Strategies for increasing drug delivery to the brain: focus on brain lymphoma

The blood-brain barrier (BBB) is a gate that controls the influx and efflux of a wide variety of substances and consequently restricts the delivery of drugs into the central nervous system (CNS). Brain tumours may disrupt the function of this barrier locally and nonhomogeneously. Therefore, the delivery of drugs to brain tumours has long been a controversial subject. The current concept is that inadequate drug delivery is a major factor that explains the unsatisfactory response of chemosensitive brain tumours. Various strategies have been devised to circumvent the BBB in order to increase drug delivery to the CNS. The various approaches can be categorised as those that attempt to increase delivery of intravascularly administered drugs, and those that attempt to increase delivery by local drug administration. Strategies that increase delivery of intravascularly injected drugs can manipulate either the drugs or the capillary permeability of the various barriers (BBB or blood-tumour barrier), or may attempt to increase plasma concentration or the fraction of the drug reaching the tumour (high-dose chemotherapy, intra-arterial injection). Neurotoxicity is a major concern with increased penetration of drugs into the CNS or when local delivery is practised. Systemic toxicity remains the limiting factor for most methods that use intravascular delivery. This review evaluates the strategies used to increase drug delivery in view of current knowledge of drug pharmacokinetics and its relevance to clinical studies of chemosensitive brain tumours. The main focus is on primary CNS lymphoma, as it is a chemosensitive brain tumour and its management routinely utilises specialised strategies to enhance drug delivery to the affected CNS compartments.     

Evolution of genomic diversity and sex at extreme environments: fungal life under hypersaline Dead Sea stress

We have found that genomic diversity is generally positively correlated with abiotic and biotic stress levels (1-3). However, beyond a high-threshold level of stress, the diversity declines to a few adapted genotypes. The Dead Sea is the harshest planetary hypersaline environment (340 g.liter-1 total dissolved salts, approximately 10 times sea water). Hence, the Dead Sea is an excellent natural laboratory for testing the "rise and fall" pattern of genetic diversity with stress proposed in this article. Here, we examined genomic diversity of the ascomycete fungus Aspergillus versicolor from saline, nonsaline, and hypersaline Dead Sea environments. We screened the coding and noncoding genomes of A. versicolor isolates by using >600 AFLP (amplified fragment length polymorphism) markers (equal to loci). Genomic diversity was positively correlated with stress, culminating in the Dead Sea surface but dropped drastically in 50- to 280-m-deep seawater. The genomic diversity pattern paralleled the pattern of sexual reproduction of fungal species across the same southward gradient of increasing stress in Israel. This parallel may suggest that diversity and sex are intertwined intimately according to the rise and fall pattern and adaptively selected by natural selection in fungal genome evolution. Future large-scale verification in micromycetes will define further the trajectories of diversity and sex in the rise and fall pattern.     

Intrathecal gadolinium (gadopentetate dimeglumine) enhanced magnetic resonance myelography and cisternography: results of a multicenter study

RATIONALE AND OBJECTIVES: This cooperative multicenter human study was designed to evaluate the safety, magnetic resonance (MR) imaging characteristics, and clinical response to a single gadolinium contrast agent: gadopentetate dimeglumine. MATERIAL AND METHODS: Ninety-five patients (age range: 1 month to 78 years; sex: 50 males, 45 females) were included in this prospective study. The patients presented clinically with a variety of cranial or spinal signs and symptoms for which an intrathecal contrast myelogram or cisternogram was requested by clinical staff. Via lumbar puncture (20-25 g needle), 3 to 5 mL/ml of cerebrospinal fluid were withdrawn and mixed with a single volume of 0.5 (n = 63), 0.7 (n = 13), 0.8 (n = 12), or 1.0 (n = 7) cc/mL of gadopentetate dimeglumine (Magnevist; Schering, Berlin, Germany). This was then injected into the subarachnoid space, and the needle was removed. Immediate and delayed (up to 96 hours) T1- and T2-weighted MR imaging was performed on super conductive, high-field (1.0-1.5 tesla) imaging units in two or three planes. All patients were hospitalized for an observation period of 24 hours following the procedure, and follow-up neurologic examinations were performed serially for 6 to 12 months afterward. RESULTS: No patient manifested gross behavioral changes, neurologic alterations, or seizure activity at any time following the procedure. Nineteen patients (20%) experienced postural postlumbar puncture headache, six patients had nausea (6%), and two patients had episodes of vomiting (2%), all which resolved within the first 24 hours of the lumbar puncture with conservative bed rest. CONCLUSION: This cooperative study demonstrates the general safety and feasibility of low dose (0.5-1.0 mL/ml) intrathecal gadopentetate dimeglumine administration. The potential useful clinical applications include the evaluation of obstructions and communications of the various subarachnoid spaces, spontaneous or traumatic/postsurgical craniospinal cerebrospinal fluid leaks, and subarachnoid space CSF flow and parenchymal CNS interstitial diffusion dynamics. This worldwide cooperative study seeks to progressively perform human studies for further definitive evaluation of the practical clinical applications, of the relationship of this technique to other imaging studies and modalities, and the long-term safety of the procedure in a larger number of subjects.     

The acquisition of multidimensional NMR spectra within a single scan

A scheme enabling the complete sampling of multidimensional NMR domains within a single continuous acquisition is introduced and exemplified. Provided that an analyte's signal is sufficiently strong, the acquisition time of multidimensional NMR experiments can thus be shortened by orders of magnitude. This could enable the characterization of transient events such as proteins folding, 2D NMR experiments on samples being chromatographed, bring the duration of higher dimensional experiments (e.g., 4D NMR) into the lifetime of most proteins under physiological conditions, and facilitate the incorporation of spectroscopic 2D sequences into in vivo imaging investigations. The protocol is compatible with existing multidimensional pulse sequences and can be implemented by using conventional hardware; its performance is exemplified here with a variety of homonuclear 2D NMR acquisitions.     

Is mechanical bowel preparation mandatory for elective colon surgery? A prospective randomized study

BACKGROUND: Bowel preparation prior to colonic surgery usually includes antibiotic therapy together with mechanical bowel preparation (MBP). Mechanical bowel preparation may cause discomfort to the patient, prolonged hospitalization, and water and electrolyte imbalance. It was assumed that with the improvement in surgical technique together with the use of more effective prophylactic antibiotics, it was possible that MBP would no longer be necessary. HYPOTHESIS: There is no statistical difference in the postoperative results of patients who undergo elective colon resection with MBP as compared with those who have no MBP.Design and PATIENTS: The study includes all patients who had elective large bowel resection at Campus Golda between April 1, 1999, and March 31, 2002. Emergency operations were not included. The patients were randomly assigned to the 2 study groups (with or without MBP) according to identification numbers. All patients were treated with intravenous and oral antibiotics prior to surgery. The patients in the MBP group received Soffodex for bowel preparation. RESULTS: A total of 329 patients participated in the study, 165 without MBP and 164 with MBP. The 2 groups were similar in age, sex, and type of surgical procedure. Two hundred sixty-eight patients (81.5%) underwent surgery owing to colorectal cancer and 61 patients (18.5%) owing to benign disease. The hospitalization period was longer in the bowel-prepared group (mean +/- SD, 8.2 +/- 5.1 days) as compared with the nonprepared group (mean +/- SD, 8.0 +/- 2.7 days). However, this difference was not statistically significant. The time until the first bowel movement was similar between the 2 groups: a mean +/- SD of 4.2 +/- 1.3 days in the nonprepared group as compared with a mean +/- SD of 4.3 +/- 1.1 days in the prepared group (P = NS). Four patients (1.2%) died in the postoperative course owing to acute myocardial infarction and pulmonary embolism. Sixty-two patients (37.6%) of the non-MBP group suffered from postoperative complications as compared with 77 patients (46.9%) of the MBP group. CONCLUSION: Our results suggest that no advantage is gained by preoperative MBP in elective colorectal surgery.     

General Anesthesia for Surgery Influences Melatonin and Cortisol Levels

The purpose of this study was to investigate the effect of general anesthesia and surgery on melatonin production, and to assess the relationship between melatonin secretion and cortisol levels. Twenty (9 males and 11 females) consecutive otherwise healthy patients aged 27 to 52 years were included in this study. The patients underwent laparoscopic cholecystectomy or laparoscopic hernioplasty. All patients had general anesthesia with the same anesthetic drugs. Serum cortisol levels were measured at several time periods. Urine collections for melatonin were performed from 18:00 to 7:00 the day prior to surgery, on the operation day, and on the first postoperative day. Baseline melatonin metabolites were measured the night prior to surgery, and the level was found to be 1979 ± 1.76 ng. The value decreased to 1802 ± 1.82 ng (NS) on the night of surgery, and it became a significantly higher, reaching 2981 ± 1.55 ng the night after surgery (p = .003). The baseline daytime cortisol level was significantly lower than the baseline night cortisol level (6.87 ± 1.51 μg/dl, 14.89 ± 1.66 micrograms/dl, respectively, p < 0.0001). Surgery induced a significant increase in both day and night cortisol levels. Daytime cortisol levels increased from 6.89 ± 1.51μg/dl to 16.90 ± 1.27μg/dl (p < 0.0001), whereas right levels increased from 14.89 ± 1.66 μg/dl to 29.20 ± 1.24 μg/dl (p <0.0001). The morning after surgery, cortisol levels decreased to 10.16 ± 1.40 μg/dl, lower than the value obtained on the day of surgery (p < 0.0001). As was true of melatonin, cortisol levels did not reach the pre operative level (p < 0.005). The finding of the current study is that melatonin and cortisol levels show an inverse correlation after surgery.     

Can external signs of trauma guide management?: Lessons learned from suicide bombing attacks in Israel

BACKGROUND: Following a suicide bombing attack, scores of victims suffering from a combination of blast injury, penetrating injury, and burns are brought to local hospitals. OBJECTIVE: To identify external signs of trauma that would assist medical crews in recognizing blast lung injury (BLI) and effectively triaging salvageable and nonsalvageable victims. DESIGN: Retrospective analysis of all 15 suicide bombing attacks that occurred in Israel from April 1994 to August 1997. SETTING: National survey. PATIENTS: One hundred fifty-three victims died and 798 were injured as a result of 15 attacks. Medical records were reviewed for external signs of trauma, such as burns and penetrating injuries, and the presence of BLI.Main Outcome Measure The odds ratio for BLI and death. RESULTS: Three settings were targeted: buses, semiconfined spaces, and open spaces. Sixty survivors (7.5%) suffered from BLI, which was more common in buses (37 of 260) than semiconfined spaces (14 of 279) and open spaces (9 of 259) (P<.001). Victims with BLI were more likely to suffer from penetrating injury to the head or torso, burns covering more than 10% of the body surface area, and skull fractures (odds ratios, 4, 11.6, and 55.8, respectively; P<.001). Victims who died at the scene were more likely to suffer from burns, open fractures, and amputations in comparison with survivors (odds ratios, 6.5, 18.6, and 50.1, respectively; P<.001). CONCLUSIONS: Following a suicide bombing attack, external signs of trauma should be used to triage victims to the appropriate level of care both at the scene and in the hospital. Triage of salvageable and nonsalvageable victims should take into account the presence of amputations, burns, and open fractures.     

Remifentanil supplementation of propofol during electroconvulsive therapy: effect on seizure duration and cardiovascular stability

OBJECTIVES: Electroconvulsive therapy (ECT) is standard treatment of severe depression. The induction of a seizure is a core event in successful ECT. Although propofol is a frequently used anesthetic agent, one of its limitations is a reduction of seizure duration. No such effects have been reported regarding remifentanil, an ultrarapid-acting opioid that is used to induce and maintain anesthesia. The simultaneous administration of propofol and remifentanil may have similar safety and efficacy in terms of induction of anesthesia during ECT as propofol alone and significantly increase seizure duration. METHODS: Twenty-one ECT patients (10 men, 11 women, aged 24 to 81 years) were recruited. Muscle paralysis was achieved with succinylcholine (0.5-0.75 mg/kg intravenously [IV]). Unconsciousness was induced by either propofol (1 mg/kg IV) or propofol (0.5 mg/kg IV) + remifentanil (1 microg/kg) in a crossover format. ECT was administered according to established clinical protocols at the Sheba Medical Center, Israel. No changes in ECT current were permitted in the 2 protocols of each patient. Statistical analysis was based on paired t tests. RESULTS: In all but 2 cases, seizure duration was significantly longer in the remifentanil group than in the control group (motor seizure 53.7 +/- 28.3 seconds vs. 29.5 +/- 10.9 seconds, t = 4.017, P = 0.0007; Electroencephalographic (EEG) seizures 60.8 +/- 25.1 seconds vs. 40.1 +/- 17.0 seconds, t = 3.971, P = 0.001). No significant differences were found in mean recovery time, post-treatment elevation in blood pressure, heart-beat, or oxygen saturation. CONCLUSION: During anesthesia, the addition of remifentanil to propofol appears to be as effective as propofol alone with regard to anesthesia efficacy and cardiovascular function while significantly increasing seizure duration. Whether this discovery is of relevance to the clinical efficacy of ECT remains to be tested.