Effect of some central nervous system acting drugs on rat brain and liver monoamine oxidase activity

A number of central nervous system acting drugs were administered to male rats. At certain time intervals after the administration of these drugs, the rats were sacrificed. Liver and brain monoamine oxidase (MAO) activities were determined. The drugs employed were: ethyl alcohol, cognac, hexobarbital, diazepam, imipramine and chloralose. Results obtained indicated that the liver MAO activity was not altered by any of these drugs. Brain MAO activity, contrary to in vitro studies, was increased by alcohol and cognac. The increase was not due to a direct effect of alcohol on the enzyme activity, since the in vitro addition of equivalent concentrations of alcohol, as those calculated to be present in vivo, to brain homogenates resulted in a decrease rather than an increase in activity.     

Fomepizole treatment of ethylene glycol poisoning in an infant

The enzyme alcohol dehydrogenase metabolizes ingested ethylene glycol (EG) to the toxic compounds glycolic and oxalic acids. Renal failure, acidosis, hypocalcemia, and death may follow. Traditional treatment of EG poisoning may require ethanol, a competitive substrate of alcohol dehydrogenase, and hemodialysis, that removes both EG and its toxic metabolites. A new alcohol dehydrogenase inhibitor, fomepizole (4-methylpyrazole), was approved in 1997 for patients at least 12 years old with suspected or confirmed EG poisoning. Fomepizole has not been studied adequately in the pediatric population. We present a case of an 8-month-old male infant who drank up to 120 mL of EG and developed acidosis and oxalate crystalluria. He was treated with fomepizole and hemodialysis. Even after the completion of hemodialysis, fomepizole appeared to effectively block the production of EG toxic metabolites and to allow the resolution of acidosis; the patient recovered within 48 hours. This is the first report of fomepizole treatment of EG poisoning in an infant.4-methylpyrazole, fomepizole, poisoning, ethylene glycol, hemodialysis, infant, child, pediatrics.     

Simple numeric abnormalities as primary karyotype changes in ovarian carcinoma

Simple near-diploid karyotypes in ovarian cancer may indicate either primary alterations related to tumor pathogenesis or abnormalities associated with early tumor progression. We have identified a series of 13 epithelial ovarian tumors with very simple karyotypes. Specifically, these karyotypes were near-diploid and displayed numeric abnormalities alone or combined with one or two structural alterations. The present series includes samples from 10 patients with newly diagnosed adenocarcinomas and 3 patients having borderline malignancies. Recurrent numeric abnormalities were identified and included 9/13 cases (69%) with + 12, eight cases (62%) with + 8, five cases (38%) with + 7, three cases (23%) each with + 3 or + 5, and two cases (15%) with -X, Five cases in this series displayed certain numeric abnormalities (+ 12, + 7, and -X) as the sole anomalies, thereby qualifying as primary karyotype changes. Of the 6 cases with structural abnormalities, 4 involved chromosome 19, 2 involved chromosome I, and the remaining abnormalities or translocation partners involved other chromosomes. These findings indicate that some numeric abnormalities are primary karyotype alterations in patients with malignant epithelial ovarian tumors and that chromosome 19 may be preferentially involved in structural rearrangements during early tumor progression. Genes Chromosom Cancer 10:262–266 (1994). © 1994 Wiley-Liss, Inc.     

Five-day storage of platelet concentrates. I. In-vitro studies

Platelet concentrates have been prepared in standard PVC (PL-146) packs and polyolefin (PL-732) packs. Comparison of pH and hypotonic stress of the platelet concentrates has shown that significantly improved values are obtained after storage of the concentrates at 22 C in PL-732 packs for 5 days than after storage for 3 days in PL-146 packs. There was no significant difference under conditions of the test between vertical and horizontal agitation of the concentrates. Since both pH and hypotonic stress recovery have shown a relationship to post-transfusion recovery and viability, evidence is presented to support the 5-day storage period of concentrates prepared and stored in PL-732 packs.     

Enhancement of the radiation response of EMT-6 tumours by a copper octabromotetracarboranylphenylporphyrin

Objective

The carborane-containing porphyrin, copper (II) 2,3,7,8,12,13,17,18-octabromo-5,10,15,20-tetrakis(3-[1,2-dicarba-closo-dodecaboranyl]methoxyphenyl)-porphyrin (CuTCPBr), was investigated as a potential radiation enhancing agent for X-ray radiotherapy (XRT) in a subcutaneously implanted EMT-6 murine carcinoma.

Method

The biodistribution and toxicological profile of this porphyrin has been shown to be favourable for another bimodal radiotherapy technique, boron neutron-capture therapy. For the XRT studies, CuTCPBr was formulated in either 9% Cremophor® (BASF Corporation, Ludwigschafen, Germany) EL and 18% propylene glycol (9% CRM) or a revised formulation comprising 1% Cremophor ELP, 2% Tween 80® (JT Baker, Mansfield, MA), 5% ethanol and 2.2% PEG 400 (CTEP formulation), which would be more clinically acceptable than the original 9% CRM formulation. Using the 9% CRM formulation of CuTCPBr, doses of 100, 210 or 400 mg kg⁻¹ of body weight were used in combination with single doses of 25–35 Gy 100 kVp X-rays.

Results

While doses of 100 mg kg⁻¹ and 210 mg kg⁻¹ did not result in any significant enhancement of tumour response, the 400 mg kg⁻¹ dose did. A dose modification factor of 1.20±0.10 was obtained based on the comparison of doses that produced a 50% local tumour control probability. With the CTEP formulation of CuTCPBr, doses of 83 and 170 mg kg⁻¹ produced significant radiation enhancement, with dose modification factors based on the TCP₅₀ of 1.29±0.15 and 1.84±0.24, respectively.

Conclusion

CuTCPBr significantly enhanced the efficacy of XRT in the treatment of EMT-6 carcinomas in mice. The CTEP formulation showed a marked improvement, with over 9% CRM being associated with higher dose modification factors. Moreover, the radiation response in the skin was not enhanced.Porphyrins are used in the treatment of cancer, as photosensitisers in clinical photodynamic therapy (PDT) and as boron carriers in preclinical studies of boron neutron-capture therapy (BNCT) [1-4]. Both approaches use the porphyrin as part of bimodal therapy, in which the cell-killing chemical species are only formed when both the porphyrin and radiation are present in the form of light or thermal neutrons, respectively. Selectivity is attained because the porphryins predominantly localise in tumour tissue within the irradiated volume. Such a strategy can also be used with conventional X-ray therapy (XRT), by using a porphyrin with a different set of physicochemical requirements, while maintaining similar biological requirements, such as tumour selectivity and low toxicity. For example, haematoporphyrin, used for PDT, has been reported to have some activity in enhancing the effect of X-rays [5,6]. The porphyrin, verteporfin, has also been used in combination therapy involving both PDT and XRT [7]. Results from animal studies, based on the endpoint of tumour growth delay, suggested a synergistic rather than just an additive effect [7]. The manganese tetrapyridylporphyrins (known as mimetics of superoxide dismutase) have also been shown to increase tumour response to XRT [8,9]. They are believed to act by inhibiting tumour angiogenesis, which is activated by oxidative stress, a well-recognised occurrence after exposure to ionising radiation.The only porphyrin-like compound currently being clinically investigated as a radiation enhancement agent is an expanded porphyrin with gadolinium at the centre, known as gadolinium texaphyrin (Gd-Tex) or motexafin [10-12]. It has a high electron affinity with a relatively positive reduction potential, which is believed to be at least partially responsible for its effectiveness. It has been shown that electron-affinic aromatic compounds can act as oxygen mimetic sensitisers in hypoxic radioresistant cells, which are frequently found in malignant tissue [13,14]. Reactive oxygen species (ROS), comprising free radicals, peroxides and superoxides, are believed to be the active species created primarily from the radiolysis of water during exposure to ionising radiation. Although many potential XRT sensitisers that maximise the concentration of ROS have been studied in pre-clinical and clinical trials, none are used routinely in the clinic. Temozolomide and cetuximab have been used with radiation, but their function is primarily chemotherapeutic [15,16]. However, there is evidence that temozolomide will inhibit the repair of radiation-induced damage to DNA in the presence of the methylated version of the MGMT (O⁶-methylguanine–DNA methyltransferase) DNA-repair gene, which explains the greater efficacy of this drug/radiation combination in the treatment of glioblastoma multiforme [17].Copper (II) 2,3,7,8,12,13,17,18-octabromo-5,10,15,20-tetrakis(3-[1,2dicarba-closo-dodecarboranyl]methoxyphenyl)-porphyrin (CuTCPBr) (Figure 1) was initially synthesised as a boron carrier for use in BNCT. It has been shown to possess the biological properties needed for this treatment modality, i.e. high tumour boron localisation and low toxicity [18]. Moreover, besides having the necessary high boron content, it should also have a significantly higher electron affinity owing to the electron-withdrawing bromo groups on the macrocycle. To determine its electron affinity, redox potentials were measured and compared with similar copper brominated porphyrins.Open in a separate windowFigure 1Porphyrin structures of CuTCPBr, CuTPP and CuTPPBr₈. Closed circles represent C or CH and open circles represent BH in CuTCPBr.The purpose of this article is to study the biodistribution of CuTCPBr and to evaluate its therapeutic efficacy in combination with single doses of X-rays using the murine EMT-6 tumour model. Data for this porphyrin were acquired using direct-current plasma atomic emission spectroscopy (DCP-AES) to assay boron concentrations, since the boron and porphyrin are covalently linked. CuTCPBr is not water soluble and, therefore, requires formulation for in vivo studies. The first approach was to use the standard preclinical formulation used for lipophilic porphyrins, which has been adopted in the Medical Department, Brookhaven National Laboratory, and comprises 9% Cremophor® (BASF Corp., Ludwigschafen, Germany) EL and 18% propylene glycol (9% CRM formulation) with a CuTCPBr concentration of approximately 3.5 mg ml⁻¹ [4,19]. However, for clinical use, more concentrated solutions with significantly lower amounts of Cremophor are required. To this end, a formulation comprising 2% Cremophor ELP, 1% Tween 80® (JT Baker, Mansfield, MA), 5% ethanol and 2.2% PEG 400 (CTEP formulation), developed by Applied Analysis Ltd (Beverley, East Yorkshire, UK) was also used.     

National audit of citrate toxicity in plateletpheresis donors

Citrate toxicity complicating plateletpheresis is not uncommon. However, the scale and severity of the problem have never been formally addressed. In order to answer these questions we undertook a national audit of 13 070-platelet procedures throughout 17 apheresis centres in England over a 3-month period from 1 April to 30 June 2000. A standard form was distributed to each centre to record the symptoms/signs of citrate toxicity which were then graded (grades 1-5) according to their severity. The following variables were studied to determine whether they influenced the frequency and severity of citrate toxicity: 1. The type of manufacturer's cell separator used (Cobe Spectra, Haemonetics, Baxter Amicus and Trima). 2 The type of procedure: single needle, dual needle, single, double or triple dose. 3 The way in which donors were instructed to report symptoms of citrate toxicity. OUTCOME: Plateletpheresis is a relatively safe procedure provided that donors who experience severe reactions receive appropriate treatment. The incidence of severe citrate toxicity (0.03% procedures) is comparable to that of severe faints following whole blood donation, indicating a comparable margin of safety. Donors should be warned of the symptoms of citrate toxicity at their first attendance only. More frequent reminders encourage donors to over-report symptoms of mild citrate toxicity.     

Cement and Concrete Nanoscience and Nanotechnology

Concrete science is a multidisciplinary area of research where nanotechnology potentially offers the opportunity to enhance the understanding of concrete behavior, to engineer its properties and to lower production and ecological cost of construction materials. Recent work at the National Research Council Canada in the area of concrete materials research has shown the potential of improving concrete properties by modifying the structure of cement hydrates, addition of nanoparticles and nanotubes and controlling the delivery of admixtures. This article will focus on a review of these innovative achievements.