Optimal Administration Regimen Research Articles

The Impact of Spironolactone Co-administration on Cyclosporin Initial Dosage Optimization for Pediatric Refractory Nephrotic Syndrome.

Cyclosporin has been used for the treatment of pediatric refractory nephrotic syndrome (PRNS). However, the narrow therapeutic window and large pharmacokinetic variability make it difficult to individualize cyclosporin administration. Meanwhile, spironolactone has been reported to affect cyclosporin metabolism in PRNS patients. This study aims to explore the initial dosage optimization of cyclosporin in PRNS based on the impact of spironolactone co-administration. Monte Carlo simulation based on a previously established cyclosporin population pharmacokinetic model for PRNS was used to design cyclosporin dosing regimen. In this study, the probability of drug concentration reaching the target and the convenience of times of administration were considered comprehensively. The optimal administration regimen in PRNS without spironolactone was 6, 5, 4 and 3 mg/kg cyclosporin split into two doses for the body weight of 5-8, 8-18, 18-46 and 46-70 kg, respectively. The optimal administration regimen in PRNS with spironolactone was 4, 3, 2 mg/kg cyclosporin split into two doses for body weight of 5-14, 14-65, and 65-70 kg, respectively. The cyclosporin dosing regimen for PRNS based on Monte Carlo simulation was systematically developed and the initial dosage optimization of cyclosporin in PRNS was recommended for the first time.

Optimal dosing regimen of biapenem based on population pharmacokinetic/pharmacodynamic modelling and Monte Carlo simulation in patients with febrile neutropenia and haematological malignancies

In the current study, a population pharmacokinetic (PPK) model was developed for biapenem in patients with febrile neutropenia (FN) and haematological malignancies. Through Monte Carlo simulation, optimal administration regimens were suggested based on the developed PPK model. In a prospective, single-centre, open-label study, 174 plasma samples from 120 Chinese patients with FN and haematological malignancies were analysed by chromatography, and PK parameters were analysed by NONMEM. The drug clearance process was influenced by crucial covariates, namely creatinine clearance (CLCR) and concomitant posaconazole (POS). The ultimate PPK model was as follows: CL (L/h)=29.81×(CLCR/121.38)0.806×(1-POS×0.297); volume of distribution (L)=114. For the target of ≥40% fT>minimum inhibitory concentration (MIC) (duration that the plasma level exceeds the MIC of the causative pathogen) and achieving the probability of target attainment ≥90%, the PK/pharmacodynamic breakpoint was 2 mg/L for the 2.4 g/day dosing regimen consisting of 600 mg q6h and 800 mg q8h. The breakpoint was 1 mg/L for the 1.2 g/day dosing regimen consisting of 300 mg q6h and 600 mg q12h. Empirical therapy would benefit from utilizing higher dosages and extended infusion durations. Therefore, it is suggested that patients with symptoms that are strongly suggestive of Pseudomonas aeruginosa or Acinetobacter baumannii infection may be suitable for combined treatment with other antibacterial drugs.

Ceftolozane-Tazobactam Pharmacokinetics in the Abdominal Tissue of Patients Undergoing Lower Gastrointestinal Surgery: Dosing Considerations Based on Site-Specific Pharmacodynamic Target Attainment.

Recently, complicated intra-abdominal infections (cIAI) have been caused not only by Escherichiacoli, Klebsiellapneumoniae, Enterobacter cloacae, and Pseudomonasaeruginosa, but also by extended-spectrum β-lactamase-producing Enterobacterales members. Ceftolozane-tazobactam (CTLZ-TAZ) is considered to exhibit therapeutic effects against cIAI. Studies on the concentrations of antibiotics in abdominal tissues directly affected by cIAI are limited. Therefore, in this study, we investigated the pharmacokinetics of CTLZ-TAZ in abdominal tissue and simulated the administration regimen required to achieve the pharmacodynamic target for cIAI-causing bacteria. Patients scheduled for elective lower gastrointestinal surgery were intravenously administered preoperative CTLZ-TAZ (1g CTLZ and 0.5g TAZ). Plasma, peritoneal fluid, peritoneum, and subcutaneous adipose tissue samples were collected during the surgery, and CTLZ as well as TAZ concentrations were measured. The noncompartmental and compartmental pharmacokinetic parameters were then estimated. Site-specific pharmacodynamic target attainment analysis using 1.5g of CTLZ-TAZ was performed. CTLZ-TAZ was administered to nine patients (once to five patients and twice to four patients). The mean peritoneal fluid-to-plasma ratio (one dose/two doses) for CTLZ was 0.74/1.15, which was slightly higher than the mean peritoneal fluid-to-plasma ratio for TAZ (0.95/1.13). The ratio for subcutaneous adipose was lower than those for peritoneal fluid and peritoneum tissues. We also discovered that the average ratio of CTLZ and TAZ concentrations in all tissues was maintained at or above 2:1. In our investigation of pharmacodynamic target attainment in each tissue, the desired bactericidal effect was attained with all CTLZ-TAZ (1.5g) administration regimens [q12h (3g/day), q8h (4.5g/day), and q6h (6g/day)]. To the best of our knowledge, this is the first study investigating the optimal pharmacodynamic level of CTLZ-TAZ in the abdominal tissue against cIAI-causing bacteria. This study also serves as a guideline for designing an optimal administration regimen based on pharmacodynamic target attainment for cIAI-causing bacteria. The institutional review board of Hiroshima University Hospital, CRB6180006. The Japan Registry of Clinical Trials, jRCTs061190025.

Combination of antiangiogenic treatment with chemotherapy as a multi‐input optimal control problem

We analyze a mathematical model for the combination of chemotherapy with antiangiogenic treatment as a multi‐input optimal control problem. Assuming that the total amounts of both agents to be given have been determined a priori based on a medical assessment of side effects, we consider the problem to minimize a weighted average of tumor volume and the carrying capacity of the tumor vasculature. For medically realistic initial conditions and data, based on a thorough theoretical analysis of the necessary conditions for optimality given by the Pontryagin maximum principle, in this paper, the optimal administration regimen for the antiangiogenic agent is determined.

Outcomes of starting low-dose pazopanib in patients with metastatic renal cell carcinoma who do not meet eligibility criteria for clinical trials

Purpose: Eligibility for clinical trials is very strict and only patients who satisfy various criteria can enter trials. The individual use of pazopanib has not been adequately investigated. An optimal administration regimen for pazopanib in “real-world” patients with metastatic renal cell carcinoma (mRCC) is required. Our purpose was to determine the tolerability and efficacy of first-line pazopanib with a low starting dose in patients with mRCC who were ineligible for clinical trials. Materials and Methods: This study included patients with mRCC who underwent treatment with first-line pazopanib and were previously excluded from clinical trials because they did not meet the inclusion criteria. A 400 mg pazopanib starting dose is used routinely in patients with mRCC; if tolerated, dose escalation up to 800 mg may occur. Results: We identified 18 patients with mRCC who received first-line pazopanib and were previously determined ineligible for clinical trials. Pazopanib dose was escalated in 12 patients (66.6%), to 600 mg/day in 8 patients (44.4%) and to 800 mg/day in 4 patients (22.2%), and was not escalated in 6 patients (33.3%). In 3 patients (16.7%), pazopanib was discontinued owing to intolerability. The most common frequent adverse event was elevated alanine aminotransferase levels in 6 patients (33.3%), followed by a decreased platelet count in 5 patients (27.8%) and anorexia in 5 patients (27.8%). Partial response was seen in 5 patients (27.8%) and stable disease in 10 patients (55.6%); median progression-free survival was 11.9 months (95% confidence interval: 6.3–28.7 months). Conclusion: Our data indicated that a low starting dose of 400 mg pazopanib did not negatively affect treatment tolerability and efficacy in patients with mRCC ineligible for clinical trials. We found that lower starting doses may lead to better results. Additional studies are needed in a larger cohort and longer follow-up to attain authentic outcomes.

Caffeine for the Treatment of Apnea in the Neonatal Intensive Care Unit: A Systematic Overview of Meta-Analyses.

BackgroundCaffeine is a common treatment for neonatal intensive care management of the developmental complication of apnea of prematurity in preterm infants. There are several systematic reviews (SRs) on the performance of caffeine in the treatment of apnea. The evidence provided by those, however, is depressed by an information overload due to high heterogeneity in the characteristics as well as the quality of these SRs.ObjectiveThe aim was to provide a systematic overview of SRs on the use of caffeine for the management of neonatal apnea. Such overviews are a recent method used to assess and filter top evidence among SRs, enabling enhanced access to targeted information of interest.MethodsA comprehensive literature search was conducted via EMBASE, Cochrane Database of Systematic Reviews (CDSR), and PubMed since inception to January 2020. Two reviewers independently conducted study selection and data extraction, and assessed the quality of methods and the risk of bias in included SRs based on A Measurement Tool to Assess Systematic Reviews (AMSTAR-2) and Risk of Bias in Systematic Reviews (ROBIS) tools. Extracted data related to study type, characteristics, patients, intervention, comparator, regimen, and outcome measures.ResultsSeven SRs with meta-analyses (SRMAs) were included in the current overview, involving a total of 63,315 neonates. SRMAs included randomized clinical and observational studies, with various types of patients, comparators, and outcomes. The quality of SRMAs ranged from critically low (n = 1), low (n = 1), moderate (n = 2), to high (n = 3), and the risk of bias was unclear (n = 2), low (n = 4), and high (n = 1). The effectiveness of caffeine with regard to treatment success and the rate of apnea was not significantly different from that of theophylline or doxapram in two SRMAs. Against control, in one SRMA, while caffeine reduced the rate of failure as well as the need for pressure ventilation, it did not significantly reduce mortality. This comparative effectiveness of caffeine was based on high-quality SRMAs with a low risk of bias. The effectiveness against apnea seems to be enhanced via the administration of early (0–2 days) or high doses of caffeine in one and three SRMAs, respectively. This, nevertheless, was based on lower-quality SRMAs with a higher risk of bias. Safety outcomes were mostly based on comparative SRMAs of different drug regimens, whereby, less tachycardia and lower risk for complications were reported with lower and earlier caffeine administrations, respectively. The evidence behind this, however, was limited in quantity and quality.ConclusionWhile limited in quantity, there is evidence of non-inferior effectiveness of caffeine against other methylxanthines or doxapram for the management of apnea in neonates. Owing to the limited quality, however, limited evidence exists in support of an optimal administration regimen for caffeine. Further controlled studies are, therefore, needed to confirm the comparative usefulness of caffeine as well as to assess its different potential regimens, including in relation to safety.Electronic supplementary materialThe online version of this article (10.1007/s40272-020-00404-4) contains supplementary material, which is available to authorized users.

Time-Dependent Memory and Gait Improvement by Intranasally-Administered Extracellular Vesicles in Parkinson's Disease Model Rats.

We have recently demonstrated that extracellular vesicles (EVs) derived from the human teeth stem cells improve motor symptoms and normalize tyrosine hydroxylase (TH) expression in the nigrostriatal structures of Parkinson's disease (PD) model rats obtained by 6-hydroxydopamine (6-OHDA) unilateral injection into the medial forebrain bundle (MFB). The aim of this study was to clarify: (1) how long therapeutic effects persist after discontinuation of 17-day intranasal administration of EVs in 6-OHDA rats; (2) may EVs reverse cognitive (learning/memory) dysfunction in these PD model rats; (3) whether and how the behavioral improvement may be related to the expression of TH and Nissl bodies count in the nigrostriatal structures. Our results demonstrated that in 6-OHDA rats, gait was normalized even ten days after discontinuation of EVs administration. EVs successfully reversed 6-OHDA-induced impairment in spatial learning/memory performance; however, the beneficial effect was shorter (up to post-treatment day 6) than that revealed for gait improvement. The shorter effect of EVs coincided with both full normalization of TH expression and Nissl bodies count in the nigrostriatal structures, while slight but significant increase in the 6-OHDA-decreased Nissl count persisted in the substantia nigra even on the post-treatment day 20, supposedly due to the continuation of protein synthesis in the living cells. The obtained data indicate the usefulness of further studies to find the optimal administration regimen which could be translated into clinical trials on PD patients, as well as to clarify other-apart from dopaminergic-neuromodulatory pathways involved in the EVs mechanism of action.

Mathematical Modelling of Intravenous Thrombolysis in Acute Ischaemic stroke: Effects of Dose Regimens on Levels of Fibrinolytic Proteins and Clot Lysis Time.

Thrombolytic therapy is one of the medical procedures in the treatment of acute ischaemic stroke (AIS), whereby the tissue plasminogen activator (tPA) is intravenously administered to dissolve the obstructive blood clot. The treatment of AIS by thrombolysis can sometimes be ineffective and it can cause serious complications, such as intracranial haemorrhage (ICH). In this study, we propose an efficient mathematical modelling approach that can be used to evaluate the therapeutic efficacy and safety of thrombolysis in various clinically relevant scenarios. Our model combines the pharmacokinetics and pharmacodynamics of tPA with local clot lysis dynamics. By varying the drug dose, bolus-infusion delay time, and bolus-infusion ratio, with the FDA approved dosing protocol serving as a reference, we have used the model to simulate 13 dose regimens. Simulation results are compared for temporal concentrations of fibrinolytic proteins in plasma and the time that is taken to achieve recanalisation. Our results show that high infusion rates can cause the rapid degradation of plasma fibrinogen, indicative of increased risk for ICH, but they do not necessarily lead to fast recanalisation. In addition, a bolus-infusion delay results in an immediate drop in plasma tPA concentration, which prolongs the time to achieve recanalisation. Therefore, an optimal administration regimen should be sought by keeping the tPA level sufficiently high throughout the treatment and maximising the lysis rate while also limiting the degradation of fibrinogen in systemic plasma. This can be achieved through model-based optimisation in the future.

Postoperative analgesic effect of hydromorphone in patients undergoing single-port video-assisted thoracoscopic surgery: a randomized controlled trial.

Objective: To study the general efficacy of hydromorphone as a systemic analgesic in postoperative pain management following single-port video-assisted thoracoscopic surgery (VATS) and to explore the optimal administration regimen.Methods: A prospective, randomized, double-blind study was designed and conducted in a tertiary hospital. In total, 157 valid patients undergoing single-port VATS were randomly allocated into three groups. A total of 53 patients received morphine bolus only for postoperative analgesia (Group Mb); 51 patients received a hydromorphone background infusion plus bolus (Group Hb + i), and 53 patients received a hydromorphone bolus only (Group Hb). The primary outcomes were patient-reported static and dynamic pain levels; the secondary outcomes included side effects, sleep quality, and recovery indexes.Results: Patients in Group Hb + i experienced lower pain intensity (approximately 10 out of 100 on the visual analog scale) in both static pain and dynamic pain in the days following surgery (P<0.01), better sleep quality during the first night only (P=0.002), and a higher satisfaction level than those in the other two groups (P=0.006). A comparison of these variables in Group Mb and Group Hb resulted in no significant differences. Lastly, side effects and recovery indexes remained the same among bolus-only groups and bolus-plus-background-infusion groups.Conclusion: There is no advantage to administering hydromorphone over morphine using bolus only mode. Within 24 h after surgery, a background infusion should be considered as a part of a standard protocol for patient-controlled intravenous analgesia. At 24 h after surgery, the background infusion should be adjusted in accordance with patient preferences and pain intensity.

Resistant hypertension: a therapeutic challenge.

Resistant hypertension: a therapeutic challenge.

Phenylephrine Infusion Versus Bolus Regimens During Cesarean Delivery Under Spinal Anesthesia

INTRODUCTION Phenylephrine is used to prevent and treat hypotension during spinal anesthesia for cesarean delivery. The optimal administration regimen is undetermined. We used a Non-invasive cardiac output monitor to test the hypothesis that a fixed-rate phenylephrine infusion regimen would cause a smaller reduction in maternal cardiac output, and result in less maternal hypotension, as compared to a phenylephrine bolus regimen. METHODS This was a double-blind, randomized clinical trial of women undergoing elective cesarean delivery under spinal anesthesia. Patients were randomized to an intermittent bolus (120 μg) or a fixed-rate infusion (120 μg/min) regimen of phenylephrine. Any decrease in systolic blood pressure from baseline was treated. The primary outcome was the maximum change in cardiac output in the predelivery period, assessed using bioreactance technology. Secondary outcomes included the maximum change in heart rate, incidence of hypo- and hypertension, nausea/vomiting and bradycardia, total dose of phenylephrine, umbilical blood gases, and Apgar scores. The hemodynamic profiles over time in each treatment arm were compared. RESULTS Sixty patients were studied. There was no significant difference in the maximum change in cardiac output between the 2 treatment arms: mean (SD) maximum change in cardiac output in the bolus group was 1.87 (1.68) L/min versus 1.9 (1.46) L/min in the infusion group (P = 0.94) (95% confidence intervals of difference in means: -0.84 to 0.78 L/min). The infusion group received significantly more phenylephrine (1740 (613) versus 964 (454) μg) (P < 0.001). In the initial 6 min after intrathecal injection, there was a significant decrease in blood pressure in the infusion group compared to the bolus group (P = 0.007). There was no significant difference in the other secondary outcomes. CONCLUSION There were no clinical benefits to administering phenylephrine as an infusion versus a bolus regimen. The bolus regimen maintained maternal arterial blood pressure closer to baseline in the initial minutes after spinal injection but this had no clinical benefits. The infusion regimen required a higher total dose of phenylephrine to maintain maternal arterial blood pressure at baseline during the predelivery period.

Phenylephrine Infusion Versus Bolus Regimens During Cesarean Delivery Under Spinal Anesthesia

Phenylephrine is used to prevent and treat hypotension during spinal anesthesia for cesarean delivery. The optimal administration regimen is undetermined. We used a Non-invasive cardiac output monitor to test the hypothesis that a fixed-rate phenylephrine infusion regimen would cause a smaller reduction in maternal cardiac output, and result in less maternal hypotension, as compared to a phenylephrine bolus regimen. This was a double-blind, randomized clinical trial of women undergoing elective cesarean delivery under spinal anesthesia. Patients were randomized to an intermittent bolus (120 μg) or a fixed-rate infusion (120 μg/min) regimen of phenylephrine. Any decrease in systolic blood pressure from baseline was treated. The primary outcome was the maximum change in cardiac output in the predelivery period, assessed using bioreactance technology. Secondary outcomes included the maximum change in heart rate, incidence of hypo- and hypertension, nausea/vomiting and bradycardia, total dose of phenylephrine, umbilical blood gases, and Apgar scores. The hemodynamic profiles over time in each treatment arm were compared. Sixty patients were studied. There was no significant difference in the maximum change in cardiac output between the 2 treatment arms: mean (SD) maximum change in cardiac output in the bolus group was 1.87 (1.68) L/min versus 1.9 (1.46) L/min in the infusion group (P = 0.94) (95% confidence intervals of difference in means: -0.84 to 0.78 L/min). The infusion group received significantly more phenylephrine (1740 (613) versus 964 (454) μg) (P < 0.001). In the initial 6 min after intrathecal injection, there was a significant decrease in blood pressure in the infusion group compared to the bolus group (P = 0.007). There was no significant difference in the other secondary outcomes. There were no clinical benefits to administering phenylephrine as an infusion versus a bolus regimen. The bolus regimen maintained maternal arterial blood pressure closer to baseline in the initial minutes after spinal injection but this had no clinical benefits. The infusion regimen required a higher total dose of phenylephrine to maintain maternal arterial blood pressure at baseline during the predelivery period.

Targeted Therapy for Advanced Renal Cell Cancer: Cytokines and Beyond

For the past 20 years cytokines have been the mainstay of treatment for advanced renal cell cancer (RCC), despite low response rates achieved and the high toxicity profile observed. The recent advances in molecular biology and the greater understanding of the von Hippel-Lindau (VHL) hypoxia-inducible factor (HIF)-hypoxia-induced gene pathway have paved the way for a plethora of novel agents that selectively inhibit key molecular events which allow the malignant process to continue. The high specificity of targeted agents should allow sparing of healthy cells thereby making them less toxic and well tolerated. However, new and unanticipated toxicities have been described with virtually all new agents, some of which may even be of a similar magnitude to cytokine therapy. Although several agents have demonstrated promising results in clinical trials, especially in terms of disease stabilization, and achieved clinical licences, issues of optimal administration regimens as well as the possible synergy when combined together are currently being explored. In this new era, IL-2 may still have a relevant role in selected subgroups of patients as well in combination with novel agents. Our review describes thoroughly the existing targeted therapies for RCC, presenting the recent clinical data and discussing the perspectives.

New Therapeutic Options for Chemotherapy-Resistant Metastatic Breast Cancer

When taxanes were introduced as anticancer agents some 20 years ago, their broad spectrum of activity was striking and engendered renewed hope for cancer patients. However, they were not without their problems, including a susceptibility to drug resistance caused by the drug efflux pump protein, P-glycoprotein. The epothilones are a new class of chemotherapeutic agents that have a mechanism of action similar enough to the taxanes to retain their broad spectrum of activity, but different enough to escape the multidrug resistance caused by P-glycoprotein. These properties are especially promising for patients with metastatic breast cancer who have run out of therapeutic options as a result of multidrug resistance. Ixabepilone, a semi-synthetic analogue of epothilone B, has recently been granted US FDA approval for the treatment of chemotherapy-resistant advanced breast cancer. Approval was based on results from a phase III study of ixabepilone in combination with capecitabine, as well as phase II studies of ixabepilone monotherapy. Significantly prolonged progression-free survival and increased objective response rates were demonstrated in the phase III study when ixabepilone was administered in combination with capecitabine compared with capecitabine alone. The phase II trials demonstrated robust antitumour activity with single-agent ixabepilone in women with metastatic breast cancer that was resistant to taxanes, anthracyclines and capecitabine. Early data from phase I trials of KOS-1584 and sagopilone are positive and suggest that these drugs may also develop into useful chemotherapeutic agents. Significant, but manageable, toxicities have been observed with the epothilones. In particular, neuropathy has led to the uneven and slower than expected clinical development of ixabepilone as optimal administration regimens were established. Some differences in tolerability profiles exist between the different analogues. Overall, it is expected that the epothilones will play an important role in the treatment of breast cancer and other tumour types.

Breakthroughs in the management of multiple myeloma.

Although multiple myeloma remains a terminal illness, the past four decades have seen a dramatic change in the outlook for a newly diagnosed patient in terms of therapies available, supportive care and insight into the pathogenesis of this disease. Among the newer agents available for treatment, thalidomide has been resurrected and discovered to be a valuable therapy for myeloma. Thalidomide appears to work, at least in part, through its anti-angiogenic properties, but much remains to be learned about its mechanism of action as well as optimal administration regimens. With the development of increasingly more potent bisphosphonates it has become possible to diminish the painful skeletal complications of myeloma, one of the most devastating problems of this disease. The most recent generation of bisphosphonates, pamidronic acid and zoledronic acid, have provided a statistically significant decrease in the skeletal complications of myeloma when used in a prophylactic manner. These agents appear to work by inhibiting osteoclast function. Progressive improvement in cytogenetic techniques has now demonstrated that almost all patients with myeloma have chromosomal abnormalities, some of which appear to confer varying degrees of prognostic significance. In particular, the changes in chromosome 13 are associated with an unusually poor outcome. These findings are serving as a guide toward learning more about the pathogenesis of myeloma as well as in identifying potential targets for therapy. Stem cell transplantation has emerged as the standard treatment for the large majority of patients with myeloma following the demonstration of superior complete remission and survival, both disease-free and overall, in a French randomised trial. Unfortunately, virtually all patients will eventually relapse following autologous stem cell transplantation, prompting continuing efforts such as tandem transplants, CD34+ selection, as well as modifications in the conditioning regimen to improve outcomes. Allogeneic bone marrow transplants appear to offer a better chance for a possible cure of myeloma but have been associated with an unusually high mortality. However, this approach is being revived with the advent of the less toxic non-myeloablative transplant that has provided an 81% short-term survival in a trial combining this approach with an initial conventional autologous bone marrow transplant. Immunotherapy with dendritic cells appears now to be a feasible way to enhance innate or acquired immunity to help eliminate minimal residual disease following autologous bone marrow transplant. Unfortunately, a cure for myeloma remains elusive but the continuing advances in management may significantly prolong survival in affected patients.

HEPARIN ANTICOAGULATION IN BLOOD PUMP EVALUATION IN CLAVES

Controlled anticoagulation is the prerequisite for biocompatibility tests of LVADs. For calves bioavailability of warfarin is not known, and the prothrombin time measurement may he erroneous when recombinant human tissue factor is used. Intravenous heparin has long been used, but the optimal administration regimen and the target level have not been established. Postoperative anticoagulation was performed with a continuous IV heparin (beef lung heparin, Pharmacia & Upjohn) with the target activated clotting time (ACT) level of 1.5 to 2.0 times of control in 8 calves implanted with a totally implatable LVAD for up to 3 months. Heparinization was commenced as soon as adequate postoperative hemostasis was obtained with the initial dosage of 14.5 U/kg/h gradually increasing the dosage to obtain the above target level within 5.4 ± 4.5 days. The kinetic study showed that it took approximately 4 hours to reach the plateau when the dosage was once changed. It was interesting to note that the dosage required to get the target level was significantly different in the early (up to 30 days, 57 ± 5 U/kg/h) and late (60–90 days, 27 ± 3 U/kg/h) phases (p < 0.0001). The dosage required in these two phases was stable and did not require adjustment. With this anticoagulation regimen no thrombus was noted in the blood pump except for one case with systemic infection in which a minute small membraneous depositions were noted. Significant hematoma formation was, however, observed in four cases where ACT exceeded 1.85 times control, indicating the upper ACT level to be less than 1.8 times normal. Currently the adequacy of ACT level of 1.3 to 1.5 times is being evaluated. For a long-term LVAD implantation, a continuous IV heparin provides a predictable level of anticoagulation. The upper level of ACT should he maintained below 1.8 times of control to avoid hemorrhagic complication.

Clinical development of anticancer agents from natural products.

Recent years have seen the introduction into clinical trials of new classes of chemotherapeutic agents which are derived from natural sources and have novel mechanisms of action. Examples of some of these newer classes of agents are presented here to illustrate both the opportunities they represent with respect to cancer treatment applications and the challenges which they represent from the clinical development perspective. Cumulatively the problems encountered with the development of the agents described are representative of the spectrum of issues encountered in the development of natural products, ranging from initial characterization and purification through the difficulties encountered in obtaining sufficient quantities of material for preclinical studies and then ultimately for clinical trials. Since these agents have unique mechanisms of action and are often exquisitely dose- and schedule-dependent in pre-clinical studies, they represent significant complexities with respect to determining the optimal regimen of administration clinically. The particular agents chosen for description here represent the spectrum of natural source-derived materials as well as mechanisms of action. The taxanes are derived from tree sources and interfere with the mitotic spindle apparatus; the camptothecins, while also derived from trees, appear to exert their activity through interactions with topoisomerase I. Bryostatin, derived from a marine animal, has powerful effects on protein kinase C (PKC), and therefore affects signal transduction pathways within cells. Fumagillin analogs appear to exhibit their important antitumor activity not through a direct effect on cancer cells but rather through effects on the tumor neovasculature. Taken as a whole, the spectrum of agents and activities described here confirms the continued importance of natural products in current anticancer agent development and reflects the complexities involved in this area of clinical research.