Episodes Of Toxicity Research Articles

A pharmacokinetic and safety study of single dose intravenous combretastatin A4 phosphate in Chinese patients with refractory solid tumours

• Three pharmacokinetic and safety studies for combretastatin A4 phosphate (CA4P), the first vascular disrupting agent, have been conducted in Western countries. • The maximum tolerated dose (MTD) was approximately 60-68 mg m(-2). • CA4P-related grade 3 or 4 adverse events were tumour pain, dyspnoea, hypoxia and syncope in patients who received doses ≥ 50 mg m(-2). • This is the first pharmacokinetic and safety study conducted in East Asian patients. • There appeared to be a trend that Chinese patients metabolized CA4 more rapidly and had greater neurotoxicity than patients in Western countries. • We observed favourable clinical responses in patients with refractory nasopharyngeal carcinoma. • CA4P-induced acute renal failure was seen in one dehydrated Chinese patient. This trial was conducted to evaluate the safety and pharmacokinetics of combretastatin A4 phosphate (CA4P) given intravenously as a single dose to Chinese patients with refractory solid tumours. METHODS Twenty-five patients were treated with single doses of CA4P according to a dose escalation scheme: 5, 10, 20, 33, 50, 65 and 85 mg m(-2) infused intravenously over 30 min. CA4P was generally well tolerated at ≤ 65 mg m(-2). Transient, moderate increases in the heart rate-corrected QT interval occurred at all doses. CA4P produced a transient dose-dependent increase in neural and gastrointestinal toxicities. Acute renal failure occurred in one dehydrated patient who had also taken paracetamol. There were seven episodes of dose-limiting toxicity at doses ≥65 mg m(-2), including two episodes of reversible ataxia at 85 mg m(-2).For CA4, at 50 mg m(-2),mean (SD) peak plasma concentration (C(max) was 0.99 (0.33) mM, area under the curve from time zero to time of last quantifiable concentration (AUC(0,t)) was 1.42 (0.30) mM h and terminal elimination half-life (t(1/2)was 1.81 (0.61) h. At 65 mg m-2,C(max) was 1.73 (0.62) mM,AUC(0,t) was 3.19 (1.47) mM h and t (1/2) was 1.90 (0.61) h [corrected]One patient with nasopharyngeal carcinoma had an obvious clinical response with central necrosis in the metastatic lung mass. CONCLUSION Doses ≤ 65 mg m(-2) given as 30 min infusions define the maximum tolerated dose in East Asian patients, and doses in the range of 50-65 mg m(-2) have been selected for further studies.

Induction cisplatin, paclitaxel, and 5FU (PTF) before definitive local therapy for locally advanced esophageal squamous cell carcinoma (SCC).

115 Background: Induction chemotherapy for locally advanced oesophageal SCC is controversial. Triple combination is under study with promising results. We analyse induction therapy with PTF before local definitive therapy in terms of response, resectability, toxicity and survival. Methods: Pts diagnosed of locally advanced oesophageal SCC have been included. Treatment schedule: paclitaxel 175 mg/m2 and CDDP 75 mg/m2 on day 1 and 5FU 800 mg/m2/day days 1-4, every 28 days. After 2-3 cycles surgery is considered. If unresectable, radical radiotherapy (64 Gy) and concomitant carboplatin (60 mg/m2, d 1–5 during 1st, 4th and, if feasible, 7th week of RT) are administered. Results: From May-02 to Feb-10 48 pts have been treated (44M, 4F). Age: 56,7 (32–70). PS 0-1: 8-40. Location: Upper: 14, Middle: 25, Distal: 8, Whole: 1. T2/3/4:1/26/21, N0/1: 12/36. M1a: 6. Weight loss over 10 kg: 11 pts. Cycles delivered: 140; median 3. Toxicity (episodes): Anemia 3: 1. Emesis 3: 2. Mucositis 3: 2. Asthenia 2-3: 8. Two pts died in remission (one of them with a pCR at necropsy) due to gastrostomy complications and oesophagus-tracheal fistula, treatment related. Two pts developed oesophagus-tracheal fistula as a late event after response to therapy. Response rates: CR 7 (14.6%), PR 16 (33.3%), SD 18 (37.5%), PD 7 (14.6%). Treatment after PTF: Surgery 14 pts (1 upper, 9 middle, 4 distal). One (distal) unresectable at surgery, one (middle) not resected because of liver cirrhosis, two not resected because of liver metastases, unexpected findings at surgery. pCR: 2. pPR 8 (R0: 7, R1: 1). Chemoradiation: 25, improving 2 SD to PR, 4 PR to CR and 3 SD to CR. One PR and 4 SD progressed immediately after chemoradiation. Progression: 33 (local 14, systemic 11, both 8); died: 34. Median progression free survival: 35.7 weeks (95% CI 30.2-41.2). Median overall survival: 50.7 weeks (95% CI 35.2-66.1). Conclusions: Induction PTF has a good toxicity profile with a high response rate and disease control during therapy. Surgical rescue is possible in middle and distal tumours. Local definitive therapy with chemoradiation is the best approach for unresectable or upper third tumours. No significant financial relationships to disclose.

Combination therapy with diltiazem plus CsA/MMF/Pred or CsA/Aza/Pred triple immunosuppressive regimens for use in clinical kidney transplantation in Northwestern China

The effects of diltiazem on 1692 kidney transplant recipients under the immunosuppressive regimen of cyclosporine A (CsA) in combination with either mycophenolate mofetil or azothioprine were assessed. The two treatment groups were compared for blood concentrations of CsA, the extent of acceptable dosage reduction for the maintenance of immunotherapy, potential effects of kidney protection, and promotion of graft function. We monitored changes of blood concentrations of CsA in the two different patient treatment groups for post-transplant graft function, episodes of acute rejection, and hepatic and renal toxicity in 1640 renal transplant recipients after treatment with diltiazem. In patients treated with the triple immunosuppressive regimen consisting of CsA, azothioprine, and prednisolone (Pred), the sub-group of patients receiving the diltiazem treatment saw a significantly reduced CsA dosage in comparison to the non-diltiazem group (control group 1) (P < 0.05), but the blood concentrations of CsA of the diltiazem group were higher than those of control group 1 (P < 0.01). Of the patients treated with CsA, mycophenolate mofetil, and Pred, the sub-group of patients also treated with diltiazem showed similar effects: CsA dosage was reduced (P < 0.01) and the blood concentrations of CsA significantly increased (P < 0.01) in comparison with those of control group 2. In addition, recovery time of graft function decreased to 4.7 ± 1.8 days and 3.9 ± 1.4 days in the two diltiazem treatment groups, respectively (P < 0.05), and the rate of acute rejection decreased to 21 (p < 0.05) and 7.9% (P < 0.01), respectively. In our cohort of renal transplantation patients, co-administration of CsA and diltiazem increased CsA blood concentration, thereby resulting in a reduction in its required dosage treatment, which lightened the patients' economic burden while improving primary and long-term kidney function by promoting the recovery of graft function and decreasing hepatic and renal toxicity. The co-administration of diltiazem may also reduce the rate of acute rejection, especially in patients who also receive the triple immunosuppressive regimen consisting of CsA, mycophenolate mofetil, and Pred.

Cardiovascular Collapse following Povidone-Iodine Wash

We present a case study of a severe episode of iodine toxicity following povidone-iodine wash with clinical manifestations of cardiovascular collapse, metabolic acidosis, renal failure and seizures. Povidone-iodine has been used as a medical antiseptic and disinfectant since 1952 Iodine toxicity secondary to povidone-iodine use is rare. Iodine toxicity is difficult to diagnose and the diagnosis is made by a high index of suspicion. Toxicity due to iodine correlates with serum and urine iodine levels. Treatment of iodine toxicity is supportive. A review of literature relating to the components of povidone-iodine, iodine metabolism, its manifestations and management of iodine toxicity secondary to povidone-iodine is also presented. An Ovid-Medline search from 1950 to 2009 revealed 1236 articles on the clinical manifestations of povidone-iodine usage but no article on iodine toxicity relating to povidone-iodine based on the following search criteria: povidone-iodine and/or iodine toxicity secondary to povidone-iodine (limited to English language, review articles, full text and human patients).

Phase I and pharmacological study of the broad-spectrum tyrosine kinase inhibitor JNJ-26483327 in patients with advanced solid tumours

Background:JNJ-26483327 is an oral, potent, multi-targeted tyrosine kinase inhibitor, inhibiting kinases of epidermal growth factor receptor (EGFR)-1, -2 and -4, rearranged during transfection (RET) receptor, vascular endothelial growth factor receptor (VEGFR)-3 and Src family (Lyn, Fyn, Yes) at low nanomolar concentrations. This phase I, accelerated titration study assessed maximum tolerated dose, safety, pharmacokinetics and pharmacodynamic effects of JNJ-26483327.Methods:Nineteen patients with advanced cancers received JNJ-26483327 continuous twice daily (BID) in escalating dose cohorts ranging from 100 to 2100 mg. Pharmacodynamic effects were assessed in paired skin biopsies and blood.Results:JNJ-26483327 was well tolerated in doses up to 1500 mg BID, with target-inhibition-related toxicity such as diarrhoea and skin rash, and other common reported toxicities being nausea, vomiting, anorexia and fatigue. At 2100 mg, two episodes of dose-limiting toxicity were observed, consisting of grade 3 anorexia and a combination of grade 3 anorexia and fatigue, respectively. Pharmacokinetics were dose proportional up to 1500 mg in which plasma levels were obtained showing anti-tumour activity in xenograft mouse models. Pharmacodynamic analysis did not show a substantial effect on expression of Ki-67, p27kip1, phosphorylated mitogen-activated protein kinase, phosphorylated Akt and EGFR, and serum levels of sVEGFR-2, VEGF-C and VEGF-D remained unchanged. Stable disease was noted in six patients (32%).Conclusion:JNJ-26483327 is well tolerated and shows a predictable pharmacokinetic profile; the recommended dose for further studies is 1500 mg BID.

Lithium for Older Adults with Bipolar Disorder

The use of lithium carbonate for the treatment of bipolar disorder in older adults is decreasing at a significant rate. This change in prescription pattern is occurring at a time when all evidence-based treatment guidelines and systematic reviews still recommend lithium as a first-line treatment for bipolar disorder. Despite having the strongest evidence base for effectiveness, lithium does pose significant concerns in the older population, including the risk of drug interactions that cause toxicity associated with decreased creatinine clearance. The evidence for lithium's impact on chronic renal disease is still controversial and is reviewed in this article. Mixed evidence exists regarding the impact of lithium on suicide risk, although there is a consensus that it does have protective properties through its mood-stabilizing effect. Because of the very limited research base regarding the use of lithium in old age, guidelines for dosing and maintenance of serum concentrations are not well established, and this may be leading to increased episodes of lithium toxicity. At the same time that these legitimate concerns about lithium are being highlighted, evidence has accumulated that suggests that lithium may have neuroprotective properties. Its action of inhibiting the enzyme glycogen synthase kinase-3 may be responsible in part for a decrease in the induction of amyloid beta peptide and hyperphosphorylated tau protein, which have been implicated in the development of Alzheimer's disease. Very little evidence supports use of alternatives to lithium such as other mood-stabilizing agents, including atypical antipsychotics, in older adults. Thus, before we abandon lithium as a first-line agent, we should ensure that the guidelines for lithium treatment are safe, practical and effective. Newer agents must be appropriately tested in older adults before replacing this longstanding first-line treatment for bipolar disorder.

Use of an automated clinical management system improves outpatient immunosuppressive care following liver transplantation

Immunosuppressive therapy following transplantation, if not managed well, can lead to increased drug toxicity or rejection episodes. We investigated whether use of an automated clinical management system in our liver transplant program would improve clinical outcomes in managing transplant recipients' immunosuppressive medications. We performed a retrospective cohort study of two patient groups receiving liver transplants at our institution. One group of 301 patients transplanted from January 1, 2004 to November 30, 2006 received outpatient immunosuppressive management using a paper charting system. After instituting an automated clinical management system, the following group of 127 patients transplanted from December 12, 2006 to April 1, 2008 received their outpatient immunosuppressive management with that system. Only patients who received tacrolimus therapy, with or without mycophenolate mofetil or prednisone, were studied. Our endpoints included percentage of patients having rejection and/or tacrolimus toxicity episodes. Various recipient, intraoperative, donor, and postoperative variables, including managing the immunosuppressive therapy with a paper charting system or an automated management system, were studied to determine which factors were associated with our endpoints. Multivariable logistic regression analysis showed the automated system was significantly associated with fewer rejection episodes and fewer tacrolimus toxicity events. Formal cost-effectiveness analysis of the nurses' salaries for 1 year showed the automated system cost US$197 per patient and the paper system cost US$1703 per patient. The automated system improved quality of life years. Use of an automated clinical management system for outpatient immunosuppressive management for liver transplant patients has resulted in a decrease in both tacrolimus toxicity and rejection episodes and is cost-effective.

Bortezomib, dexamethasone, cyclophosphamide and lenalidomide combination for newly diagnosed multiple myeloma: phase 1 results from the multicenter EVOLUTION study

This phase 1 study (Clinicaltrials.gov: NCT00507442) was conducted to determine the maximum tolerated dose (MTD) of cyclophosphamide in combination with bortezomib, dexamethasone and lenalidomide (VDCR) and to assess the safety and efficacy of this combination in untreated multiple myeloma patients. Cohorts of three to six patients received a cyclophosphamide dosage of 100, 200, 300, 400 or 500 mg/m(2) (on days 1 and 8) plus bortezomib 1.3 mg/m(2) (on days 1, 4, 8 and 11), dexamethasone 40 mg (on days 1, 8 and 15) and lenalidomide 15 mg (on days 1-14), for eight 21-day induction cycles, followed by four 42-day maintenance cycles (bortezomib 1.3 mg/m(2), on days 1, 8, 15 and 22). The MTD was the cyclophosphamide dose below which more than one of six patients experienced a dose-limiting toxicity (DLT). Twenty-five patients were treated. Two DLTs were seen, of grade 4 febrile neutropenia (cyclophosphamide 400 mg/m(2)) and grade 4 herpes zoster despite anti-viral prophylaxis (cyclophosphamide 500 mg/m(2)). No cumulative hematological toxicity or thromboembolic episodes were reported. The overall response rate was 96%, including 20% stringent complete response (CR), 40% CR/near-complete response and 68% >or=very good partial response. VDCR is well tolerated and highly active in this population. No MTD was reached; the recommended phase 2 cyclophosphamide dose in VDCR is 500 mg/m(2), which was the highest dose tested.

A stratified phase II trial investigating sorafenib (SORA) in patients (pts) with metastatic or locally advanced angiosarcoma (AS).

10026 Background: AS represent an aggressive subtype of sarcoma. Preclinical data and limited clinical experience suggest that SORA has some antitumor activity against AS. Methods: We had conducted a stratified phase II trial. The primary endpoint was progression- free rate (PFR) at 9 months according to RECIST. A 2-stage design (Optimal Simon Design) was used. Patients received for 9 months SORA 400 mg b.i.d until unacceptable toxicity or tumor progression. Central pathological review was performed. Data of strata A (superficial AS) and strata B (visceral AS) are currently available. Results: [Strata A] From 06/2008 to 07/2009, 23 pts with superficial AS (8 scalp and skin/10 breast/6 soft tissue) have been enrolled (16 women/median age: 63 [31-82]). Twelve (52%) cases arose in irradiated fields. Sixteen tumors were metastatic (74%) and 7 locally advanced (26%). Eighteen patients (78%) have previously received chemotherapy (anthracyclines in 15 cases and taxanes in 8 cases). Grade-3 toxicities occurred in 5 pts (21%, mainly skin toxicities). Transient discontinuation and dose reduction were necessary in 9 (39%) and 10 (43%) cases, respectively. The best responses were: 2 CR (8%), 2 PR (8%), 4 SD (17%) and 15 PD (67%). The 4-month and 6-month PFR were 6/23 (26%) and 4/23 (17%). All pts experiencing SD at 6 month had had breast radio-induced AS. [Strata B] From 06/2008 to 11/2009, 15 pts with visceral AS have been enrolled (7 women/ median age: 49 [19-67]). One case arose in irradiated field. Metastases were present in 8 cases. Eight pts have received previous chemotherapy (anthracyclines in 7 cases and taxanes in 3 cases). Nine pts experienced at least one episode of grade-3 toxicity. Transient discontinuation and dose reduction were necessary in 3 and 4 cases. 7 pts are currently assessable for response. Best responses were: 4 SD and 3 PD. The 4-month and 6-month PFR were both 2/7. Conclusions: SORA provides a 6-month PFR of about 20% of pts with AS. Exploration of biological predictive factors is ongoing. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bayer

Counterpoint: Is Pharmacokinetic or Pharmacodynamic Monitoring of Calcineurin Inhibition Therapy Necessary?

Individual dose adjustment of cyclosporine (CsA)1 and tacrolimus (TAC), which are critical-dose drugs widely used in transplantation, is important not only to prevent acute rejection but also to prolong graft (and patient) survival. New therapeutic regimens such as calcineurin inhibitor (CNI)-sparing strategies have recently strengthened the need for fine individual dose adjustment of these drugs. A good treatment-personalization strategy should employ a marker or a set of markers with (a) strong relationships with therapeutic and/or adverse effects; (b) low intraindividual variability; (c) established, and ideally, validated target values; and (d) easy and fast measurement. So far, dose individualization has mainly been based on pharmacokinetics, which monitors the handling of the drug by the body. Pharmacodynamics (PD), which focuses on the biologic effect of the drug on its target(1), might also be useful as a replacement or an adjunct. Early on in the use of CsA, monitoring of the predose (trough, C) concentration became the standard of care(2). However, no trial has been conducted in transplantation patients to determine whether C monitoring is superior to no therapeutic monitoring with respect to efficacy or toxicity(2), and conducting such a trial now would not be ethically acceptable given the obvious improvements brought to transplantation patients by therapeutic drug monitoring. However, it has long been recognized that the results of C monitoring are suboptimal, and retrospective analysis of transplantation populations monitored on C has shown that the full interdose area under the concentration-time curve (AUC0–12h), abbreviated AUCs (AUC0–6h or AUC0–4h), and Cmax (maximum concentration) have stronger links with the residual inefficacy or toxicity episodes than C. Because of the impracticability of routine AUC0–12h monitoring, limited sampling strategies have been proposed as a more practical approach. In 2002, the CONCERT (Consensus …

Benefits of the Intermittent Use of 6-Mercaptopurine and Methotrexate in Maintenance Treatment for Low-Risk Acute Lymphoblastic Leukemia in Children: Randomized Trial From the Brazilian Childhood Cooperative Group—Protocol ALL-99

PURPOSE To describe event-free survival (EFS) and toxicities in children with low-risk acute lymphoblastic leukemia (ALL) assigned to receive either continuous 6-mercaptopurine (6-MP) and weekly methotrexate (MTX) or intermittent 6-MP with intermediate-dose MTX, as maintenance treatment. PATIENTS AND METHODS Between October 1, 2000, and December 31, 2007, 635 patients with low-risk ALL were enrolled onto Brazilian Childhood Cooperative Group for ALL Treatment (GBTLI) ALL-99 protocol. Eligible children (n = 544) were randomly allocated to receive either continuous 6-MP/MTX (group 1, n = 272) or intermittent 6-MP (100 mg/m(2)/d for 10 days, with 11 days resting) and MTX (200 mg/m(2) every 3 weeks; group 2, n = 272). RESULTS The 5-year overall survival (OS) and EFS were 92.5% +/- 1.5% SE and 83.6% +/- 2.1% SE, respectively. According to maintenance regimen, the OS was 91.4% +/- 2.2% SE (group 1) and 93.6% +/- 2.1% SE (group 2; P = .28) and EFS 80.9% +/- 3.2% SE (group 1) and 86.5% +/- 2.8% SE (group 2; P = .089). Remarkably, the intermittent regimen led to significantly higher EFS among boys (85.7% v 74.9% SE; P = .027), while no difference was seen for girls (87.0% v 88.8% SE; P = .78). Toxic episodes were recorded in 226 and 237 children, respectively. Grade 3 to 4 toxic events for groups 1 and 2 were, respectively, 273 and 166 for hepatic dysfunction (P = .002), and 772 and 636 for hematologic episodes (P = .005). Deaths on maintenance were: seven (group 1) and one (group 2). CONCLUSION The intermittent use of 6-MP and MTX in maintenance is a less toxic regimen, with a trend toward better long-term EFS. Boys treated with the intermittent schedule had significantly better EFS.

Raltegravir, tenofovir, and emtricitabine in an HIV-Infected patient with HCV chronic hepatitis, NNRTI intolerance and protease inhibitors-induced severe liver toxicity

Backgroundin HIV-infected patients with HCV-related chronic hepatitis, liver impairment and drug toxicity may substantially reduce the number of possible therapeutic options.Case Descriptionwe here describe the case of an HCV-HIV coinfected woman who had repeated severe episodes of drug-related liver toxicity with indinavir, saquinavir, fosamprenavir, and darunavir, with minimal further therapeutic options left in this class. Previous treatment-limiting side effects with efavirenz and nevirapine also precluded use of non-nucleoside reverse transcriptase inhibitors. Introduction of an integrase-inhibitor regimen based on raltegravir, tenofovir, and emtricitabine allowed a prompt achievement of undetectable viral load and a substantial rise of CD4 count to high levels, with no subsequent episodes of hepatic toxicity, and no other side effects.Conclusionsgiven the relatively common prevalence of HCV-related chronic hepatitis among people with HIV, raltegravir might represent an important alternative option for a substantial number of patients who cannot be treated with protease inhibitors or NNRTI because of drug-related hepatic toxicity.

Molecular characterization of Streptococcus pyogenes from invasive disease and streptococcal toxic shock syndrome episodes

Streptococcus pyogenes causes a variety of common human diseases, including pharyngitis, scarlet fever and impetigo. Nevertheless, the past decades have witnessed a worldwide resurgence in invasive disease and streptococcal toxic shock syndrome (STSS). The objective of the present study is to evaluate the genetic diversity, virulence gene distribution (spe, sme and ssa genes) and susceptibility pattern of 10 S. pyogenes isolates causing invasive disease and STSS. The isolates were recovered from blood cultures of hospitalized patients at Hospital Santamarina and Nueva Clínica Chacabuco, Tandil, Buenos Aires, Argentina between 12/2000-04/2005. Two pulse field gel electrophoretic patterns predominated. The most frequent one included 5 characteristic isolates of emm1-T1 type, toxin gene profile speA, speB, speF, speG and smeZ. The second pattern included 2 characteristic isolates of emm3-TNT type (speB, speF, speG). The other 3 isolates corresponded to types emm49-TNT (speB, speC, speF, speG), emm75-T25 (speB, speF, speG) and emm83-TNT (speB, speF, speG, ssa, smeZ). All isolates were susceptible to penicillin, cefotaxime, erythromycin, clindamycin, chloramphenicol, tetracycline and rifampicin. The data from the present study demonstrated genetic diversity among the strains. Types emm1 and emm3 were prevalent in invasive disease. The empirical treatment with the combination of penicillin and clindamicin is still valid.

Integrated ecotoxicological and chemical approach for the assessment of pesticide pollution in the Ebro River delta (Spain)

Application of pesticides in the Ebro River delta (NE Spain) during the rice growing season is suspected to be one of the major causes behind the shellfish mortality episodes that occur yearly in this area at spring time. In an attempt to shed light on this suspicion, a monitoring study combining ecotoxicity measurements in water using three different bioassays and pesticides analysis in both water and shellfish has been carried out in this area in April–June 2008. Water and shellfish samples have been collected at six selected sites, two of them located in the bays where seafood (mussels and oysters) are grown, and four located in the main draining channels discharging the output water from the rice fields into the bays. Toxicity of the water samples has been evaluated using three standardized bioassays: 24–48 h immobilization of Daphnia magna, growth inhibition of Pseudokirchneriella subcapitata (formerly known as Selenastrum capricornutum) and bioluminescence inhibition of Vibrio fischeri. Analysis of pesticides (six triazines, four phenylureas, four organophosphorous, one anilide, two chloroacetanilides, one thiocarbamate and four acid herbicides) in water has been carried out by on-line solid-phase extraction-liquid chromatography–tandem mass spectrometry (SPE-LC–MS/MS). Analysis of pesticides in shellfish has been performed by pressurized liquid extraction (ASE), followed by SPE clean-up and analysis by gas chromatography–mass spectrometry (GC/MS). Results have shown individual pesticides concentrations in water above 100 ng/L for about 50% of the compounds investigated, and total pesticides levels above 5 μg/L in the draining channels some days. The most ubiquitous compounds have been bentazone and MCPA and the highest levels have been observed for malathion (up to 5825 ng/L) and MCPA (up to 4197 ng/L). In shellfish, malathion has shown the highest concentration (53 mg/kg). A reasonable coherence has been observed between pesticide concentration (in water and shellfish), toxicity, and mortality episodes of shellfish, for the different locations studied. Taking into consideration the pesticides concentrations found, the toxicity values for the individual compounds, and the toxicity data measured on real samples, the pesticides suspected to be the main contributors to the total ecotoxicity are malathion, and to a lesser extent diazinon and molinate.

Generation of monoclonal antibodies for the specific immunodetection of the toxic dinoflagellate Alexandrium minutum Halim from Spanish waters

In recent years, Alexandrium minutum ( A. minutum) has provoked repeated toxic episodes of harmful algal blooms. The existing method for accurate identification of this dinoflagellate is based on morphological traits and requires taxonomic expertise. However, this is impractical when rapid identification of toxic strains is required, when the microalgae are in low density or when automatic monitoring is needed. In this study, the generation and application of two monoclonal antibodies (M90.3 and M54.3) directed against an intracellular antigen of the A. minutum strain AL1V are described. Specificity and cross-reactivity were tested with cells from clonal cultures. In an immunofluorescence assay, confocal microscopy and flow cytometry showed that the antibodies specifically labeled the two tested A. minutum strains (AL1V and AMP13) and did not show cross-reaction with other Alexandrium species, such as Alexandrium tamarense SZN19, A. tamarense MDQ1096, Alexandrium catenella IEO715 and Alexandrium andersonii SZN12, or tested members of other phylogenetic classes. Furthermore, M90.3 showed highly specific recognition when used for the detection of A. minutum in natural seawater samples. Thus, the mAbs presented here could be used in microalgae monitoring, allowing a specific unequivocal identification of the toxic dinoflagellate A. minutum.

What's new in… Toxicity of drugs of abuse

Toxicity caused by drugs of abuse is a frequent reason for presentation to hospital. Cannabis is the most widely used recreational agent. Although not often associated with acute toxicity requiring hospital admission, there is increasing recognition of its cardiovascular, respiratory and central effects. Strong opioids like heroin and methadone are still the most common causes of fatal recreational drug poisoning, but morbidity and mortality caused by cocaine has been increasing. Numerous hospital presentations continue to occur following ecstasy use. Although less common, episodes of toxicity relating to other drugs of abuse, such as newer stimulants (e.g. piperazines), gamma hydroxybutyrate and its precursors, and ketamine, are increasingly encountered by medical staff. This article is an update on the toxicity of recreational drugs, concentrating on recent research findings and emerging issues.

Detoxification enhancement in the gymnodimine-contaminated grooved carpet shell, Ruditapes decussatus (Linné)

In the Gulf of Gabès (Tunisia, Eastern Mediterranean sea), the grooved carpet shell Ruditapes decussatus has been seen to contain persistent levels of gymnodimine (GYM) for several years. The present experimental work represents the first attempt to assess detoxification kinetics of fast-acting toxins (FAT) in marine molluscs fed specific diets of non-toxic algae ( Isochrysis galbana). To find an optimal detoxification method, two experiments were performed in which clams were first fed the toxic dinoflagellate Karenia selliformis to artificially contaminate them with GYM, thus simulating the effect of natural toxic episodes. As a second step, the same clams were fed a non-toxic algae, I. galbana, to speed up the detoxification process. Changes in toxin content over the whole experiment were assessed by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) analysis. The first results revealed (i) faster detoxification rates in digestive gland (DG) when clams were fed on I. galbana compared with a starved control (no food) and (ii) a typical detoxification pattern, i.e. a rapid drop in toxin content within the first days followed by a secondary slower decrease. GYM levels could be reduced approximately to less than 5% within 7–8 days in clams fed I. galbana, according to the initial toxin levels of 1400 and 9400 μg GYM/kg of DG, respectively. At the end of the second experiment, DSP mouse bioassay was negative when GYM was less than 100 μg/kg DG.

Concomitant docetaxel plus gemcitabine versus sequential docetaxel followed by gemcitabine in anthracycline-pretreated metastatic or locally recurrent inoperable breast cancer patients: a prospective multicentre trial of the Central European Cooperative Oncology Group (CECOG)

Docetaxel (D) plus gemcitabine (G) is an active combination in anthracycline pre-treated breast cancer. Impact of sequential administration of these drugs is unclear. This trial aimed to compare concomitant DG with sequential D --> G. Patients were randomised to eight cycles of gemcitabine 1,000 mg/m2 on days 1 + 8 plus docetaxel 75 mg/m2 on day 8, or 4 cycles of docetaxel 100 mg/m2 on day 1, followed by four cycles of gemcitabine 1,250 mg/m2 on days 1 + 8, in a 21-day schedule. Time to progression (TTP) was defined as primary endpoint; secondary endpoints were overall response rate (ORR), response duration (RD), overall survival (OS) and toxicity. Due to poor recruitment, the trial was terminated after 100 of a pre-planned 430 patients. Patient characteristics were well balanced. No significant difference was observed in terms of TTP, ORR, RD and OS. Grade 3/4 adverse events encompassed leucopoenia (29 vs.68%, P < 0.001), neutropoenia (49 vs. 83%, P < 0.001) and febrile neutropoenia (4 vs. 9%, n.s.), all favouring D --> G. No difference in efficacy was observed between concomitant and sequential treatment. D --> G produced significantly more episodes of haematological toxicity due to the administration of docetaxel at 100 mg/m2 without GCSF support.

Hydrogen sulphide and methane emissions on the central Namibian shelf

Hydrogen sulphide occurs frequently in the waters of the inner shelf coastal upwelling area off central Namibia. The area affected coincides with hatching grounds of commercially important pelagic fish, whose recruitment may be severely affected by recurring toxic sulphidic episodes. Both episodic biogenic methane gas-driven advective and molecular diffusive flux of hydrogen sulphide have been implicated as transport mechanisms from the underlying organic-matter-rich diatomaceous mud. To test hypotheses on the controls of hydrogen sulphide transport from the sediments on the inner Namibian shelf, water column and sediment data were acquired from four stations between 27 and 72 m water depth over a 3 year long period. On 14 cruises, temperature, salinity, dissolved oxygen, nitrate, methane, and total dissolved sulphide were determined from water column samples, and pore water dissolved methane, total dissolved sulphide, biomass of benthic sulphide-oxidising bacteria Beggiatoa and Thiomargarita, and bacterial sulphate reduction rates were determined from sediment cores. Superimposed on a trend of synchronous changes in water column oxygen and nutrient concentrations controlled by regional hydrographic conditions were asynchronous small-scale variations at the in-shore stations that attest to localized controls on water column chemistry. Small temporal variations in sulphate reduction rates determined with 35S-labeled sulphate do not support the interpretation that variable emissions of sulphide and methane from sediments are driven by temporal changes in the degradation rates of freshly deposited organic matter. The large temporal changes in the concentrations of hydrogen sulphide and the co-occurrence of pore water sulphate and methane support an interpretation of episodic advection of methane and hydrogen sulphide from deeper sediment depths – possibly due to gas bubble transport. Effective fluxes of hydrogen sulphide and methane to the water column, and methane and sulphide concentrations in the bottom waters were decoupled, likely due to the activity of sulphide-oxidising bacteria. While the causal mechanism for the episodic fluctuations in methane and dissolved sulphide concentrations remains unclear, this data set points to the importance of alternating advective and diffusive transport of methane and hydrogen sulphide to the water column.

Harmful algae and their potential impacts on desalination operations off southern California

Seawater desalination by reverse osmosis (RO) is a reliable method for augmenting drinking water supplies. In recent years, the number and size of these water projects have increased dramatically. As freshwater resources become limited due to global climate change, rising demand, and exhausted local water supplies, seawater desalination will play an important role in the world's future water supply, reaching far beyond its deep roots in the Middle East. Emerging contaminants have been widely discussed with respect to wastewater and freshwater sources, but also must be considered for seawater desalination facilities to ensure the long-term safety and suitability of this emerging water supply. Harmful algal blooms, frequently referred to as ‘red tides’ due to their vibrant colors, are a concern for desalination plants due to the high biomass of microalgae present in ocean waters during these events, and a variety of substances that some of these algae produce. These compounds range from noxious substances to powerful neurotoxins that constitute significant public health risks if they are not effectively and completely removed by the RO membranes. Algal blooms can cause significant operational issues that result in increased chemical consumption, increased membrane fouling rates, and in extreme cases, a plant to be taken off-line. Early algal bloom detection by desalination facilities is essential so that operational adjustments can be made to ensure that production capacity remains unaffected. This review identifies the toxic substances, their known producers, and our present state of knowledge regarding the causes of toxic episodes, with a special focus on the Southern California Bight.