Introduction of vincristine mini-bags and an assessment of the subsequent risk of extravasation.

INTRODUCTION: Numerous international organisations have advocated the preparation of vincristine in small volume intravenous bags in order to eliminate inadvertent intrathecal administration. However, the risk of extravasation is a significant deterrent, and adoption of this practice has been variable and only hesitantly accepted in the clinical setting. PURPOSE: We carried out a study with the aims of establishing the incidence of reported extravasation of vincristine administration to paediatric and adult patients in mini-bags; here we describe motivating factors and barriers faced by clinical staff. The secondary aim was to support the need for change and implementation of the international recommendations. METHODS: Chemotherapy-certified nurses completed a survey spanning August 2009 to August 2011, to ascertain the incidence of extravasation associated with the administration of vincristine in mini-bags. RESULTS: This period captured 421 occasions of vincristine administration in 25-ml or 50-ml mini-bags (in 0.9% sodium chloride). The median age of patients was 13 years (range 2.5 months to 99 years). Vincristine was administered through peripheral lines (26.4%), portacath (52.0%), PICC line (15.9%) and Hickman line (5.7%). The majority of infusions were over at least 10 minutes (50.1%). There were no cases of extravasation reported. CONCLUSIONS: The administration of vincristine in small volume intravenous bags was safe, practical, and feasible in all patient groups. The successful implementation of the international recommendations for vincristine administration in mini-bags to eliminate potential inadvertent intrathecal administration was dependent on stakeholder buy-in.

The development and application of a novel safety-catch linker for BOC-based assembly of libraries of cyclic peptides.

Cyclic peptides are appealing targets in the drug-discovery process. Unfortunately, there currently exist no robust solid-phase strategies that allow the synthesis of large arrays of discrete cyclic peptides. Existing strategies are complicated, when synthesizing large libraries, by the extensive workup that is required to extract the cyclic product from the deprotection/cleavage mixture. To overcome this, we have developed a new safety-catch linker. The safety-catch concept described here involves the use of a protected catechol derivative in which one of the hydroxyls is masked with a benzyl group during peptide synthesis, thus making the linker deactivated to aminolysis. This masked derivative of the linker allows BOC solid-phase peptide assembly of the linear precursor. Prior to cyclization, the linker is activated and the linear peptide deprotected using conditions commonly employed (TFMSA), resulting in deprotected peptide attached to the activated form of the linker. Scavengers and deprotection adducts are removed by simple washing and filtration. Upon neutralization of the N-terminal amine, cyclization with concomitant cleavage from the resin yields the cyclic peptide in DMF solution. Workup is simple solvent removal. To exemplify this strategy, several cyclic peptides were synthesized targeted toward the somatostatin and integrin receptors. From this initial study and to show the strength of this method, we were able to synthesize a cyclic-peptide library containing over 400 members. This linker technology provides a new solid-phase avenue to access large arrays of cyclic peptides.

Different heparin lots: Does it matter?

OBJECTIVE: To assess the impact of heparin lot on the correlation between heparin concentration and activated partial thromboplastin time (aPTT), the aPTT therapeutic range, and the heparin level. DESIGN: Retrospective analysis of data from 2 previous studies. SETTING: Teaching institution with 929 beds. PATIENTS: Ninety-five patients receiving heparin with 5 different lots (study 1) and 35 patients receiving heparin with 3 different lots (study 2). MAIN OUTCOME MEASURES: Laboratory-based aPTT and heparin level by anti-factor Xa analysis. Standard heparin curves were created for each lot. Each patient's heparin level was determined off each standard curve. RESULTS: Correlations between heparin concentration and aPTT ranged from 0.87 to 0.89 (study 1) and 0.86 to 0.87 (study 2). Slopes of regression lines were not significantly different. Therapeutic ranges generated from lot-specific heparin levels were similar. Average bias in heparin levels from varying lots ranged from 0.005 to 0.036 units/mL. CONCLUSIONS: The recommendation to reevaluate the aPTT therapeutic range with each new lot of heparin requires further evaluation.

Use of the activated partial thromboplastin time for heparin monitoring.

The objectives of the present study were to evaluate the relationship between heparin concentration and activated partial thromboplastin time (aPTT) results, define a heparin concentration-derived therapeutic range for each aPTT instrument, compare aPTT- and heparin concentration-guided dosage adjustment decisions, and compare laboratory- and bedside aPTT-guided decisions. In phase 1, 102 blood samples were analyzed for bedside and laboratory aPTTs and heparin concentration (used to establish aPTT therapeutic range). In phase 2, 100 samples were analyzed in the same manner. Correlations for aPTT compared with heparin ranged from 0.36 to 0.82. Dosage adjustment decisions guided by the aPTT agreed with those based on heparin concentration 63% to 80% of the time. Laboratory and bedside aPTT dosage adjustment decisions agreed 59% to 68% of the time. The correlation of aPTT with heparin concentration and agreement between aPTT- and heparin-guided decisions vary with the aPTT instrument. Decisions guided by laboratory aPTT results often disagree with decisions guided by bedside aPTT results.

Proteolysis of human hemoglobin by schistosome cathepsin D.

Schistosomes feed on human blood. They employ proteases to degrade hemoglobin from ingested erythrocytes, using the residues released for amino acid metabolism. However, the identity and the role of the participating protease(s) are unclear and controversial. Confocal microscopy localized schistosomal cathepsin D to the parasite gastrodermis, and revealed elevated protease expression in females. At sub-cellular level, cathepsin D was localized to superficial digestive vacuoles of the gut and to cisternae of the gastrodermal rough endoplasmic reticulum. Schistosome cathepsin D, expressed in insect cells, autoactivated at pH 3.6 to a approximately 40 kDa form that cleaved the substrates o-aminobenzoyl-Ile-Glu-Phe-nitroPhe-Arg-leu-NH(2) and hemoglobin. The NH(2)-terminal residues of mature cathepsin D of Schistosoma japonicum and Schistosoma mansoni were Asn1 and Gly1, respectively, revealing that the proregion peptide was comprised of 35 residues. The proteases cleaved hemoglobin at pH 2.5--4.6, releasing numerous fragments. S. Japonicum cathepsin D cleaved at 13 sites, S. mansoni cathepsin D at 15 sites. Early cleavage sites were alpha Phe33-Leu34 and beta Phe41-Phe42, while others included alpha Leu109-Ala-110 and beta Leu14-Trp15, demonstrating a preference for bulky hydrophobic residues at P1 and P1'. Most of the schistosomal cathepsin D cleavage sites were discrete from those of human cathepsin D. The gastrodermal location, elevated expression in females, acidic pH optima, similar substrate preferences in two species, and the discrete substrate preferences compared with human cathepsin D together provide compelling support for the hypothesis that schistosomal cathepsin D plays an integral role in hemoglobin proteolysis, and might be selectively targeted by drugs based on protease inhibition.

Anaphylactoid reaction to levofloxacin.

Anaphylactoid and/or anaphylactic reactions to fluoroquinolones are estimated to occur in 0.46-1.2/100,000 patients. A 49-year-old woman with a history of asthma was admitted for a presumed asthma exacerbation related to an infectious process. She was given levofloxacin and standard management for an acute exacerbation. On two occasions the patient's respiratory distress worsened, requiring intubation. The second reaction occurred immediately after levofloxacin administration and was accompanied by a marked cutaneous reaction. Levofloxacin was discontinued, and supportive care was provided. No further symptoms occurred. The patient later was found to have been started on levofloxacin before admission for a suspected upper respiratory infection.

An activated O --> N acyl transfer auxiliary: efficient amide-backbone substitution of hindered "difficult" peptides.

Overcoming the phenomenon known as "difficult" synthetic sequences has been a major goal in solid-phase peptide synthesis for over 30 years. In this work the advantages of amide backbone-substitution in the solid-phase synthesis of "difficult" peptides are augmented by developing an activated N(alpha)()-acyl transfer auxiliary. Apart from disrupting troublesome intermolecular hydrogen-bonding networks, the primary function of the activated N(alpha)()-auxiliary was to facilitate clean and efficient acyl capture of large or beta-branched amino acids and improve acyl transfer yields to the secondary N(alpha)()-amine. We found o-hydroxyl-substituted nitrobenzyl (Hnb) groups were suitable N(alpha)()-auxiliaries for this purpose. The relative acyl transfer efficiency of the Hnb auxiliary was superior to the 2-hydroxy-4-methoxybenzyl (Hmb) auxiliary with protected amino acids of varying size. Significantly, this difference in efficiency was more pronounced between more sterically demanding amino acids. The Hnb auxiliary is readily incorporated at the N(alpha)()-amine during SPPS by reductive alkylation of its corresponding benzaldehyde derivative and conveniently removed by mild photolysis at 366 nm. The usefulness of the Hnb auxiliary for the improvement of coupling efficiencies in the chain-assembly of difficult peptides was demonstrated by the efficient Hnb-assisted Fmoc solid-phase synthesis of a known hindered difficult peptide sequence, STAT-91. This work suggests the Hnb auxiliary will significantly enhance our ability to synthesize difficult polypeptides and increases the applicability of amide-backbone substitution.

The use of calcium salts in the prevention and management of verapamil-induced hypotension.

OBJECTIVE: To review the available literature on the use of intravenous calcium salts for the prevention of hypotension associated with intravenous verapamil. METHODS: A MEDLINE search (1966-June 1999) identified pertinent articles; references from these articles were identified to serve as additional resources. DISCUSSION: Verapamil is effective in inhibiting atrioventricular nodal conduction, thereby controlling ventricular rate in patients with atrial fibrillation/flutter and terminating paroxysmal supraventricular tachycardia. However, hypotension may be caused by the negative inotropic and vasodilating effects of verapamil. In vitro and animal data suggest that calcium pretreatment may minimize the effects of verapamil on cardiac output and blood pressure. Case reports suggest that intravenous calcium may be useful for both prevention and reversal of the hemodynamic effects of verapamil. A number of small clinical trials have been performed, suggesting that calcium administered prior to intravenous verapamil results in a decreased incidence of hypotension. The most common adverse effect of intravenous calcium is flushing. CONCLUSIONS: Calcium pretreatment prior to intravenous calcium-channel blocker administration should be considered in patients in whom further reductions in blood pressure may precipitate hypoperfusion or worsen underlying cardiovascular status. A dose of calcium gluconate 1 g (ionized calcium 90 mg) administered over three minutes is recommended for preventing or lessening the hypotensive effect of verapamil without affecting the antiarrhythmic effects of verapamil.

Correlation of activated clotting time and activated partial thromboplastin time to plasma heparin concentration.

STUDY OBJECTIVE: To determine the correlation between activated clotting time (ACT) or activated partial thromboplastin time (aPTT) and plasma heparin concentration. DESIGN: Two-phase prospective study. SETTING: University-affiliated community hospital. PATIENTS: Thirty patients receiving continuous-infusion intravenous heparin. INTERVENTIONS: Measurement of ACT, aPTT and plasma heparin concentrations. MEASUREMENTS AND MAIN RESULTS: Linear and log linear correlations were determined between clotting time tests and heparin concentrations. Linear correlations yielded r values of 0.58 for ACT (p=0.008) and 0.89 for aPTT (p=0.0001). Log linear correlations yielded r values of 0.60 for ACT (p=0.005) and 0.88 for aPTT (p=0.0001). A decision analysis was performed to determine possible consequences of dosage adjustments based on either test in relationship to the decision based on plasma heparin concentration. The decision analysis based on ACT disagreed with corresponding decisions based on plasma heparin concentration in 15 of 30 patients; 13 disagreements may have increased the risk of bleeding, and the other 2 may have increased the risk of thrombosis. Decisions based on aPTT disagreed with corresponding decisions based on plasma heparin concentration in 13 of 30 patients; 2 disagreements may have increased the risk of bleeding, and the other 11 may have increased the risk of thrombosis. CONCLUSION: There are significant statistical linear and log linear correlations between both clotting time tests and plasma heparin concentrations, with aPTT showing stronger correlation than ACT. However, decisions regarding heparin therapy based on ACT may increase a patient's risk of bleeding, whereas decisions based on aPTT may increase the risk of thrombus progression or rethrombosis.

Power planning, accelerated implementation, and orchestration management.

Staggering adjustments are being demanded in the medical world. New laws, regulations, technology, and competition are forcing decision makers to adopt new approaches relating to how they manage their institutions. This article discusses an organized program that employs an array of management tools and techniques that can be of great value to those who are embarking on a program of deliberate methods change.

Pharmaceutical care in medical progressive care patients.

OBJECTIVE: To develop, implement, and assess the outcomes of a system for providing pharmaceutical care to medical progressive care patients. METHODS: A system for providing pharmaceutical care was developed and implemented for an 8-week period beginning in June 1995. Both patient care outcomes and drug therapy cost change from the intervention period were compared with those of an 8-week baseline period. Variables compared included unit length of stay, hospital length of stay, transfers to the intensive care unit, readmissions, and adverse drug reactions requiring treatment. Differences between periods for these variables were assessed by using chi 2 tests and t-tests with alpha set at p less than 0.05. The clinical significance of the interventions were assessed independently by four physicians: two intensivists and two internists. The total drug therapy cost change from the intervention period was calculated as follows: total cost avoidance from individual recommendations subtracted from the total cost incurred from individual recommendations. RESULTS: The pharmacist evaluated 152 patients during the intervention period. A total of 235 pharmacotherapy recommendations were made on 103 patients, of whom 86.4% were accepted. Significantly fewer adverse drug reactions (ADRs) received treatment during the intervention period (p = 0.027). The mean unit length of stay was lower during the intervention period (4.8 +/- 3.7 d) than during the baseline period (6.0 +/- 5.6 d); however, this difference was not significant (p = 0.053). Individual physician assessment of the pharmacists' recommendations revealed that 75.8% were considered somewhat significant, significant, or very significant. The total drug therapy cost change from the intervention period was -$6534.53. The projected annual drug therapy cost reduction from this study is $42,474.45. CONCLUSIONS: The provision of pharmaceutical care to medical progressive care patients was associated with a substantial decrease in drug therapy cost and a decrease in the number of ADRs that required treatment.

Serotonin syndrome secondary to phenelzine-venlafaxine interaction.

A 44-year-old woman accidentally ingested phenelzine along with venlafaxine. Thirty minutes after the ingestion the woman began to feel nauseous and anxious. Approximately 45 minutes later a friend noted that the woman had lower extremity shaking and increasingly rapid respirations. The friend brought the woman to the emergency department and she was subsequently diagnosed with serotonin syndrome. Serotonin syndrome is usually precipitated by combinations of serotonin-potentiating agents and can lead to devastating outcomes. When using combinations of drugs that elevate serotonin levels in the central nervous system, the possibility of serotonin syndrome should be considered.

Automation: triumph or trap?

Automation, a hot topic in the laboratory world today, can be a very expensive option. Those who are considering implementing automation can save time and money by examining the issues from the standpoint of an industrial/manufacturing engineer. The engineer not only asks what problems will be solved by automation, but what problems will be created. This article discusses questions that must be asked and answered to ensure that automation efforts will yield real and substantial payoffs.

Proteolytic degradation of host hemoglobin by schistosomes.

Schistosomes acquire amino acids for growth, development, and reproduction by catabolizing hemoglobin obtained from ingested host erythrocytes. While the biochemical pathway(s) involved has not been determined definitively, a number of proteases including schistosome legumain and cathepsin L-, D-, B- and C-like enzymes have been ascribed roles in the degradation of hemoglobin to diffusible peptides. Transcripts encoding these schistosome proteases, which appear to be expressed in the gastrodermis and cecum of the schistosome, have been reported. Because these enzymes are candidate targets at which to direct novel anti-schistosomal therapies, the comparative biochemistry of these and their counterpart mammalian proteases is now the focus of research in a number of laboratories. This paper reviews reports dating from 40 years ago to the present on how schistosomes digest host-derived hemoglobin, and interprets apparent anomalies in some earlier compared to later reports, the latter having benefited from the availability of PCR and gene cloning technologies. More specifically, the review concentrates on five proteolytic enzymes, and their associated genes, which have been ascribed key roles in the pathway of hemoglobin degradation.