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Damage control resuscitation and early thoracotomy have been used to increase survival after severe injury in combat. There has been a renewed interest in resuscitative endovascular balloon occlusion of the aorta (REBOA) in both civilian and military medical practices. REBOA may result in visceral and limb ischaemia that could be harmful if use of REBOA is premature or prolonged. The purpose of this paper is to align our experience of combat injuries with the known capability of REBOA to suggest an implementation strategy for the use of REBOA in combat care. It may replace the resuscitative effect of thoracotomy; can provide haemostasis of non-compressible torso injuries such as the junctional and pelvic haemorrhage caused by improvised explosive devices. However, prehospital use of REBOA must be in the context of an overall surgical plan and should be restricted to deployment in the distal aorta. Although REBOA is technically easier than a thoracotomy, it requires operator training and skill to add to the beneficial effect of damage control resuscitation and surgery.
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BACKGROUND: In a care under fire situation, a first line response to haemorrhage is to apply a tourniquet and return fire. However, there is little understanding of how tourniquets and other haemorrhage control devices impact marksmanship. METHODS: We compared the impact of the iTClamp and the Combat Application Tourniquet (CAT) on marksmanship. Following randomisation (iTClamp or CAT), trained marksmen fired an AR15 at a scaled silhouette target in prone unsupported position (shooting task). Subjects then attempted to complete the shooting task at 5, 10, 15, 30 and 60â min post-haemorrhage control device application. RESULTS: All of the clamp groups (n=7) completed the 60â min shooting task. Five CAT groups (n=6) completed the 5â min shooting task and one completed the 5 and 10â min shooting task before withdrawing. Four CAT groups were stopped due to unsafe handling; two stopped due to pain. When examining hits on mass (HOM) for the entire shooting task, there was no significant difference between tourniquet and iTClamp HOM at 5â min (p=0.18). However, there was a significant difference at 10â min, p=0.003 with tourniquet having significantly fewer HOM (1.7±2.7 HOM) than the iTClamp (8.1±3.3 HOM) group. The total effective HOM for the entire 60â min shooting task showed that the iTClamp group achieved significantly (p=0.001) more HOM than the tourniquet group. Over the entire 60â min shooting exercise, the iTClamp group achieved a median 72% (52/72) of available HOM while the tourniquet group obtained 19% (14/72). CONCLUSIONS: Application of a tourniquet to the dominant arm negates effective return of fire in a care under fire setting after a brief time window. Haemorrhage control devices that preserve function may have a role in care under fire situations, as preserving effectiveness in returning fire has obvious operational merits.
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Desenho de Equipamento , Técnicas Hemostáticas , Análise e Desempenho de Tarefas , Torniquetes , Adulto , Feminino , Voluntários Saudáveis , Hemorragia/terapia , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Decreased plasma fibrinogen concentration shortly after injury is associated with higher blood transfusion needs and mortality. In North America and the UK, cryoprecipitate transfusion is the standard-of-care for fibrinogen supplementation during acute haemorrhage, which often occurs late during trauma resuscitation. Alternatively, fibrinogen concentrate (FC) can be beneficial in trauma resuscitation. However, the feasibility of its early infusion, efficacy and safety remain undetermined. The objective of this trial was to evaluate the feasibility, effect on clinical and laboratory outcomes and complications of early infusion of FC in trauma. METHODS: Fifty hypotensive (systolic arterial pressure ≤100 mm Hg) adult patients requiring blood transfusion were randomly assigned to either 6 g of FC or placebo, between Oct 2014 and Nov 2015 at a tertiary trauma centre. The primary outcome, feasibility, was assessed by the proportion of patients receiving the intervention (FC or placebo) within one h of hospital arrival. Plasma fibrinogen concentration was measured, and 28-day mortality and incidence of thromboembolic events were assessed. RESULTS: Overall, 96% (43/45) [95% CI 86-99%] of patients received the intervention within one h; 95% and 96% in the FC and placebo groups, respectively (P=1.00). Plasma fibrinogen concentrations remained higher in the FC group up to 12 h after admission with the largest difference at three h (2.9 mg dL - 1 vs. 1.8 mg dL - 1; P<0.01). The 28-day mortality and thromboembolic complications were similar between groups. CONCLUSIONS: Early infusion of FC is feasible and increases plasma fibrinogen concentration during trauma resuscitation. Larger trials are justified.
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Fibrinogênio/uso terapêutico , Ressuscitação/métodos , Ferimentos e Lesões/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Método Duplo-Cego , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto JovemRESUMO
INTRODUCTION: The COVID-19 pandemic has posed major challenges for infection control within training centres, both civilian and military. Here we present a narrative review of an outbreak that occurred at the Royal Military Academy Sandhurst (RMAS) in January-March 2021, in the context of the circulating, highly transmissible SARS-CoV-2 variant B.1.1.7. METHODS: Testing for SARS-CoV-2 was performed using a combination of reverse transcriptase PCR and Lateral Flow Devices (LFDs). Testing and isolation procedures were conducted in line with a pre-established symptom stratification system. Genomic sequencing was performed on 10 sample isolates. RESULTS: By the end of the outbreak, 185 cases (153 Officer Cadets, 32 permanent staff) had contracted confirmed COVID-19. This represented 15% of the total RMAS population. This resulted in 0 deaths and 0 hospitalisations, but due to necessary isolation procedures did represent an estimated 12 959 person-days of lost training. 9 of 10 (90%) of sequenced isolates had a reportable lineage. All of those reported were found to be the Alpha lineage B.1.1.7. CONCLUSIONS: We discuss the key lessons learnt from the after-action review by the Incident Management Team. These include the importance of multidisciplinary working, the utility of sync matrices to monitor outbreaks in real time, issues around Officer Cadets reporting symptoms, timing of high-risk training activities, infrastructure and use of LFDs. COVID-19 represents a vital learning opportunity to minimise the impact of potential future pandemics, which may produce considerably higher morbidity and mortality in military populations.
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COVID-19 , Militares , Humanos , COVID-19/epidemiologia , SARS-CoV-2 , Pandemias , Surtos de DoençasRESUMO
Previous studies have demonstrated that the perceived direction of motion of a visual stimulus can be decoded from the pattern of functional magnetic resonance imaging (fMRI) responses in occipital cortex using multivariate analysis methods (Kamitani and Tong, 2006). One possible mechanism for this is a difference in the sampling of direction selective cortical columns between voxels, implying that information at a level smaller than the voxel size might be accessible with fMRI. Alternatively, multivariate analysis methods might be driven by the organization of neurons into clusters or even orderly maps at a much larger scale. To assess the possible sources of the direction selectivity observed in fMRI data, we tested how classification accuracy varied across different visual areas and subsets of voxels for classification of motion-direction. To enable high spatial resolution functional MRI measurements (1.5mm isotropic voxels), data were collected at 7T. To test whether information about the direction of motion is represented at the scale of retinotopic maps, we looked at classification performance after combining data across different voxels within visual areas (V1-3 and MT+/V5) before training the multivariate classifier. A recent study has shown that orientation biases in V1 are both necessary and sufficient to explain classification of stimulus orientation (Freeman et al., 2011). Here, we combined voxels with similar visual field preference as determined in separate retinotopy measurements and observed that classification accuracy was preserved when averaging in this 'retinotopically restricted' way, compared to random averaging of voxels. This insensitivity to averaging of voxels (with similar visual angle preference) across substantial distances in cortical space suggests that there are large-scale biases at the level of retinotopic maps underlying our ability to classify direction of motion.
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Mapeamento Encefálico/métodos , Interpretação de Imagem Assistida por Computador/métodos , Percepção de Movimento/fisiologia , Córtex Visual/fisiologia , Humanos , Imageamento por Ressonância Magnética , Estimulação LuminosaRESUMO
Tactical combat casualty care and the application of extremity tourniquets have saved lives in combat. In the modern combat environment junctional injuries are common and difficult to treat. Recently, junctional tourniquets have emerged as a potential solution to this problem. Junctional tourniquets can be used as an adjunct to persistent haemorrhage despite application of conventional tourniquets or in the persistently hypotensive casualty. Surgeons must have an approach to receiving patients with junctional tourniquets in place in the operating room. The algorithms presented allow for an evidence-based and command-driven implantation of junctional tourniquets as part of tactical combat casualty care.
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Extremidades/cirurgia , Hemorragia/terapia , Guerra/tendências , Extremidades/lesões , Hemorragia/classificação , Hemorragia/prevenção & controle , Humanos , Medicina Militar/métodos , Salas Cirúrgicas/métodos , Salas Cirúrgicas/tendências , Torniquetes/normasRESUMO
BACKGROUND: COVID-19 has the potential to cause outbreaks in hospitals. Given the comorbid and elderly cohort of patients hospitalized, hospital-acquired COVID-19 infection is often fatal. Pathogen genome sequencing is becoming increasingly important in infection prevention and control (IPC). AIM: To inform the understanding of in-hospital SARS-CoV-2 transmission in order to improve IPC practices and to inform the future development of virological testing for IPC. METHODS: Patients detected COVID-19 positive by polymerase chain reaction on Ward A in April and May 2020 were included with contact tracing to identify other potential cases. Genome sequencing was undertaken for a subgroup of cases. Epidemiological, genomic, and cluster analyses were performed to describe the epidemiology and to identify factors contributing to the outbreak. FINDINGS: Fourteen cases were identified on Ward A. Contact tracing identified 16 further patient cases; in addition, eight healthcare workers (HCWs) were identified as being COVID-19 positive through a round of asymptomatic testing. Genome sequencing of 16 of these cases identified viral genomes differing by two single nucleotide polymorphisms or fewer, with further cluster analysis identifying two groups of infection (a five-person group and a six-person group). CONCLUSION: Despite the temporal relationship of cases, genome sequencing identified that not all cases shared transmission events. However, 11 samples were found to be closely related and these likely represented in-hospital transmission. This included three HCWs, thereby confirming transmission between patients and HCWs.
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The global threat of antimicrobial resistance is driving an urgent need for novel antimicrobial strategies. Functional surfaces are essential to prevent spreading of infection and reduce surface contamination. In this study we have fabricated and characterized multiscale-functional nanotopographies with three levels of functionalization: (1) nanostructure topography in the form of silicon nanowires, (2) covalent chemical modification with (3-aminopropyl)triethoxysilane, and (3) incorporation of chlorhexidine digluconate. Cell viability assays were carried out on two model microorganisms E. coli and S. aureus over these nanotopographic surfaces. Using SEM we have identified two growth modes producing distinctive multicellular structures, i.e. in plane growth for E. coli and out of plane growth for S. aureus. We have also shown that these chemically modified SiNWs arrays are effective in reducing the number of planktonic and surface-attached microorganisms.
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In a questionnaire-based survey of 285 randomly selected diabetic patients, diarrhea was found to occur in 8%; this was found to be similar to that in 150 nondiabetic control patients attending other medical clinics (8%). When the diabetic patients were divided into separate therapeutic groups, metformin-treated (with or without sulfonylureas) patients had a markedly greater prevalence of diarrhea (20%) than those not on this drug (6%). A majority of patients with metformin-associated diarrhea had soiling of clothes as a problem, while at least two complained of frank loss of control over their anal sphincter. These patients did not have autonomic neuropathy, and in all who stopped this drug, diarrhea settled within 2-5 days. Only 6% of insulin-dependent diabetic individuals (IDD) had diarrhea, one of whom had explosive nocturnal stools with incontinence and features diagnostic of autonomic neuropathy. Metformin is by far the commonest cause of diarrhea and incontinence in our diabetic clinic, where it is used routinely. In contrast, diarrhea due to autonomic neuropathy is rare.
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Diabetes Mellitus Tipo 2/tratamento farmacológico , Diarreia/induzido quimicamente , Metformina/efeitos adversos , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 2/complicações , Diarreia/etiologia , Humanos , Metformina/uso terapêutico , Compostos de Sulfonilureia/uso terapêuticoRESUMO
The presence of neuropsychological disturbances in HIV-positive, pre-symptomatic individuals is a controversial issue. Neuroimaging studies have not shown brain atrophy or hyperintensity in the white matter, whereas proton magnetic resonance spectroscopy has revealed some abnormality of cerebral biochemistry. Using an antibody to beta-amyloid precursor protein (beta-APP), we previously demonstrated frequent and widespread axonal changes in the brains of AIDS patients. In this study, we extended the use of beta-APP to asymptomatic patients in order to establish a possible morphological correlation with neuropsychological disorders. Brain samples from 29 patients were examined. Results showed bundles of beta-APP-positive axons in 8/29 cases (27%). The changes, seen in both superficial and deep white matter, were either focal or diffuse, could not be visualized by silver or ubiquitin stains, and did not coexist with any change in distribution or morphology of astrocytes and microglial cells. We conclude that in HIV-positive asymptomatic individuals, axonal changes: (a) may be related to the state of immune activation with consequent presence of toxic substances, including cytokines, observed in these patients; (b) may represent mild changes that could undergo repair, unless other pathological events, such as the supervening of the AIDS stage and the specific encephalitis, make them permanent.
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Precursor de Proteína beta-Amiloide/metabolismo , Axônios/metabolismo , Axônios/patologia , Soropositividade para HIV/metabolismo , Soropositividade para HIV/patologia , Encéfalo/metabolismo , Encéfalo/patologia , DNA Viral/metabolismo , Soropositividade para HIV/genética , HIV-1/genética , Humanos , Imuno-Histoquímica , Reação em Cadeia da Polimerase , Distribuição TecidualRESUMO
Major depression with psychotic features, dementia, and focal neurologic abnormalities appeared in a Haitian man without AIDS or other syndromes of immune compromise. Neurologic evaluation, including brain biopsy, was nondiagnostic, but CSF culture revealed human immunodeficiency virus (HIV).
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Síndrome da Imunodeficiência Adquirida/diagnóstico , Doenças do Sistema Nervoso Central/diagnóstico , Demência/diagnóstico , Síndrome da Imunodeficiência Adquirida/líquido cefalorraquidiano , Síndrome da Imunodeficiência Adquirida/microbiologia , Adulto , Doenças do Sistema Nervoso Central/líquido cefalorraquidiano , Doenças do Sistema Nervoso Central/microbiologia , Demência/líquido cefalorraquidiano , HIV/isolamento & purificação , Humanos , MasculinoRESUMO
Caenorhabditis elegans possesses 22 FMRFamide-like peptide (flp) genes predicted to encode 60 different FMRFamide-related peptides with a range of C-terminal signatures. Peptides from five flp genes (1, 6, 8, 9 and 14) are known to modulate the ovijector of Ascaris suum in vitro. This study examines the physiological effects of peptides from the remaining 17 flp genes such that the variety of FMRFamide-related peptide-induced ovijector response types can be delineated. Five categories of response were identified according to the pattern of changes in contractile behaviour and baseline tension. Peptides encoded on 16 flp genes (1, 2, 3, 4, 6, 7, 9, 10, 11, 12, 13, 14, 15, 16, 17 and 20) had qualitatively similar inhibitory (response type 1) actions, with the lowest activity thresholds (1 nM) recorded for peptides with FIRFamide or FLRFamide C-terminal signatures. Peptides encoded on four flp genes (2, 18, 19 and 21), and on the A. suum afp-1 gene, had excitatory actions on the ovijector (response type 2), with PGVLRFamides having the lowest activity threshold (1 nM). An flp-2 peptide (LRGEPIRFamide) induced a transient contraction of the ovijector (activity threshold, 10nM) that was designated response type 3. Response type 4 comprised a transient contraction followed by an extended period of inactivity and was observed with peptides encoded on flp-5 (AGAKFIRFamide, APKPKFIRFamide), flp-8 (KNEFIRFamide) and flp-22 (SPSAKWMRFamide). SPSAKWMRFamide was the most potent peptide tested with an activity threshold of 0.1 nM. A single peptide (AMRNALVRFamide; activity threshold 0.1 microM), encoded on flp-11, induced response type 5, a shortening of the ovijector coupled with an increase in contraction frequency. Although most flp genes encode structurally related peptides that trigger one of the five ovijector response types, flp-2 and flp-11 co-encode FMRFamide-related peptides that induce distinct responses. Within the ovijector of A. suum FaRPs play a complex role involving at least five receptor subtypes or signalling pathways.
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Ascaris suum/efeitos dos fármacos , Caenorhabditis elegans/química , FMRFamida/farmacologia , Genitália Feminina/efeitos dos fármacos , Animais , Ascaris suum/fisiologia , Caenorhabditis elegans/genética , Relação Dose-Resposta a Droga , FMRFamida/química , FMRFamida/genética , Feminino , Genes de Helmintos , Genitália Feminina/fisiologia , Contração Muscular/efeitos dos fármacos , Contração Muscular/fisiologia , Suínos/parasitologiaRESUMO
A 30-year-old woman with panic disorder and phobic avoidance responded partially to treatment with alprazolam but recovered fully while receiving clonazepam, which blocked her panic attacks and anticipatory anxiety. Before treatment, the patient underwent a carbon dioxide inhalation test as a challenge and sustained a full-featured panic attack. After clonazepam therapy and retesting under identical conditions, no panic attack was reported. This is the first report of provoked panic blocked by clonazepam, a putative, clinically effective antipanic agent.
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Transtornos de Ansiedade/tratamento farmacológico , Benzodiazepinonas/uso terapêutico , Dióxido de Carbono/farmacologia , Clonazepam/uso terapêutico , Medo/efeitos dos fármacos , Pânico/efeitos dos fármacos , Adulto , Alprazolam , Transtornos de Ansiedade/induzido quimicamente , Benzodiazepinas/uso terapêutico , Dióxido de Carbono/antagonistas & inibidores , Clonazepam/farmacologia , Feminino , HumanosRESUMO
Serum samples obtained from 20 insulin-dependent diabetics (IDD), 23 non-insulin-dependent diabetics (NIDD) and 30 controls were assayed for their pancreatic lipase activity, immunoreactive trypsin concentration and glycosylated haemoglobin (HbA1) respectively. The distribution of serum pancreatic lipase activity in normal subjects and diabetics was nonparametric. The median serum lipase activity in IDDs (86 U/l) was significantly lower that that in controls (131 U/l, p less than 0.002) and NIDDs (126 U/l, p less than 0.001). There was a significant correlation between serum pancreatic lipase activity and serum IRT concentration (r = 0.65, p less than 0.001). Neither pancreatic lipase activity nor IRT was related to HbA1 concentrations. These data show for the first time that serum pancreatic lipase activity is diminished in IDDs.
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Diabetes Mellitus/enzimologia , Lipase/sangue , Pâncreas/enzimologia , Diabetes Mellitus/tratamento farmacológico , Humanos , Insulina/uso terapêutico , Tripsina/sangueRESUMO
An investigation of serum immunoreactive trypsin concentration and pancreatic isoamylase activity in patients with diabetes mellitus has shown that exocrine pancreatic deficit is maximal in insulin dependent diabetics, intermediate in those controlled with sulphonylureas, and absent in patients controlled with biguanides or diet or both. A significant correlation between the serum concentrations of both these pancreatic enzymes and C peptide was found. Serum pancreatic enzyme concentrations were not related to glycosylated haemoglobin concentrations, the dosage of insulin, or the age of onset of diabetes. The concentration of immunoreactive trypsin was found to be low in most of the insulin dependent diabetics in whom this enzyme was measured at the time of the clinical onset of diabetes. Thus exocrine pancreatic deficit in diabetes closely parallels the endocrine beta cell deficit and occurs concurrently with, or antedates, the clinical presentation of type I diabetes. It is therefore possible that in type I diabetes similar mechanisms are entailed in the pathogenesis of impaired endocrine and exocrine pancreatic function.
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Diabetes Mellitus Tipo 1/fisiopatologia , Pâncreas/fisiopatologia , Biguanidas/uso terapêutico , Peptídeo C/sangue , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/metabolismo , Dieta para Diabéticos , Hemoglobina A/metabolismo , Humanos , Isoamilase/metabolismo , Compostos de Sulfonilureia/uso terapêutico , Tripsina/sangueRESUMO
We tested the ventilatory and anxiety response to hypercapneic (CO2) challenge in women with panic disorder as well as in normal women in the premenstrual phase and mid-points of their menstrual cycles. Panic disorder patients were challenged on two occasions, each time while in the premenstrual phase of the menstrual cycle, receiving an open trial of alprazolam through the intervening 8 weeks between tests. This study confirms previous reports indicating increased sensitivity to CO2 in patients with panic disorder and that this sensitivity can be attenuated by treatment. We found a significant decrease in the ventilatory response of panic disorder patients comparing pre- and post-therapy. We also observed that normal females, while in the premenstrual phase of their menstrual cycle, have a heightened anxiety response to CO2 challenge.
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Alprazolam/uso terapêutico , Dióxido de Carbono , Ciclo Menstrual/fisiologia , Transtorno de Pânico/tratamento farmacológico , Adulto , Nível de Alerta/efeitos dos fármacos , Nível de Alerta/fisiologia , Dióxido de Carbono/sangue , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Ciclo Menstrual/efeitos dos fármacos , Transtorno de Pânico/diagnóstico , Transtorno de Pânico/fisiopatologiaRESUMO
Approximately 30% of a breeding colony of Sprague-Dawley rats homozygous for an autosomal recessive mutation mf ("mutilated foot") associated with a peripheral sensory neuropathy have been found unexpectedly to suffer spontaneous epileptiform attacks. Seizures ranged from brief episodes of compulsive running to tonic-clonic convulsions lasting for up to 30 s, recurring at intervals of hours or days. EEG recordings during seizures showed high-voltage 8-10 Hz spike trains that abated over the ensuing 1-2 min. Interictal records were usually normal. Twice-daily kindling of the amygdala (200 microA sinewave for 1.0 s) was unexpectedly ineffective. Most of the rats that had suffered spontaneous seizures failed to develop kindled afterdischarges, even after 30 kindling stimulations. Other mf rats developed prolonged high-amplitude kindled afterdischarges that were arrested at stage 2 and failed to evolve into convulsive seizures. Hippocampal dentate granule cells of kindled mf rats, stained for zinc by Timm's method, showed significantly less mossy fibre sprouting than wild-type Sprague-Dawley rats after the same number of kindled afterdischarges. A minority of the mf rats tested (2 of 14) kindled normally. Auditory stimulation (n = 23) or stroboscopic flicker (n = 14) failed to elicit seizures or running fits in any mf rat. Peripheral neuropathy corresponding to that in the mf rat, with resistance to kindling and diminished mossy fibre sprouting, have also been reported in transgenic mice with defective p75NGFR neurotrophin receptors. A homologous genetic defect in the rat could account for most of the features of the mf phenotype.
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Excitação Neurológica/genética , Convulsões/genética , Estimulação Acústica , Animais , Comportamento Animal/fisiologia , Encéfalo/patologia , Eletrodos Implantados , Eletroencefalografia , Hipocampo/patologia , Excitação Neurológica/fisiologia , Fibras Musgosas Hipocampais/fisiologia , Mutação , Estimulação Luminosa , Ratos , Ratos Sprague-Dawley , Convulsões/patologia , Convulsões/psicologiaRESUMO
To describe the current understanding of suicide risk among persons with human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS), we reviewed published reports on suicidal ideation, attempted suicide, and suicide in the HIV/AIDS population. We also drew on our own clinical experience. Suicidal ideation, attempted suicide, and suicide occur at a higher rate across the spectrum of patients with HIV infection than in the general population. Individuals with HIV and AIDS are subject to disease-specific stressors and to a greater number of general suicide risk factors. The assessment of suicide risk in these patients involves a careful exploration of these vulnerabilities.
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Síndrome da Imunodeficiência Adquirida/mortalidade , Infecções por HIV/mortalidade , Suicídio/estatística & dados numéricos , Síndrome da Imunodeficiência Adquirida/psicologia , Adulto , Causas de Morte , Feminino , Infecções por HIV/psicologia , Humanos , Masculino , Pessoa de Meia-Idade , Risco , Papel do Doente , Suicídio/psicologia , Tentativa de Suicídio/psicologia , Tentativa de Suicídio/estatística & dados numéricosRESUMO
The microsomal N-oxidation of phentermine (Ia) to N-hydroxyphentermine (Ib) and to alpha,alpha-dimethyl-alpha-nitroso-beta-phenylethane (Ic was investigated. Maximum activities were obtained with microsomal (9000 g supernatant and microsomes) fractions of rabbit liver in the presence of an NADPH generating system. Incubation of Ia with hepatic washed microsomes from a phenobarbitone pretreated rabbit increased the formation of Ib and decreased that of Ic but the total amount of N-oxidized metabolites (i.e. Ib + Ic) was not affected. The ratio of the metabolically produced Ic to Ib but not the total amount of N-oxygenated metabolites varied greatly depending of the liver microsomal fractions used in the incubation mixtures of Ia; more Ib was produced from Ia using 9000 g supernatant and conversely, more Ic was formed using the washed microsomes of the same liver. The nitroso compound (Ic) was metabolically reduced to Ib and Ib to Ia by the hepatic 9000 g supernatant and soluble fraction; under the same conditions, washed microsomes had only limited reductive properties towards Ic and Ib. N-Hydroxyphentermine (Ib) was not metabolically oxidized to Ic when incubated with washed microsomes from rabbit liver. The use of known carbon-oxidation inhibitors showed that cytochrome P-450 is not involved in the incorporation of oxygen at the nitrogen centre of Ia. The metabolic characteristics and kinetic behavior of the microsomal N-oxidation of Ia supported a recently proposed mechanism explaining the independent formation of Ib and Ic from a common precursor resulting from metabolic N-oxidation of Ia.
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Microssomos Hepáticos/metabolismo , Fentermina/metabolismo , Animais , Galinhas , Cricetinae , Sistema Enzimático do Citocromo P-450/metabolismo , Citocromos/metabolismo , Depressão Química , Cobaias , Técnicas In Vitro , Cinética , Camundongos , Microssomos Hepáticos/enzimologia , Oxirredução , Fentermina/análogos & derivados , Proteínas/metabolismo , Coelhos , Ratos , Fatores de TempoRESUMO
A direct gas chromatographic method for unstable amino ketones, using a neutral column and moderately alkaline conditions during extraction has been developed. Its application has given a new perspective to the relative importance of the metabolic routes in the complex metabolism of diethylpropion which after oral administration in man is rapid and extensive (only 3-4% of the drug remains unchanged). Mono-N-de-ethylation is the main pathway (about 35% of the dose). N-De-ethylation is more important than carbonyl-reduction, occurring mainly with the unchanged drug (about 20% of the dose). Norephedrine, thought previously to be one of the main metabolites, has been shown to be present only in negligible amounts. About 30% of the dose, which cannot be accounted for as the sum of the amines recovered in urine, is probably metabolized by deamination, followed by oxidation and conjugation to give hippuric acid.