in vivo.

PURPOSE: The melanoma cellular adhesion molecule, also known as MUC18, is highly expressed on several tumors, including bone sarcomas. The level of MUC18 expression has been found to correlate directly with tumor progression and metastatic potential. These observations have established MUC18 as a candidate mediator of tumor growth and metastasis, and suggest that blockade of MUC18 might be a potential target for immunotherapy against several MUC18-expressing tumors, including human bone sarcomas. EXPERIMENTAL DESIGN: To investigate whether blockade of MUC18 might be a potential target for immunotherapy against osteosarcoma, we have recently developed a fully human anti-MUC18 antibody, ABX-MA1. We studied the effect of ABX-MA1 on growth, adhesion, invasion, and metastasis of human osteosaroma cells both in vitro and in vivo. RESULTS: MUC18 was widely expressed on both osteosarcoma and Ewing's sarcoma cells. ABX-MA1 had no effect on the proliferation of osteosarcoma cells in vitro, nor did it significantly inhibit the growth of KRIB human osteosarcoma cells when they were orthotopically implanted into the tibias of nude mice. However, after 6 weeks, significantly fewer ABX-MA1-treated mice developed spontaneous pulmonary metastases than did IgG-treated control mice. Additionally, ABX-MA1 decreased the invasion of osteosarcoma cells through Matrigel-coated filters and disrupted homotypic adhesion between osteosarcoma cells and their heterotypic interaction with human vascular endothelial cells. CONCLUSIONS: Our findings demonstrate that MUC18 plays a central role in the metastasis of osteosarcoma and suggest that targeted inhibition of this antigen by ABX-MA1 may be a novel immunotherapeutic approach in the management of this tumor.