A phase I and pharmacokinetic trial of terephthalamidine (NSC 57155) as a 120-hour continuous infusion

In this phase I study, terephthalamidine was administered as a 120-hour continuous infusion repeated every 21 days. Thirteen patients received 27 courses of terephthalamidine at four dose levels (14, 28, 46, and 70 mg/m²/day). Dose-limiting toxicity consisted of profound and intractable anorexia, weight loss and prostration in all patients. Toxicity was delayed and accompanied by hyponatremia and hypokalemia. No hematologic or other toxicity was documented. One patient with adenocarcinoma of the lung had a 40% decrease in mediastinal lymph nodes and resolution of a pleural effusion lasting 2 months. Pharmacokinetic analysis by HPLC was performed in all patients during their first course. The harmonic mean terminal half-life for terephthalamidine was 23 hours with a plasma clearance of 1.7 l/hr/m². Both plasma concentrations achieved during infusion (r² = 0.9) and area under the curve (AUC) (r² = 0.8) were proportional to increase in dose (p < 0.002). Renal excretion accounted for 64% of the total cumulative dose, with an average renal clearance of 1.16 l/hr/m². Due to the unacceptable toxicity seen at all doses with this schedule, no further studies are recommended unless the mechanism of toxicity is better understood and can be prevented.     

Cation exchange contribution to the retention of specific quaternary ammonium compounds in reversed-phase high-performance liquid chromatography

The influence of electrolytes on the retention of organic cationic solutes in reversed-phase high-performance liquid chromatography (RP-HPLC) has been investigated. The effects of the nature and concentration of electrolytes and mobile phase pH on the retention of two model quaternary ammonium compounds were studied on mu-Bondapak C18 stationary phase with aqueous methanolic eluents. The nature and concentration of inorganic cations added to the mobile phase modified the retention of the solutes. The counter anion of the added electrolyte did not perceptibly influence solute retention at constant mobile phase pH, although it did significantly influence solute retention when the electrolytes were added to unbuffered mobile phases. The retention data are consistent with the inclusion of an ion exchange contribution to the retention of cationic solutes in the systems investigated.     

Lidocaine has a narrow antiarrhythmic dose range against ventricular arrhythmias induced by programmed electrical stimulation in conscious postinfarction dogs

Summary The aim of the present study was to investigate the dose-dependent antiarrhythmic efficacy of lidocaine against electrically induced tachycardias in conscious, chronically instrumented postinfarction dogs. Programmed electrical stimulation (PES) was performed in 16 dogs 8 to 21 days after a 4 h occlusion of the left anterior descending coronary artery (LAD). Infusion of saline in 8 control animals with sustained ventricular tachycardia (SVT) inducible at baseline did not affect subsequent inducibility. In the treatment group 7 of 8 animals responded with SVT and one exhibited ventricular fibrillation at baseline. After an initial bolus of 1 mg/kg lidocaine intravenously (i.v.), the drug was infused at infusion rates of 40, 80 and 120 g/kg/min (i.v.). During 80 g/kg/min lidocaine (mean plasma level 3.5 g/ml) 7 out of 8 animals displayed an antiarrhythmic response; both the lower and the higher infusion rate were associated with a smaller antiarrhythmic efficacy (3 of 8 animals responded to 40 g/kg/min and 4 of 8 to 120 g/kg/min). Licocaine did not affect ventricular refractory periods, but induced an increase in intraventricular conduction time at all infusion rates, from 66.2 ms at baseline to 67.7 ms (p<0.05), 67.7 ms (p<0.05), 70.0 ms (p<0.01) respectively.In conclusion the present study demonstrates that lidocaine is of considerable value in the management of PES-induced ventricular arrhythmias in the postinfarction phase. However there is only a small optimal therapeutic plasma level range, where lidocaine exhibits its antiarrhythmic efficacy against this type of arrhythmia; this makes a carefully titration of the drug necessary both in the experimental and in the clinical setting. Send offprint requests to K. Krejcy at the above address     

Serotonergic function and late luteal phase dysphoric disorder

Thirty-eight subjects who met criteria for the DSM-III-R diagnosis late luteal phase dysphoric disorder (LLPDD) were compared with 18 controls in 5-HT uptake kinetics of the platelets in the premenstrual (day 26) as well as in the postmenstrual phase (day 4) of the cycle. Furthermore, 5-hydroxytryptophan (5-HTP) was administered to LLPDD patients and controls in both phases of the cycle, to investigate pituitary sensitivity for serotonin. Plasma samples for the measurement of cortisol and -endorphin were taken before and after oral administration of 200 mg 5-HTP, and considered as an index of pituitary-adrenal function. LLPDD was not associated with a lower platelet 5-HT uptake and content in the premenstrual phase of the cycle, compared with the postmenstrual phase. Patients appeared not to be different from controls in 5-HT uptake kinetics of platelets in the premenstrual phase of the cycle. No main differences were observed between LLPDD patients and controls in their ability to respond with secretion of cortisol and -endorphin to 5-HTP stimulation, either in the premenstrual, or in the postmenstrual phase. This observation could not be attributed to differences in 5-HTP metabolism. The findings of the present study do not support a specific role for 5-HT in the pathophysiology LLPDD.     

Motion artifact reduction with three-point ghost phase cancellation.

A novel method for "ghost" artifact suppression is introduced. It suppresses ghosts induced by motion in any direction, as well as other types of quasi-periodic signal modulation. Because it requires neither special hardware nor intensive data processing, it can be easily implemented on conventional magnetic resonance (MR) imagers. The method is based on the concept of decomposition of a ghosted complex image into a ghost mask and ideal image. A set of deliberately designed acquisitions are used to generate a set of ghosted complex images in which the ghost components are related in a simple manner. With use of equations describing image decomposition and ghost correlation, the ideal image can be calculated pixel by pixel. The ideal image obtained (representing the time-averaged spin-density distribution) is shown to be a truer representation of physical reality than the ghost-free image obtained with ordered phase encoding. In this technique, both interview and intraview effects are taken into account. The technique is also useful in simultaneously suppressing ghosts from multifrequency signal modulations such as respiratory and cardiac motions. The method was successfully tested with three time-interleaved, phase-encoding-order-shifted acquisitions. Experimental results have shown that it is a simple but effective technique.     

New indolicidin analogues with potent antibacterial activity*

Abstract: Indolicidin is a 13‐residue antimicrobial peptide amide, ILPWKWPWWPWRR‐NH₂, isolated from the cytoplasmic granules of bovine neutrophils. Indolicidin is active against a wide range of microorganisms and has also been shown to be haemolytic and cytotoxic towards erythrocytes and human T lymphocytes. The aim of the present paper is two‐fold. First, we examine the importance of tryptophan in the antibacterial activity of indolicidin. We prepared five peptide analogues with the format ILPXKXPXXPXRR‐NH₂ in which Trp‐residues 4,6,8,9,11 were replaced in all positions with X = a single non‐natural building block; N‐substituted glycine residue or nonproteinogenic amino acid. The analogues were tested for antibacterial activity against both Staphylococcus aureus American type culture collection (ATCC) 25923 and Escherichia coli ATCC 25922. We found that tryptophan is not essential in the antibacterial activity of indolicidin, and even more active analogues were obtained by replacing tryptophan with non‐natural aromatic amino acids. Using this knowledge, we then investigated a new principle for improving the antibacterial activity of small peptides. Our approach involves changing the hydrophobicity of the peptide by modifying the N‐terminus with a hydrophobic non‐natural building block. We prepared 22 analogues of indolicidin and [Phe^4,6,8,9,11] indolicidin, 11 of each, carrying a hydrophobic non‐natural building block attached to the N‐terminus. Several active antibacterial analogues were identified. Finally, the cytotoxicity of the analogues against sheep erythrocytes was assessed in a haemolytic activity assay. The results presented here suggest that modified analogues of antibacterial peptides, containing non‐natural building blocks, are promising lead structures for developing future therapeutics.     

Clinical phase I study with one-hour paclitaxel infusion

Background: Paclitaxel (PAC) is one of the major anti-cancer drugs,effective in different tumors. Studies with 24-hour infusion with 135mg/m² and a three-hour infusion with 175 mg/m²showed a significant schedule-dependent toxicity. We evaluated a one-hourinfusion schedule within a phase I study to determine the dose limitingtoxicity (DLT), the maximum tolerated dose (MTD), and the anti-cancerefficacy.Patients and methods: Patients with advanced malignant tumors weretreated within cohorts by one-hour infusional paclitaxel starting with 150mg/m² and stepwise escalation with 25 mg/m²increments. Therapy was repeated in three-week intervals. Cycles wererepeated until progression. Toxicity was closely monitored, anti-cancerefficacy was only evaluated in those patients who received at minimum twotreatment cycles.Results: Thirty-four patients entered the study (11 NSCLC, five SCLC,seven ovarian cancer, one cervix cancer, nine MBC, one HN cancer). The MTDwas PAC 250 mg/m². The DLT was central and peripheralneuropathy (WHO grade 3). Other significant toxicities were fatigue,myalgia/arthralgia and paraesthesia. No significant myelotoxicity wasobserved. Totally twentyone patients were evaluable for response. A partialresponse was observed in five (24%) patients (two NSCLC, two ovariancancer, one head and neck cancer). Three (14%) patients had stabledisease and in 13 (62%) patients progressive disease was observed.Conclusions: Paclitaxel 225 mg/m² on day 1 administered asone-hour infusion and repeated every three weeks can be given safely, featuredno relevant myelotoxicity, and is the recommended dose for phase II studies.     

Examining the effects of lipopolysaccharide and cholecystokinin on water ingestion: comparing intake and palatability

Lipopolysaccharide (LPS) and cholecystokinin (CCK) have been shown to have anorectic properties in a variety of species. The present study examined the effects of LPS and CCK, both alone and in combination, on two different aspects of water ingestion, water intake and palatability. On test days, animals were first injected intraperitoneally (i.p.) with either LPS (200 microg/kg) or NaCl vehicle, and 2 h later received a second injection of either CCK (8 microg/kg) or NaCl vehicle. In Experiment 1, water intake was monitored for 1 h on 3 separate test days 72 h apart; while in Experiment 2, water palatability was assessed using the taste reactivity test (TRT), on two separate test days 72 h apart. Both LPS and CCK significantly (p<0.05) reduced water intake, with the effects of combined LPS with CCK being more pronounced than either agent injected alone. Rats developed a rapid tolerance to the effects of LPS on water intake on subsequent exposures to LPS. Results from the TRT indicated that LPS enhanced water palatability (p<0.05), as evidenced by a high level of ingestive responding, whereas CCK produced a pattern of responding indicative of satiety. LPS plus CCK reduced ingestive responding on the first test day, but these responses were significantly increased on the second test day (p<0.05). These results demonstrate that although LPS reduces water intake, it enhances water palatability. The results further underscore the necessity for examining palatability changes in addition to intake measures when studying the regulation of feeding and drinking.     

Light-induced phase-shifts in the circadian expression rhythm of mammalian period genes in the mouse heart

To investigate the molecular mechanism that regulates circadian rhythms in mammalian peripheral tissues, we examined the phase shifts evoked by light exposure in the circadian mRNA expression rhythms of mammalian Period genes (mPer1, mPer2 and mPer3) and a clock-controlled gene Dbp, in the mouse heart, by Northern blot analysis. The light pulse did not induce any acute mRNA expression of mPer in the heart, but the pulse gave rise to phase shifts in the circadian mRNA rhythms. On the first day after the exposure, only mPer1 mRNA showed a phase shift, whereas obvious phase shifts were not observed in the rhythms of mPer2, mPer3 and Dbp mRNAs. On the second day, phase shifts occurred to a similar extent in the mRNA rhythms of all four genes examined. The rhythm of mPer1 mRNA shifted fastest among those of the three mPers. Therefore mPer1 seems to play an important role in phase resetting of mammalian peripheral oscillators. Immediate responses to light pulses in mRNA expression of mPers may not be required for phase shifting of peripheral circadian oscillators. Our findings suggest that mammals require more than one day to have peripheral oscillators entrained to a new daily schedule.