Fluid Retention Syndrome Research Articles

Interpretation and review of Clinical Practice Guidelines for Management of Hypertension in China (2020 edition) and exploration of traditional Chinese medicine for antihypertensive treatment

Hypertension is the most important risk factor for cardiovascular disease-related deaths among urban and rural residents, and it has become a significant global public health issue. In October 2022, the Clinical Practice Guidelines for the Management of Hypertension in China(hereinafter referred to as the Practice Guidelines) were jointly released by the National Cardiovascular Center and other academic organizations. The Practice Guidelines sparked extensive discussions as they clearly lowered the diagnostic criteria for hypertension, raised the blood pressure targets for elderly patients, and proposed changes in the timing of early medication intervention. While these adjustments have some international evidence-based support, there is still debate regarding the cardiovascular benefits of intensified blood pressure control based on the existing level of evidence. Furthermore, whether the series of new standards proposed in the Practice Guidelines are suitable for the Chinese population and whether the hypertension control level in primary care in China can adapt to the new diagnostic and treatment standards require further in-depth research. In contrast to the strict blood pressure control concept emphasized in the Practice Guidelines, traditional Chinese medicine(TCM) emphasizes the concept of comprehensive prevention and treatment and holistic therapy in the treatment of hypertension, including prehypertension, hypertension, and target organ damage. In recent years, based on abundant clinical trial research and high-quality evidence-based support, the advantages of TCM in treating hypertension have gradually emerged. Previous studies by this research team have found that the pathogenesis of hypertension includes three major types: fire syndrome, fluid retention syndrome, and deficiency syndrome. TCM treatment of hypertension features stable blood pressure reduction, gentle blood pressure lowering, and long-lasting effects. In addition to blood pressure reduction, it also has effects such as reversing risk factors and protecting target organ damage. It demonstrates the characteristics of multiple targets, multiple components, and comprehensive regulation, and can be applied throughout the entire process of prevention and treatment, including prehypertension, hypertension, and target organ damage in the early, middle, and late stages of hypertension. Therefore, it has certain clinical application prospects.

Phase 1 Study to Evaluate the Safety of Reducing the Prophylactic Dose of Dexamethasone around Docetaxel Infusion in Patients with Prostate and Breast Cancer.

There is little evidence that supports the registered high dose of dexamethasone used around docetaxel. However, this high dose is associated with considerable side effects. This study evaluates the feasibility of reducing the prophylactic oral dosage of dexamethasone around docetaxel infusion. Eligible patients had a histologically confirmed diagnosis of prostate or breast cancer and had received at least three cycles of docetaxel as monotherapy or combination therapy. Prophylactic dexamethasone around docetaxel infusion was administered in a de-escalating order per cohort of patients. Primary endpoint was the occurrence of grade III/IV fluid retention and hypersensitivity reactions (HSRs). Of the 46 enrolled patients, 39 were evaluable (prostate cancer (n = 25), breast cancer (n = 14). In patients with prostate cancer, the dosage of dexamethasone was reduced to a single dose of 4 mg; in patients with breast cancer, the dosage was reduced to a 3-day schedule of 4 mg-8 mg-4 mg once daily, after which no further reduction has been tested. None of the 39 patients developed grade III/IV fluid retention or HSR. One patient (2.6%) had a grade 1 HSR, and there were six patients (15.4%) with grade I or II edema. There were no differences in quality of life (QoL) between cohorts. It seems that the prophylactic dose of dexamethasone around docetaxel infusion can be safely reduced with respect to the occurrence of grade III/IV HSRs or the fluid retention syndrome.

Traditional Chinese medicine insights of newly-diagnosed and young hypertension and clinical practice of Tianma Gouteng Decoction for hypertension treatment

Hypertension is a global major public health problem. Early intervention and timely blocking are necessary for newly-diagnosed hypertensive and young hypertensive patients. Tianma Gouteng Decoction recorded in Zabing Zhengzhi Xinyi written by HU Guangci has the major functions in treating excess syndrome and wind-Yang disturbance syndrome with effects in calming liver-wind, clearing heat and activating blood, and nourishing liver and kidney. As we known, Tianma Gouteng Decoction is a classical formula for treating hypertension. However, due to the limitation of historical conditions, some problems impede Tianma Gouteng Decoction from being handed down successfully, such as uncertain diagnosis, uncertain antihypertensive efficacy and treatment-course. In this case, we ask whether Tianma Gouteng Decoction can be used as antihypertensive therapy and the exactly decrease of systolic and diastolic blood pressure, and wonder the half-life of Tianma Gouteng Decoction and the relationship with Western medicine. Therefore, defined prescription and syndrome, efficacy, treatment-course are important in clinical practice. According to the findings, ① previously, we thought that hypertension was a liver-Yang hyperactivity and liver-wind stirring syndrome, and the liver-based therapy theory was effective. However, based on our study, long-term treatment with Western medicine could block disease progression, control the increased blood pressure and change the pathogenesis and syndrome of traditional Chinese medicine. Therefore, the frequency of liver-Yang hyperactivity syndrome "fire syndrome" decreased sharply, and the main syndrome was fluid-retention syndrome and deficiency syndrome. The etiology and pathogenesis of hypertension was prone to deficiency syndrome accompanied with excess syndrome. Therefore, it was necessary to intervene hypertension in "liver-wind" and "liver-Yang" excess syndrome stage, and the early intervention and treatment are important. ② The newly-diagnosed hypertensive and young hypertensive patients usually had no Western medicine intervention. Thus, the etiology and pathogenesis of hypertension were free from Western medicine, which maintained the initial stage of hypertension in line with the liver-Yang hyperactivity syndrome. ③ The pathological mechanisms of newly-diagnosed and young hypertension were mainly increase in sympathetic activity, active renin-angiotensin-aldosterone system, change in morphology of vascular smooth muscle cells and endothelial cell dysfunction. ④ According to the syndrome of Tianma Gouteng Decoction, in modern medicine, Tianma Gouteng Decoction was widely used to treat the early-stage hypertension and the early-intervention of hypertension without Western medicine, particularly newly-diagnosed, young hypertension, Ⅲ hypertension, hypertensive crisis and hypertensive emergency. Tianma Gouteng Decoction can treat such symptoms as headache, dizziness, fullness of head, slurring of speech; facial flushing, conjunctival congestion and blurred vision; dysphoria, anxiety, palpitation, insomnia, mental disorder and hot flushes; dry-mouth with bitter taste and sweeting; myasthenia of limbs and lassitude in loin and legs; brown urine with burning sensation during urination; a solid or liquid stool consistency; red tongue, slippery and rapid pulse, wiry and rapid pulse over to Cunkou. ⑤ After treatment with Tianma Gouteng Decoction for three to six months, the blood pressure was decreased, and the symptoms were improved with reduction or even discontinuance of Western medicine. ⑥ According to recent studies, Caul is Polygoni Multiflori of Tianma Gouteng Decoction induced certain hepatotoxicity and increased the risk of long-term treatment. However, with the regular monitoring of biomedical index, long-term treatment with Caulis Polygoni Multiflori(3-10 g·d~(-1) for 3 to 6 months) didn't show hepatic dysfunction. ⑦ The pharmacological activity of Tianma Gouteng Decoction coincided with the pathology and disease mechanism of newly-diagnosed and young hypertension. Therefore, Tianma Gouteng Decoction was the specific recipe for newly-diagnosed and young hypertension. Therefore, further studies of efficacy, safety and molecular mechanism of Tianma Gouteng Decoction may make a medical breakthrough for hypertension treatment.

Mufangji Decoction formula tracing and its effect on emergency and severe cases

Mufangji Decoction is a famous herbal formula from Synopsis of Golden Chamber. However,it is easy to be misunderstood due to so its unique compatability. The syndromes treated by Mufangji Decoction included the following aspects:(1) in terms of modern medicine,it could be used to treat acute and chronic heart failure,heart failure aggravated by lung infection,chronic obstructive pulmonary disease acute episode,pulmonary heart disease,bilateral pleural effusion,acute attack of gout,rheumatic fever,rheumatoid arthritis,and rheumatoid arthritis;(2) in terms of symptoms,it could be used to treat asthma,chest tightness,wheeze impacting prostration and dyspnea impacting sitting posture; gastric distention; dark face,cyanotic,and mitral valvular face; edema of head and extremities; dry mouth,thirsty,unwilling to wear thick clothes,intolerance of heat,and irritable; fatigue,shortness of breath,poor appetite,constipation,less urine,yellow color,poor response to diuretics,and diuretic resistance; fast heart rate,which is hard to be controlled by Western medicine and has no response to Zhenwu Decoction; dark red tongue,dry tongue with yellow fur,rapid pulse,or deep tight pulse. In emergency and severe cases,Yang deficiency and fluid retention are normal syndromes of heart failure,while Yang deficiency,fluid retention,and heat are metamorphic syndromes of heart failure,which possessed complex mechanisms of pathophysiology; the mechanisms of Shaoyin heat-conversion syndrome is similar to Yang deficiency,fluid retention,and heat syndrome; the reason of application of gypsum in Mufangji Decoction shall be further studied; the " empty" and " real" in modified Mufangji Decoction are physical signs,rather than pathogenesis.

Clinical characteristics of Yinhua Miyanling Pian users based on real world study

Clinical characteristics of Yinhua Miyanling Pian user group were analyzed based on real world hospital information system (HIS)database. The information was collected from the HIS in sixteen hospitals of grade Ⅲ-A. Normalizing the data and descriptive analysis was performed. Among the 5 312 cases, female patients(63.67%) were more than male patients (36.33%). The median age was 49 years old. The age of 18-65 accounted for 74.52%.The patient was admitted to the hospital's department of obstetrics and gynecology(28.71%) and urology(28.43%). The median single dose is 2 g, accounted for 49.55%. The median daily dose is 6 g. 88.80% of patients were treated for less than 7 d. The median hospitalization were 12 d, most were 7-14 d accounted for 41.70%. Most hospitalization expenses payment by medicare, accounted for 80.22%. The median hospitalization expenses was 12 211.47 RMB. Most patients with benign tumor(27.36%) and malignant tumor(15.56%), next is the obstruction of urinary tract(15.49%) and urinary calculi(10.52%). The most common syndromes were damp heat syndrome(32.46%), liver and kidney deficiency syndrome(15.33%) and splenasthenic fluid-retention syndrome(15.01%). Clinical use is combined with antibiotics, as well as traditional Chinese medicine heat clearing agents, tonic drugs and so on. Finally, 44.22% were cured and 51.05% were better. Most of the drug users were adults, and mostly were female. Most with the tumor, urinary tract obstruction or stones. TCM syndrome is mainly characterized by dampness and heat, deficiency of liver and kidney, and dampness of spleen. In clinical practice, it was mainly combined with Western medicines, and Chinese medicines were also a-vailable. And most are combined with antibiotics.The medication basically conforms to the drug instruction. Based on the results of the real world HIS，Yinhua Miyanling Pian could provide theidea and reference for regulating the medication in adolescent patients.

DYNAMICS OF THE POLYUNSATURATED FATTY ACIDS VALUES IN THE BLOOD OF CHRONIC HEART FAILURE PATIENTS

Aim. To assess the dynamics of levels of eicosapentaenoic (EPA), docosahexaenoic (DHA), arachidonic (AA) and linoleic (LA) fatty acids (FA), omega-3 index, relation of omega-3/omega-6 polyunsaturated FA (PUFA) in the blood of decompensated chronic heart failure (CHF) patients under the standard management. Material and methods. The values of 22 FA were assessed in stable CHF (SCHF, n=12) and decompensated CHF (DCHF, n=24) and after decompensation treatment. The omega-3 index was calculated (relation of the sum of EPA and DHA to the sum of all FA) and relation of the sum of EPA and DHA to the sum of AA and LA. Results. Values of EPA and DHA, omega-3 index in DCHF group were lower in SCHF (0,085 [0,06;0,17] vs 0,26 [0,15;0,4] mM/mL, p=0,0005; 0,37 [0,16;0,62] vs 0,84 [0,55;1,10] mM/mL, p=0,004; 1,11 [0,65;2,11] vs 2,44 [1,80;3,71]%, p=0,0008, respectively). After the treatment of DCHF, levels of EPA and DHA, omega-3 index raised, and reached 0,16 [0,11;0,21] mM/mL, p=0,0016; 0,46 [0,35;0,76] mM/mL, p=0,045; 1,74 [1,14;2,42]%, p=0,043, respectively. Statistically significant differences of AA and LA in the blood of SCHF and DCHF were not found. With the treatment, there was increase of AA value growth (3,40 [2,56;4,91] mM/mL, p=0,011) and tendency of LA increase (9,13 [5,08;11,28] mM/mL, p=0,09). Dynamics of omega-3/omega-6 relation witnessed the predominant part of omega-6 of PUFA in all participants, especially in DCHF. After treated fluid retention syndrome in patients this relation changed due to the raise of omega-3 PUFA. Conclusion. In the DCHF there is significant increase of omega-3 index in the blood, concentrations of EPA and DHA. Standard therapy of CHF decompensation supports the increase of EPA, DHA, AA, omega-3 index. Mechanisms of the revealed PUFA dynamics in CHF patients, including the treatment outcomes, are subject for further investigation.

Fluid Retention Syndrome in Women

Fluid Retention Syndrome in Women

Meta-analysis of the effectiveness of traditional Chinese herbal formula Zhen Wu Decoction for the treatment of hypertension

ObjectivesZhen Wu Decoction (ZWD), a famous classic herbal formula documented in traditional Chinese medicine (TCM), is widely available in China for treating hypertensive patients with kidney yang deficiency and fluid...

Chinese classical formulas for treatment of essential hypertension

Essential hypertension is one of the most prevalent and important public health concerns in both westernized and developing countries. Recent studies have demonstrated that successful long-term treatment of hypertension has a significant impact on morbidity and mortality from cardiovascular diseases (CVDs) and stroke. Chinese classical formulas, which are important components of traditional Chinese medicine (TCM), have been increasingly accepted by patients with CVDs worldwide. According to TCM theory and syndrome differentiation, hypertension could be categorized into 3 patterns including fire syndrome, fluid retention syndrome, and deficiency syndrome. Chinese classical formulas, including Chaihu Jia Longgu Muli tang, Tianma Gouteng yin, Zhen Gan Xifeng tang, Banxia Baizhu Tianma tang, Liu Wei Dihuang wan, etc, play an important role in the treatment of essential hypertension, which could be further research priorities.

Predictive and Diagnostic Value Of Circulating Angiopoietin-2 For Transplant-Related Complications

BackgroundNon-infectious transplant-related complications (TRC) early after allogeneic hematopoietic cell transplantation (allo-HCT) are associated with considerable morbidity and mortality. Recently, research interests have been focused on endothelial cell (EC) dysfunction and angiogenesis which is a common feature implicated in the pathogenesis of TRC. Angiopoiein-2 (ANG2) plays an essential role in promoting endothelial instability in the process of angiogenesis and predisposing tissue damage. Recent studies have indicated that high level of ANG2 is associated with graft-versus host disease (GVHD) but the role of ANG2 in TRC remains unclear. Thus, we evaluated the association between plasma ANG2 levels and TRC. Patients and MethodsPatients who received allo-HCT between 2000 and 2012 and had available blood samples at transplant (day0) were included in the analysis. Patients who had undergone any prior transplantation within one year were excluded. A total of 153 patients were evaluated and the median age of patients was 49 years (range: 16-68). TRC was defined as sinusoidal obstruction syndrome (SOS), systemic transplant-associated microangiopathy (TAM), capillary leak syndrome (CLS) and grade III/IV acute GVHD with massive fluid retention or hemophagocytic syndrome (HPS). Plasma ANG2 levels were measured by ELISA kit and we set the cut-off value of 2.0ng/mL for ANG2 at transplant. Multiple characteristics including ANG2 were evaluated for their association with TRC, GVHD and overall survival (OS). ResultsMedian follow-up duration of surviving patients after transplant was 5 years. Seventy percent of the patients received allo-HCT for acute myeloid leukemia or myelodysplastic syndrome and the disease risk was high (not in remission) in 38% of the patients. Sixty-five percent of the patients received allo-HCT from unrelated donor and the source of graft was HLA-matched in 53%, mismatched in 18%, and cord blood in 29% of the patients. Seventy-five percent of the patients received myeloablative conditioning regimen and 67% of the patients received GVHD prophylaxis with tacrolimus. ANG2 level at the onset of TRC was significantly higher compared to the peak levels of the patients who had no complication during the transplant (control) {median of ANG2 ng/ml (range): control, 2.5 (1.4-4.0); TRC, 6.4 (2.4-15.7), p<0.001}. ANG2 was not elevated at the onset of pre-engraftment immune reaction, engraftment syndrome, HPS, and documented bacterial infection. Twenty-four percent of the patients showed ANG2 level of more than 2.0ng/mL at transplant and multivariate analysis with logistic regression revealed that male, more than 10% of blast in the bone marrow at the transplant and conditioning regimen with melphalan were significantly associated with high ANG2. Cumulative incidence of TRC at day100 after transplant was 30% and 48% of these patients also experienced grade III/IV acute GVHD during the transplant. Cumulative incidences of TRC at day100 after transplant for patients with or without high ANG2 were 73% and 17%, respectively (Fig. 1). Univariate analysis with Cox proportional hazard model revealed that high ANG2 at transplant was significantly associated with the risk of latter TRC (Hazard ratio [HR]: 6.9, p<0.001) but was not associated with the risk of grade III/IV acute GVHD (HR: 1.5, p=0.327). Multivariate analysis revealed that transplant from unrelated donor (HR: 3.1, p=0.052) and high ANG2 (HR: 11.8, p<0.001) were independently associated with the risk of TRC. One-year overall survivals after transplant for patients with or without high ANG2 at transplant were 42% and 74% (Fig. 2). High ANG2 was also an independent risk factor for OS (HR: 2.9, p=0.006) along with high disease risk at transplant (HR: 2.0, p=0.008) and transplant from unrelated donor (HR: 2.2, p=0.036). ConclusionsHigh plasma ANG2 at transplant was significantly associated with TRC but not with grade III/IV acute GVHD. High ANG2 at transplant could serve as a potential risk marker for latter TRC and inferior survival. Further investigations are needed for prevention strategies for TRC navigated by plasma ANG2.▪ Disclosures:No relevant conflicts of interest to declare.

A Feasibility Study of Weekly Docetaxel with Capecitabine in Ovarian Cancer: A Promising Combination of Two Active Drugs with a Potential for Synergism

Objectives: To evaluate the safety and efficacy of weekly docetaxel with capecitabine in patients with recurrent/persistent epithelial ovarian cancer (EOC). Patients and Methods: Women treated for recurrent/persistent EOC in our department (January 2004 through December 2005) were recruited into this feasibility study. They received 35 mg/m² docetaxel on days 1 and 8 and 1,000 mg/m² capecitabine twice daily on days 1–14 in a 21-day cycle. Results: Nine patients were enrolled. The median age was 64 years (37–80). Time to progression ranged from 1.67 to 11.27 months: 1 had complete response, 3 had partial responses, 4 had stable disease and 1 had disease progression. There was no grade 3 or 4 bone marrow toxicity. Nonhematological toxicity included partial hair loss (n = 4), fatigue (n = 7), hand and foot syndrome (n = 2), diarrhea (n = 5) and fluid retention syndrome (n = 1). Conclusion: There was good antitumor activity but frequent moderate-to-severe nonhematological toxicities when weekly docetaxel and capecitabine were used as second-line therapy for recurrent EOC. Further investigation of this combination is warranted.

Cystoid Macular Edema with Docetaxel Chemotherapy and the Fluid Retention Syndrome

Docetaxel (Taxotere) is an anticancer agent used to treat a wide range of malignancies including breast, lung, and prostate cancer. In this report, we describe a patient with bilateral vision loss due to cystoid macular edema (CME) associated with docetaxel therapy. This report documents for the first time the optical coherence tomography (OCT) findings of CME despite the lack of leakage with flourescein angiography and its association with the Fluid Retention Syndrome (FRS). Successful management of CME with oral acetazolamide is also discussed.

A new docetaxel (D) gemcitabine (G) regimen as first-line chemotherapy in advanced non-small cell lung cancer (NSCLC): A phase II study

7288 Background: Non containing cisplatin doublets could be an alternative chemotherapy in some NSCLC patients (pts). The optimal schedule of a DG regimen and the optimal duration of G infusion has not yet been determined. Methods: We evaluated the activity and toxicity of a regimen with D 50mg/m2in 60mn and G 1200mg/m2 in 120mn q2 wks at the first step for 10 pts followed in the absence of grade 4 toxicity by D 50mg/m2 in 60mn and G 1500mg/m2 in 150mn q2 wks for the second step. Eligibility criteria were the following: 18–75 years old pts with histologically confirmed NSCLC stage IIIB or IV, PS ≤2, measurable disease (RECIST criteria), no prior radiotherapy or chemotherapy, no symptomatic cerebral metastasis, adequate biological parameters. Results: Between April 2002 and June 2004, 42 eligible pts were enrolled in the study, M/F 34/8, median age 59y (46–77), stade IIIB/IV 8/34, PS≤1 88%. In intent-to-treat analysis, overall response rate was 21,4% (respectively 50% and 19,6% in stage IIIB and IV). With a median follow-up of 7 months (mo), median progression-free survival was 5,5 mo, median overall survival was 13,5 mo and 1-year survival was 51%. Grade 3–4 toxicities per pt were neutropenia (28,6% with 2,4% febrile neutropenia), fluid retention syndrome (7,1%), anemia (4,8%), thrombocytopenia (4,8) and diarrhea (2,4%). Grade 2 alopecia was observed in 16,7% of pts. Conclusion: This two-week regimen has a manageable toxicity profile and achieves an encouraging one-year survival rate of 51% in this poor prognosis population of patients. No significant financial relationships to disclose.

Phase II Study of Concurrent Administration of Doxorubicin and Docetaxel as First-Line Chemotherapy for Metastatic Breast Cancer

Objective: To evaluate the efficacy and toxicity of concurrent administration of doxorubicin and docetaxel, without prophylactic use of granulocyte colony-stimulating factor, as first-line chemotherapy in patients with metastatic breast cancer (MBC). Methods: This multi-institutional study enrolled 40 women; 37 were assessable for efficacy and all 40 patients were evaluated for toxicity. Treatment consisted of 50 mg/m² doxorubicin and 60 mg/m² docetaxel on day 1 every 3–4 weeks. Results: Patients received a total of 251 cycles of chemotherapy (median, 5 cycles; range, 1–13 cycles). Of the 37 patients assessable for efficacy, 2 had a complete response and 24 had partial responses, which accounted for a 70% objective response rate (95% confidence interval, 53–84%). The median time to treatment failure was 30.1 weeks (range, 3.3–80.7 weeks). Grade 4 neutropenia was observed in 88% of patients and was the most frequent haematological toxicity. Febrile neutropenia was seen in 40% of patients, but no severe infections were observed. Non-haematological toxicity was generally tolerable. There were 2 grade 4 adverse events, which included 1 bleeding duodenal ulcer and 1 hypersensitivity reaction, but grade 3 episodes were infrequent. None of the patients developed congestive heart failure or asymptomatic decrease of left ventricular ejection fraction to less than 50%. Fluid retention syndrome ≤ grade 2 was observed in 25% of patients at a median cumulative dose of docetaxel of 270 mg/m². Conclusion: Concurrent administration of 50 mg/m² doxorubicin and 60 mg/m² docetaxel is active with a manageable toxicity profile as first-line chemotherapy for MBC.

Phase II study of weekly docetaxel in patients with metastatic breast cancer

BackgroundThis study was conducted to investigate the efficacy and toxicity of weekly docetaxel administration in patients with metastatic breast cancer. Patients and methodsThirty-seven women were treated with 1 h infusions of docetaxel at 40 mg/m2/week after pre-medication with 8 mg dexamethazone. Each cycle consisted of three consecutive weekly treatments followed by a 1 week rest. All patients were assessed for toxicity; five patients were not assessable for clinical response, time to progression (TTP) and overall survival (OS) because of early treatment failure, but they were included in intention-to-treat analysis. ResultsPatients received a median of four cycles (range, 1–9), with a median dose intensity of 28 mg/m2/week (range 22–30) and a median relative dose intensity of 0.95 (range 0.73–1.0). No patients showed complete response, whereas 14 had partial response, which accounted for 38% of objective response rate [95% confidence interval (CI) 22% to 53%]. In addition, three patients (8%, 95% CI 0% to 17%) had stable disease over 6 months. Clinical responses were achieved at a median of three cycles (range 1–4 cycles). The median TTP and OS were 5 and 12 months, respectively. The weekly docetaxel regimen was generally well tolerated. About half of the patients experienced grade ≥1 neutropenia; only 19% had grade 3/4 neutropenia, including one case of grade 4. No febrile neutropenia was observed and fluid retention syndrome was uncommon. Non-hematologic toxicity, however, such as asthenia/fatigue, nail damage, tearing or hearing disorders, was seen with successive treatment cycles. ConclusionsWeekly docetaxel at 40 mg/m2/week is an active and feasible regimen for patients with metastatic breast cancer.

Risks and benefits of taxanes in breast and ovarian cancer.

The taxanes are a unique class of agents with a broad spectrum of clinical activity. They act by binding to tubulin, producing unnaturally stable microtubules and subsequent cell death. The distribution and elimination of paclitaxel depend on dose and administration rate. This nonlinearity is much less evident at lower infusion rates (24-hour infusions) and more evident at high plasma concentrations (3-hour infusions). The pharmacokinetics of docetaxel also suggest the presence of nonlinear pathways, but these appear to be clinically insignificant at the current doses utilised (60 to 100 mg/m2). Both agents undergo hepatic metabolism and biliary excretion and require dose adjustment in the setting of liver dysfunction. Drug interactions are quite common with these agents, some of which are sequence-dependent and clinically significant. The optimal dose of paclitaxel is not known at this time, and controversy over possible dose- or schedule-related differences in efficacy still remain. Docetaxel is somewhat more consistent in its dose and scheduling information, but controversy remains regarding a dose-benefit relationship as well as scheduling differences (weekly vs every 3 weeks). Toxicity profiles for these agents are somewhat different. Paclitaxel is more likely to be associated with peripheral neuropathy and myalgias/arthralgias than docetaxel. Docetaxel is more likely to be associated with a cumulative fluid retention syndrome that can be dose limiting. Paclitaxel and docetaxel are both highly active agents against breast cancer, including tumours that are resistant to anthracyclines. Docetaxel tends to have higher response rates overall, but direct comparisons at maximally tolerated doses have not been completed. Combination regimens with many different agents are attempting to improve on the responses seen with single-agent taxanes. The combination of paclitaxel and a platinum compound should be utilised as first-line therapy of advanced ovarian cancer. Controversy lies in the choice of the platinum compound and the dose and administration schedule of paclitaxel. Substitution of docetaxel for paclitaxel in these platinum-containing regimens is also being investigated. The taxanes also exhibit activity against ovarian cancer in patients previously exposed to platinum agents. These agents may also be administered intraperitoneally for local therapy of metastatic ovarian cancer. Although docetaxel and paclitaxel are often considered similar in activity and tolerability, this review emphasises the fact that these agents are indeed different. Clinicians need to be familiar with the benefits and adverse events related to each agent in order to make informed, appropriate clinical decisions.

Taxanes: an overview of the pharmacokinetics and pharmacodynamics

Paclitaxel and docetaxel have emerged in the last two decades as effective antitumor agents in a variety of malignancies. Paclitaxel is a semisynthetic taxane isolated from bark of the Pacific yew tree. Docetaxel is a semisynthetic taxane derived from the needles of the European yew ( Taxus baccata). These compounds bind to tubulin, leading to microtubule stabilization, mitotic arrest and, subsequently, cell death. Plasma clearance of paclitaxel exhibits nonlinear kinetics, which results in a disproportionate change in plasma concentration and area under the curve (AUC) with dose alterations. In contrast, docetaxel has a linear disposition over the dose ranges used clinically, so its concentration changes linearly with changes in the dosage. Premedicating with corticosteroids and histamine H 1 and H 2 receptor antagonists is advocated prior to paclitaxel administration; prior to docetaxel administration, premedication with corticosteroids is suggested. The taxanes are metabolized in the liver by the cytochrome P-450 enzymes and are eliminated in the bile. The known metabolites are either inactive or less potent than the parent compounds. The toxic effects associated with paclitaxel therapy are mainly neutropenia, peripheral neuropathy, and, rarely, cardiotoxicity. Docetaxel toxicity produces mainly myelosuppression and a cumulative dose fluid retention syndrome. Paclitaxel demonstrates sequence-dependent interactions with cisplatin, cyclophosphamide, and doxorubicin. Docetaxel has shown increased myelosuppression with preceding ifosfamide in a preliminary study. The future holds increasing indications for taxanes in newer combination regimens; consideration of their pharmacologic characteristics is an important aspect of designing and applying new taxane-based treatment regimens.

Efficacy and safety of docetaxel (Taxotere™) in heavily pretreated advanced breast cancer patients: the French compassionate use programme experience

The aim of this investigation was to assess retrospectively docetaxel safety and efficacy in advanced breast cancer patients in a French compassionate use programme. Patients had received >1 prior chemotherapy regimen for advanced disease, were either anthracycline-resistant (that is progressed within 6 months after anthracycline-based chemotherapy) or had received the maximum cumulative dose. The recommended docetaxel dose was 100 mg/m 2/cycle (75 mg/m 2 in case of liver function impairment: transaminases >1.5×upper limit of normal (ULN), alkaline phosphatases >3×ULN). Between August 1993 and December 1995, 889 patients were treated in 67 French centres, of whom 870 were evaluable for safety and 825 were evaluable for patient and treatment characteristics and efficacy. 20.5% (of the 825 patients evaluable for baseline characteristics) had poor performance status (PS≥2), 49.3% liver metastasis and 9.6% biological liver dysfunction. 98.4% had been previously treated by anthracyclines, 50.8% had resistant disease and 37.1% had received >2 prior palliative chemotherapy lines. The most frequent severe toxicity, febrile neutropenia (reported in 223/870 (25.6%) patients evaluable for safety), caused 10 deaths, 6 of these being patients with severe liver impairment before inclusion. Fluid retention syndrome and other common non-haematological toxicities were well tolerated. 3.1% (28/889) of all patients and 11.4% of those with liver dysfunction, died from treatment-related causes. The overall response rate in 825 assessable patients was 22.9% (95% confidence interval (CI): 20.2–26.2%). Median time to treatment failure was 4 months (95% CI: 3.6–4.3) and median survival was 9.8 months (95% CI: 8.8–10.7). This report on the largest series of unselected advanced breast cancer patients treated with docetaxel, supports previous phase II studies, confirming docetaxel's utility in patients relapsing after failing anthracycline-containing palliative chemotherapy.

The Fluid Retention Syndrome: Recognition, Risk Factors and Management

A complaint of bloating or swelling of sufficient severity to lead to medical consultation is the lead symptom of a syndrome (the fluid retention syndrome) which includes affective, somatic and autonomic symptoms. These appear to have a primary origin in a neuroendocrine disturbance of limbic and hypothalamic function and form a substantial part of the work-load of a menopause clinic. The fluid retention syndrome, in turn, is one component of a spectrum of affective-somatic-autonomic disorders which comprise a significant part of the general practitioner's work load. Major risk factors for the fluid retention syndrome comprise a strong family history of swelling symptoms and/or diabetes mellitus, affective illness, including major life events, weight gain and obesity. Short term exacerbations of swelling are precipitated by emotional stress, high carbohydrate meals, alcohol, prolonged standing and exercise, high ambient temperatures and rebound oedema following the withdrawal of diuretic therapy. Management involves recognition of the syndrome, a clear explanation of its nature to the patient, the control of weight-related fluid retention by reduction to a pre-morbid target weight and the avoidance of inappropriate drug therapy. In particular, diuretics should not be prescribed for fluid-retaining symptoms. Hormone replacement therapy (HRT) should be prescribed for patients with the fluid retention syndrome if there is biochemical evidence of ovarian failure. The role of HRT in inducing rapid bloating independently of weight gain requires evaluation by a randomised controlled clinical trial. More effective management of the syndrome awaits further understanding of the neuroendocrine substrate for the disorder.

Transient Encephalopathy Followed by Seizures after Docetaxel Infusion

The efficacy of the new semi-synthetic taxane compound docetaxel (Taxotere®, Rhone-Poulenc SA, France) has been demonstrated in a variety of tumours. While dose-dependent neutropenia is the most important adverse effect of docetaxel, hypersensitivity reactions, a fluid retention syndrome, gastrointestinal and skin toxicity, and sensory neuropathy may occur. Taxane-associated central nervous system (CNS) toxicity is rare, but such cases have been reported after paclitaxel infusion.[1] In this report we describe the first patient who developed a self-resolving encephalopathy followed by seizures after administration of docetaxel, with recurrent episodes after subsequent infusions.