Biomedical subjects
Publications and source records attributed to W R Wilson.
We report a case of the first successful implantation of the HeartMate left ventricular assist system as a bridge to heart transplant in the state of Missouri. Indications, technique of insertion, patient selection, outcomes and future applications are discussed.
PURPOSE: 5,6-dimethylxanthenone-4-acetic acid (DMXAA) selectively damages tumor vasculature and is currently in clinical trial as an antitumor agent. Its ability to induce synthesis of tumor necrosis factor (TNF), and its apparent selectivity for poorly-perfused regions in tumors, suggests it possible use in combination with radiotherapy. This investigation examines activity of DMXAA as a radiation modifier using two murine tumors. METHODS AND MATERIALS: Tumor growth delay was evaluated using i.m. RIF-1 and MDAH-MCa-4 tumors irradiated in unanaesthetised, restrained mice (cobalt-60) using single dose or multiple fractions (8 x 2.5 Gy over 4 days) with DMXAA administered i.p. at various times in relation to irradiation. RESULTS: Administration of DMXAA (80 micromol/kg, i.p.) immediately after radiation resulted in a large increase in tumor growth delay, giving a radiation dose modifying factor of 2.3 for RIF-1 and 3.9 for MDAH-MCa-4. The combination was less active when radiation was given 1-4 h after DMXAA, but was highly active 12-48 h after DMXAA. At the latter times, clamping the tumor blood supply caused a large increase in radioresistance. These studies suggest that cells surviving DMXAA are hypoxic for only a short period. DMXAA increased overall growth delay when administered daily during fractionated irradiation, giving an approximately additive response. CONCLUSIONS: The marked synergy between DMXAA and single dose ionising radiation may reflect the complementarity of these agents at the microregional level, with DMXAA preferentially killing hypoxic cells in poorly perfused regions. Despite additional hypoxia shortly after DMXAA treatment, surviving cells appear to reoxygenate quickly which makes it feasible to use DMXAA before and during fractionated radiotherapy. The combination of fractionated radiation and DMXAA appears to be less effective than for single dose radiation (possibly because of the smaller contribution of hypoxia under these conditions), but may be therapeutically useful.
PURPOSE: Hypoxia-selective cytotoxic agents, like tirapazamine (TPZ), must diffuse considerable distances in tumors to reach their target cell population. This study uses a new three-dimensional tissue culture model, in which cells are grown as multicellular layers (MCL), to investigate whether metabolic consumption of TPZ is sufficiently rapid to compromise its extravascular diffusion in tumors. METHODS AND MATERIALS: V79-171b and MGH-U1 cells were grown as MCL to thicknesses of approximately 120 and 360 microm respectively. The extent of hypoxia in MCL, as assessed by EF5 binding, was modulated by altering gas-phase O2 content, and flux of TPZ through MCL was investigated by high-performance liquid chromatography (HPLC). Data were fitted to a diffusion-reaction mathematical model to determine the diffusion coefficient of TPZ in the MCL (DM) and the rate of its metabolic consumption under anoxia. These parameters were used to simulate TPZ transport in tumors. RESULTS: The flux of TPZ through well-oxygenated MCL (equilibrated with 95% O2) was well fitted as Fickian diffusion without reaction, with a D(M) of 7.4 x 10(-7) cm2s(-1) (12-fold lower than in culture medium) for V79 and 1.3 x 10(-6) cm2s(-1) for MGH-U1 MCL. Flux of TPZ was suppressed under anoxia, and fitting the data required inclusion of a reaction term with a rate constant for metabolic consumption of TPZ of 0.52 min(-1) for V79 and 0.31 min(-1) for MGH-U1 MCL. These transport parameters would translate into a 43% or 30% decrease respectively in TPZ exposure, as a result of drug metabolism, in the center of a slab of anoxic tissue 100 microm in thickness. CONCLUSIONS: MCL cultures provide an in vitro model for investigating the interaction between metabolic consumption and diffusion of bioreductive drugs. If rates of diffusion and metabolism similar to those measured in V79 and MGH-U1 MCL apply in tumors, then cells in large confluent regions of hypoxia would be partially protected by failure of TPZ penetration. Simulation of extravascular transport of TPZ-like bioreductive drugs demonstrates that the optimum metabolic rate constant is determined by two competing requirements: it should be high enough to ensure potent cytotoxicity under hypoxia, yet low enough that penetration is not severely compromised.
A four-step synthesis of 5-[N,N-bis(2-chloroethyl)amino]-1-methyl-2-nitroimidazole from 1-methyl-2-nitroimidazole is described. This compound showed similar hypoxia-selective cytotoxicity to the dinitrobenzamide mustard SN 23,862 in UV4 cells (ca. 40-fold), and superior selectivity (> 7-fold) in repair-competent AA8 cells.
New technology involving the use of high-frequency inductive power distribution (HID) has recently been developed for use in materials handling and personnel transfer. Sinusoidal magnetic fields at a frequency of 10 kHz with field intensities of approximately 0.2 mT are generated directly between the current-carrying coils of this equipment. Effects of 10 kHz magnetic fields on cell division, migration, and differentiation have never been previously investigated. To evaluate potential effects on these parameters, a rodent reproductive study was undertaken using Wistar rats. Exposures were at 0.095, 0.24, and 0.95 mT with a background exposure of 5-10 microT. Three sets of parental rats were exposed continuously for 20-23.5 h/day to the fields: maternal rats during gestation, paternal rats for at least 45 days prior to mating and maternal rats 1 month prior to mating. Exposure phases thus covered spermatogenesis, maturation of the ovum and ovulation, fertilization, implantation, embryogenesis, organogenesis, and maturation of the fetus immediately prior to parturition. In all experiments pregnancy outcome was assessed. These studies failed to demonstrate any reproductive toxicity resulting from maternal or fetal exposure during gestation or following paternal or maternal exposure for several weeks prior to mating. No quantitative or qualitative effects on spermatogenesis occurred after exposure, and no effects on the estrous cycle or ovulation could be demonstrably linked to the 10 kHz magnetic field exposure at 0.095, 0.25, or 0.95 mT. Where possible, parental clinical chemistry and hematology were also examined. As in mouse toxicology studies previously reported, minor differences were observed between control and treated groups. These were regarded as statistically, but not biologically, significant and could not categorically be attributed to magnetic field exposure.
PURPOSE: To determine the safety and efficacy of trabeculectomy with adjunctive mitomycin C in patients 17 years of age or younger, and to identify risk factors for failure of this surgical technique. METHODS: Retrospective review of consecutive cases of pediatric glaucoma that underwent mitomycin C augmented trabeculectomy between January 1991 and December 1995. Forty-nine patients (60 eyes) with a mean age of 7.6 years (range, 6 weeks to 17.6 years) were identified and followed up until repeat glaucoma surgery, or after a minimum of 6 months. Success was defined as intraocular pressure control of 22 mm Hg or less with or without topical glaucoma control medication, no evidence of glaucoma progression, no further glaucoma surgery necessary, and no visually devastating complication. RESULTS: Cumulative probabilities of success +/- SD for 49 eyes (one eye per patient) were 67% +/- 13% at 12 months and 59% +/- 15% at 24 months. Multivariate regression analysis yielded the following characteristics as significantly increased risk for failure: age of less than 1 year at time of surgery (risk ratio, 5.6; confidence interval, 2.1 to 14.7; P = .0005), and aphakia (risk ratio, 2.7; confidence interval, 1.1 to 6.9; P = .0364). Shallow anterior chamber (17 [28%] of 60 eyes) and serous choroidal detachment (13 [22%] of 60 eyes) were the most common complications. Four (11%) of 38 eyes with obtainable Snellen acuity were noted to have a decrease in best-corrected visual acuity of more than 2 Snellen lines or loss of light perception. In 5 (8%) of 60 eyes bleb-related endophthalmitis was noted. CONCLUSIONS: Trabeculectomy with adjunctive mitomycin C is generally effective for the treatment of pediatric glaucoma, especially in phakic children over 1 year of age. However, late-onset bleb-related endophthalmitis is a substantial risk in this patient population.
BACKGROUND: Implantable cardioverter-defibrillators have been infrequently used in children as therapy for resuscitated sudden death and syncope due to ventricular arrhythmias unresponsive to antiarrhythmics. METHODS: The medical records of 5 children with implantable cardioverter-defibrillators were retrospectively reviewed. All patients had experienced syncope and 3 (60%) an out-of-hospital cardiac arrest. Underlying pathology included hypertrophic cardiomyopathy in 2, long QT syndrome in 2, and ventricular arrhythmia after remote repair of congenital heart disease in 1. Open thoracotomy with epicardial lead placement and transvenous endocardial approaches were used. RESULTS: There was no early or late mortality in the 5 pediatric patients undergoing implantable cardioverter-defibrillator placement. Postoperative complications occurred more frequently when open thoracotomy was used for placement. At mean follow-up of 34 months, 4 of the 5 (80%) have received shocks. CONCLUSIONS: Implantable cardioverter-defibrillator is a safe and reliable therapy for children with resuscitated sudden death and syncope due to ventricular tachycardia unresponsive to antiarrhythmics. Transvenous lead placement lowers morbidity and hospital length of stay.
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Streptococci cause a wide range of infections in humans including respiratory tract infections, endocarditis, meningitis, bacteremias, and skin and soft tissue lesions. Mutations in the penicillin binding proteins target sites in these organisms have recently caused resistance to penicillins and cephalosporins. The passage of resistant genetic material from one streptococcal species to another has been recognized as one of the mechanisms by which this resistance has occurred and spread. Such resistance has been a particular problem in Streptococcus pneumoniae and viridans group streptococci with penicillin resistance levels in excess of 25%, now common in both groups of organisms worldwide. Fourth-generation cephalosporins, with their enhanced antibacterial activity against Gram-positive organisms (cefpirome > cefepime) and their increased stability to the beta-lactamases produced by many bacterial species, offer a new option for the treatment of potentially life-threatening infections such as pneumococcal pneumonia and meningitis with or without bacteremia. Clinical trials are currently in place to evaluate the role of these agents in these, and other, indications of Gram-positive infections. Prior studies of cefpirome therapy for infections caused by Streptococcus spp. were successful, and recent expanded in vitro investigations profess a future for expanded use of cefpirome to treat infections produced by several Gram-positive species.
For many years, the third-generation cephalosporins have been utilized in the treatment of a broad range of infections. The reduction in the efficacy of these antimicrobials in hospitals seen in recent years is a result of the development of resistance to these compounds. This resistance, caused in part by the production of beta-lactamases which can spread from species to species, has intensified the search for alternative agents. Compared with third-generation cephalosporins, fourth-generation cephalosporins possess enhanced activity against Gram-positive organisms, excellent penetration into Gram-negative bacilli, and are more stable against the activity of some beta-lactamases. Accordingly, fourth-generation cephalosporins are attractive candidates to replace third-generation cephalosporins for the treatment of many nosocomial infections.
The tumour blood flow inhibitor 5,6-dimethylxanthenone-4-acetic acid (DMXAA) causes dramatic haemorrhagic necrosis in murine tumours, but activity is seen only at doses close to the toxic limit. This study investigates two approaches for increasing the therapeutic ratio of DMXAA. The first approach combines DMXAA with a second tumour blood flow inhibitor, 5-hydroxytryptamine (5-HT). Co-administration of 5-HT (700 micromol kg(-1)) to C3H mice caused marked enhancement of DMXAA effects against MDAH-MCa-4 tumours, with dose-modifying factors (DMFs) of >3 for blood flow inhibition (at 4 h), 2.3 for necrosis (at 12 h) and 2.0 for growth delay, without compromising the maximum tolerated dose of DMXAA (90 micromol kg(-1)). The data are consistent with ischaemic injury to the tumour being the major mechanism of anti-tumour activity. The second approach combines DMXAA (+/- 5-HT) with hypoxia-selective bioreductive drugs. Anti-tumour activity of all three bioreductive drugs tested (tirapazamine, CI-1010, SN 23816) was strongly potentiated by DMXAA, suggesting that there is a population of reversibly hypoxic tumour cells after DMXAA treatment. Co-administration of 5-HT further potentiated anti-tumour activity, but also increased host toxicity of tirapazamine and CI-1010 so that little therapeutic benefit was achieved. In contrast, the host toxicity of the dinitrobenzamide mustard SN 23816 was only slightly increased by DMXAA/5-HT, whereas the tumour growth delay at the maximum tolerated dose of SN 23816 was increased from 3.5 to 26.5 days. This study demonstrates that 5-HT and/or bioreductive drugs can improve the therapeutic activity of DMXAA in mice, and that with SN 23816 both approaches can be used together to provide considerably enhanced anti-tumour activity.
The purpose of this case report is to familiarize the sinus surgeon with the possibility of the rapid development of internal carotid artery aneuryams from fungal infections of the sphenoid sinuses. A renal dialysis patient with progressive loss of vision was treated with high doses of steroids for the presumed diagnosis of temporal arteritis. Subsequent work-up included a magnetic resonance arteriogram (MRA) and computed tomography (CT) with contrast that failed to demonstrate aneurysmal changes of the carotid arteries but suggested the presence of a mycotic infection of the sphenoid sinuses. During a sphenoidotomy two days later, in addition to the anticipated aspergillus infection of the sinuses, an aneurysm extending from the left internal carotid artery into the sphenoid sinus was encountered. An emergency arteriogram immediately following the surgery revealed a second newly developed large mycotic aneurysm of the right internal carotid artery filling the right sphenoid sinus as well. This case report documents the rapidity with which mycotic aneurysms can develop from a sphenoid sinus infection secondary to aspergillosis in an immunocompromised host.
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This randomized, multicenter, open-label study compared the efficacy and safety of monotherapy with 2 g of intravenous ceftriaxone once daily for 4 weeks with those of combination therapy with 2 g of intravenous ceftriaxone and 3 mg of intravenous gentamicin/kg once daily for 2 weeks as therapy for endocarditis due to penicillin-susceptible streptococci. Sixty-one patients were enrolled in the study. Clinical cure was observed for 51 evaluable patients both at termination of therapy and at the 3-month follow-up: 25 (96.2%) of 26 monotherapy recipients and 24 (96%) of 25 combination therapy recipients. Of the 23 patients in each treatment group who were microbiologically evaluable, 22 (95.7%) in each group were considered cured. No patient had evidence of relapse. Fourteen patients (27.5%) required cardiac surgery after initiation of treatment, including five monotherapy recipients and nine combination therapy recipients. Adverse effects were minimal in both treatment groups. We conclude that 2 g of ceftriaxone once daily for 4 weeks and 2 g of ceftriaxone in combination with 3 mg of gentamicin/kg once daily for 2 weeks are both effective and safe for the treatment of streptococcal endocarditis.
We performed a comprehensive analysis of the molecular, serological, and clinical features of 16 consecutive cases of invasive streptococcal disease (ISD). The majority of cases were linked to two group A streptococcus (GAS) clones closely related by pulsed-field gel electrophoresis (PFGE) and designated as PFGE-1 and PFGE-1.1. These clones, serotyped as M-3, T-3/B3264, carried an allelic variant of the gene that encodes pyrogenic exotoxin A (speA3) and the gene that encodes streptococcal superantigen (SSA) but different emm alleles that encode M-protein. The characteristics and clinical features of patients were similar to those described in previous reports, regardless of the responsible GAS clone. However, worse clinical outcomes (shock and death) were more frequent when patients infected with PFGE1/1.1 clones were considered as a group and compared with all other patients as a group. One striking feature in some patients with deep tissue infection was a lack of inflammatory cells despite the presence of numerous streptococci. An evaluation of PFGE profiles of GAS isolated elsewhere demonstrated that the PFGE-1 clone has caused invasive disease in other locations in the United States and in Japan.
Systemic anti-proliferative agents (cytotoxins) have been the most successful single design concept for anti-cancer drugs. However, they have inherent limitations (they target dividing cells rather than cancer cells) which limit their clinical efficacy, especially toward the more slowly-growing solid tumours. New concepts are required to improve the selectivity of their killing of tumour cells. One possibility is the use of prodrugs which can be activated selectively in tumour tissue. Several potential mechanisms for this are being explored, including tumour hypoxia, low extracellular pH, therapeutic radiation and tumour-specific endogenous or exogenous enzymes. In the last approach the exogenous enzyme can be delivered by attachment to monoclonal antibodies (ADEPT) or as DNA constructs containing the corresponding gene (GDEPT). A limitation of both approaches is that only a small proportion of the tumour cells become activation-competent, but this can be substantially overcome by the design of appropriate prodrugs capable of killing activation-incompetent cells via a bystander effect. We have proposed a modular approach to prodrug design in which a trigger unit determines tumour selectivity and an effector unit achieves the desired level of killing of cells when the trigger is activated. For ADEPT and GDEPT prodrugs the primary requirement of the trigger is efficient and selective activation by the appropriate enzyme; the released effector must be a potent, diffusible cytotoxin which fully exploits the small proportion of cells capable of activating the prodrug. A wide variety of chemistries has been used, but many of the existing effectors do not have all of these properties. We report work on two types of cytotoxin derived from very potent anti-tumour antibiotics (enediynes and amino-seco-cyclopropylindolines) as effectors in prodrugs for ADEPT and GDEPT applications.
Nitroarylmethyl quaternary ammonium nitrogen mustards are bioreductive drugs designed to release mechlorethamine, when reduced metabolically, via fragmentation of the initial nitro radical anion to a benzylic-type radical. This proposed mechanism (termed Type I) is analogous to the well-known reductive fragmentation of 2-nitrobenzyl halides. The lead nitroarylmethyl quaternary mustard SN 25246 (NSC 656581), which contains a 2-nitrobenzyl electron acceptor, was shown previously to release mechlorethamine in hypoxic cell cultures and to be a highly selective hypoxic cytotoxin. In the present work the mechanism of reductive release of mechlorethamine from nitroarylmethyl quaternary prodrugs was investigated by steady-state radiolysis with product analysis by high-performance liquid chromatography. SN 25246 releases mechlorethamine in high yield upon reduction, but several reducing equivalents are required (Type II mechanisms). Investigation of other nitroarylmethyl units identified two heterocyclic analogues, the 1-methyl-4-nitro-5-imidazolyl derivative SN 25341 and the 1-methyl-5-nitro-2-pyrrolyl derivative SN 26581, which have a reduction stoichiometry of about one reducing equivalent and which release mechlorethamine efficiently. The other products from reduction of SN 25341 are also consistent with Type I fragmentation, via intramolecular electron transfer, to give the 1-methyl-4-nitroimidazole-5-CH2. radical. The sensitivity of the 4-nitroimidazole and 5-nitropyrrole nitroarylmethyl quaternary mustards to Type I reductive fragmentation suggests that these electron acceptor units may be well suited to development of prodrugs which release tertiary amine effectors after metabolic or radiolytic reduction in hypoxic regions of tumors.