Phase I clinical and pharmacokinetic study of cyclophosphamide administered by five-day continuous intravenous infusion

Summary A total of 14 patients, 7 male and 7 female, received in all 21 evaluable courses of cyclophosphamide administered by 5-day continuous infusion. Cyclophosphamide doses were escalated from 300 to 400 mg/m² per day for 5 days and repeated every 21–28 days. The patient population had a median age of 55 years (range 38–76) and a median Karnofsky performance status of 80 (range 60–100). Only 1 patient had not received prior therapy; 5 patients had received only prior chemotherapy, 1 had received only prior radiotherapy, and 7 had received both. Tumor types were gastric (1), lung (2), colon (4), urethral adenocarcinoma (1), cervical (2), chondrosarcoma (1), melanoma (1), uterine leiomyosarcoma (1), and pancreatic (1). The dose-limiting toxicity was granulocytopenia, with median WBC nadir of 1700/l (range 100–4800) in 8 heavily pretreated patients treated at 350 mg/m² per day for 5 days. One patient without heavy prior treatment received two courses at 400 mg/m² and had WBC nadirs of 800/l and 600l. WBC nadirs occurred between days 9 and 21 (median 14). Drug-induced thrombocytopenia occurred in only one patient (350 mg/m² per day, nadir 85000/l). Neither hyponatremia nor symptomatic hypoosmolality was observed. Radiation-induced hemorrhagic cystitis may have been worsened in one patient. Nausea and vomiting were mild. Objective remissions were not observed. The maximum tolerated dose for previously treated patients is 350 mg/m² per day for 5 days. This dose approximates the doses of cyclophosphamide commonly used with bolus administration. Plasma steady-state concentrations (Css) of cyclophosphamide, measured by gas liquid chromatography, were 2.09–6.79 g/ml. Steady state was achieved in 14.5±5.9 h (mean ±SD). After the infusion, cyclophosphamide disappeared from plasma monoexponentially, with a t^1/2 of 5.3±3.6 h. The area under the curve of plasma cyclophosphamide concentrations versus time (AUC) was 543±150 g/ml h and reflected a cyclophosphamide total-body clearance (CL_TB) of 103±31.6 ml/min. Plasma alkylating activity, assessed by p-nitrobenzyl-pyridine, remained steady at 1.6–4.3 g/ml nor-nitrogen mustard equivalents. Urinary excretion of cyclophosphamide and alkylating activity accounted for 9.3%±7.6% and 15.1%±2.0% of the administered daily dose, respectively. The t^1/2 and AUC of cyclophosphamide associated with the 5-day continuous infusion schedule are similar to those reported after administration of cyclophosphamide 1500 mg/m² as an i.v. bolus. The AUC of alkylating activity associated with the 5-day continuous infusion of cyclophosphamide is about three times greater than the AUC of alkylating activity calculated after a 1500-mg/m² bolus dose of cyclophosphamide. Daily urinary excretions of cyclophosphamide and alkylating activity associated with the 5-day continuous infusion schedule are similar to those reported after bolus doses of cyclophosphamide.     

Response rates in metastatic neuroendocrine tumors receiving peptide receptor radionuclide therapy and implications for future treatment strategies

BackgroundPeptide receptor radionuclide therapy is a targeted therapy used to treat unresectable somatostatin receptor-positive neuroendocrine tumors. The objective of this study was to evaluate response rates among neuroendocrine tumors of different primaries and identify factors relevant to future treatment strategies.MethodsWe retrospectively reviewed patients who received peptide receptor radionuclide therapy for neuroendocrine tumors from 2018 to 2019 at our institution. Patients were assessed with computed tomography/magnetic resonance imaging and ⁶⁸Ga-DOTATATE-positron emission tomography before and after 2 or 4 cycles of peptide receptor radionuclide therapy. Tumor response was evaluated by RECIST 1.1. Statistics included multinomial logistic regression models and Fisher exact test.ResultsTwenty-seven patients underwent 92 cycles of peptide receptor radionuclide therapy: pancreas (n = 11), small bowel (n = 7), and other (n = 9) neuroendocrine tumors. Overall, 30% (8 of 27) had partial response, 59% (16 of 27) stable disease, and 11% (3 of 27) progressed. Pancreatic neuroendocrine tumors responded differently from small bowel neuroendocrine tumors regardless of cycle number (P = .01). The majority of pancreatic neuroendocrine tumors (6 of 11) had partial response to peptide receptor radionuclide therapy, while all small bowel neuroendocrine tumors had stable disease. Pancreatic neuroendocrine tumors stable after 2 cycles were more likely to respond to additional cycles versus other neuroendocrine tumors (probability: 60% vs 11%).ConclusionPatients with unresectable advanced or metastatic pancreatic neuroendocrine tumors may benefit from a full course of peptide receptor radionuclide therapy, whereas other neuroendocrine tumors appear less likely to respond. Large prospective studies are needed to confirm these findings.     

Differences in the mother-infant relations of squirrel monkeys housed in social and restricted environments

Mother and infant squirrel monkeys were housed together in either a group or a restricted environment until the infants were approximately 22 weeks of age. Observations of the mothers' and infants' behavior during this period revealed clear differences between the rearing conditions. Mothers in the socially restricted environment avoided and punished their infants more and were generally less protective than those in the group environment. However, these differences did not appear to reflect differences in maternal attitudes per se, but rather the extent to which infants in the two environments engaged in certain activities. Infants in the restricted environment attempted to play with their mother more often and remained closer to her as they became older.     

Materials management with a bar code reader

A materials management system capable of inventory control, accounting and the automatic recording of supplies for a clinical department has been developed for the George Washington University Hospital Department of Anesthesia. This system combines a microprocessor-based computer for data storage and a hand-held bar code reader to record the bar code scan of each item in the inventory. A relational software program with easy-to-use menus and help keys was written. Bar code information stored for each item includes item number, quantity, date and time of issue. Accumulated bar code scans are loaded into the computer by use of a serial port and then used to update current inventory in the computer. Comparison between current inventory and reorder levels by the computer will initiate automatic printing of appropriate purchase orders. Reorder levels are adjusted regularly, by comparing previous year or month usage to current needs; items already on order, items on back order and delivery lag time are also taken into account.     

A continuing controversy: magnesium sulfate in the treatment of eclamptic seizures

It would appear from the above that Pritchard agrees with the use of some agents other than magnesium sulfate that have known anticonvulsant properties. We believe that the subject at issue is whether magnesium sulfate should be used in treating the seizures of eclampsia. In our "Controversies" article, we do not address the issue of whether magnesium sulfate modifies pathophysiological factors leading to preeclampsia, but restrict ourselves to the treatment of the seizure per se, once seizures supervene, and the avoidance of their recurrence. The pathophysiological mechanisms and optimal treatment of preeclampsia and of eclampsia (excepting seizures) remain to be determined, as does the use of magnesium sulfate in this condition. Eclamptic seizures are clinically and electroencephalographically indistinguishable from generalized tonic-clonic seizures. Whether seizures arise in or out of the setting of preeclampsia, they should be treated as are other seizures, with known anticonvulsants. Controlled clinical trials are needed to address the effectiveness of alternative antiseizure regimens.     

Recent advances in understanding the pathogenesis of the hemolytic uremic syndromes

One of the requirements for an agent to cause hemolytic uremic syndrome (HUS) is its ability to injure endothelial cells. Shiga-like toxin (SLT) can do this. SLT is produced byEscherichia coli andShigella dysenteriae serotype 1; both have been implicated as causes of typical HUS. Endothelial cells have receptors (GB₃) for SLT and the toxin can inhibit eukaryotic protein synthesis, thereby causing cell death. Glomerular endothelial cell injury or death results in a decreased glomerular filtration rate and many of the perturbations seen in HUS. It is no longer certain that hemolysis is the result of a microangiopathy. Cell injury results in release of von Willebrand multimers; if these are ultra-large, thrombosis may ensue. There is also increasing evidence that neutrophils have a role in the pathogenesis of typical HUS.Streptococcus pneumoniae can also cause HUS and care must be taken to avoid giving plasma to patients withS. pneumoniae-associated HUS. There is compelling evidence that types of HUS are inherited by autosomal recessive and autosomal dominant modes. Patients with autosomal recessive HUS may have recurrent episodes. Mortality and morbidity rates are high for the inherited forms.     

Immune responses to the expressed products of the CSP antige n gene of Plasmodium falciparum southern China isolate FCC1/HN in Hela cell

Objective To construct a eukaryotic expression system with pcDNA3-PfCSP/Hela for the Circ umsporozoite protein (CSP) gene of Plasmodium falciparum (P.falciparum), t o observe the immune responses in BALB/c mice induced by the expressed proteins .Methods The recombinant plasmid pcDNA3-PfCSP was transformed into the Hela cell line. The expressed protein was isolated and analyzed by using SDS-PAGE and used for immunization of BALB/c mice by subcutaneous, intravenous, and intraperitone al adminstration.Enzyme-linked immunosorbent assay(ELISA), Dot-ELISA, Wester n blot, T lymphocyte proliferation test, natural killer cell(NKC) activity assay , and CD4(+) and CD8(+) T cell detection were used for observation of humoral an d cellular immune responses.Results Immune sera strongly reacted with the expressed protein, antibody titer was up to 1∶6400 as detected by ELISA.Western blot analysis revealed a specific b and at 38.3 Kda.When the spleen cells of normal and immunized BALB/c mice we re specifically stimulated with expressed protein, the optical densities were 0 .12±0.03 and 0.34±0.04, respectively.The latter were significantly highe r than the former (P<0.01).We used the MTT colorimetric assay to measure NKC activity of mice spleen.The results showed that the NKC activity of immuni zed BALB/c mice was remarkably higher than that of the controls (P<0.05). CD4(+) and CD8(+) T cells were detected by using monoclonal antibody immunofluor escence methods.The results showed that the percentage of CD4(+) and CD8(+) T cells of immunized group were significantly higher than that of control group ( P<0.05).Conclusions The humoral and cell-mediated immune responses and elevated NKC activity to pr oducts made with a eukaryotic expression system could be specifically detected i n BALB/c mice.These findings indicate that the expressed protein could enhance the immune function in mice.     

消痔灵和强的松龙混合液治疗鼻息肉

0　引言　我科 1996 / 1998分别应用消痔灵与强的松龙混合液、消痔灵液、强的松龙液行鼻息肉内 ,鼻息肉蒂部注射治疗鼻息肉各 5 0例 ,并设对照组为鼻腔滴入及口服类固醇激素 5 0例 ,合计 2 0 0例 ,观察并对比其疗效 .1　对象和方法1.1　对象　男 12 8例 ,女 72例 ,年龄 8～ 78(平均 38)岁 ,病程 32 a～ 45 (平均 4.5 ) a.其中在本次治疗前做过一次鼻息肉摘除术后复发的 2 7例 ,做过 2次或 2次以上手术的 12例 .主要症状为鼻塞、流脓涕、头痛及嗅觉减退 .全部病例治疗前均行鼻窦 X线拍片 ,其中上颌窦炎 12 5例、筛窦炎 5 8例、蝶窦炎 2例、…     

Professional associations and managed care. How four provider groups are helping their members

Managed care is facilitating rapid change in the day-to-day practice of many addiction treatment and mental health professionals. It is only natural, therefore, that the associations representing the various disciplines in behavioral healthcare should seek to present short- and long-term plans, advice, and programs for their members. We have asked leaders from four prominent groups to present what their organizations are doing today to assist professionals in adapting to the new realities of the healthcare system. The comments below are by no means conclusive, and are representative of a few efforts and thoughts. It is our mission at Behavioral Healthcare Tomorrow to provide an independent platform for dialogue in the world of mental health and addiction treatment. It is our hope that the proposals and ideas published here stimulate even more planning amongst providers as managed care assertively enters public sector services.     

Nabumetone in elderly patients with osteoarthritis: economic benefits versus ibuprofen alone or ibuprofen plus misoprostol

Nonsteroidal anti-inflammatory drugs (NSAIDs) vary in their potential to produce gastropathy. We compared the 3-month direct medical costs, including those associated with treating NSAID-induced adverse events, of nabumetone, ibuprofen, or ibuprofen plus misoprostol in 171 elderly patients with osteoarthritis. Total direct medical costs per patient treated were $US183 for nabumetone, $US252 for ibuprofen, and $US270 for ibuprofen plus misoprostol. Differences resulted from higher costs associated with treatment of drug-related adverse events with ibuprofen, and higher drug acquisition prices with the combination regimen. Sensitivity analyses demonstrated that direct costs with nabumetone approached those for the other 2 regimens if the price of nabumetone increased by 60%, the probability of lesion formation with nabumetone increased 4-fold, the probability of a lesion greater than 0.5cm being symptomatic and needing treatment was 31%, or the price of misoprostol decreased by 50%. Although this study found more lesions because of mandated endoscopies than might be recognised or treated in clinical practice, the results suggest an economic benefit of nabumetone.