Meningococcal disease in healthcare workers. Long term effects and costs are unclear.
Explore the source record for details and available documents.
Antibiotic Prophylaxis↗
Biomedical subjects
B Fulton
Publications and source records attributed to B Fulton.
Sleep-related breathing disorders following discharge from intensive care.
OBJECTIVES: To determine the incidence of sleep-related breathing disorders and nocturnal hypoxaemia in patients discharged from ICU following prolonged mechanical ventilation. DESIGN: Prospective, consecutive patient observational study. SETTING: The medical and surgical wards of a University Hospital. PATIENTS AND PARTICIPANTS: Fifteen consecutive, adult patients discharged from the ICU who had received more than 48 h of mechanical ventilation were studied. Ten healthy volunteers acted as controls. MEASUREMENTS AND RESULTS: Overnight, multi-channel pneumographic studies were performed on all patients and controls. Chest and abdominal wall movement, air flow, oxygen saturation and snoring were continuously recorded. Data was analysed by both visual inspection of the traces and by computer-based algorithms. An apnoea/hypopnoea index was calculated for each patient and volunteer. Volunteers had an apnoea/hypopnoea index of less than 5 and had no episodes of nocturnal oxygen desaturation (SaO2 < 90%). Despite oxygen therapy 13/15 patients had episodes of desaturation and 9/15 spent more than 2 h with an SaO2 < 90%. Eleven patients had an abnormal apnoea/hypopnoea index (range 5-34 events/h). Four patients had predominantly obstructive events while 7 primarily had hypopnoeas. CONCLUSIONS: Significant overnight oxygen desaturation is common in patients discharged from ICU who have received prolonged mechanical ventilation. This group also has a significant incidence of sleep-related breathing disorders and this mechanism is likely to be important in the pathogenesis of the hypoxaemia.
Adult↗
CRASH trial is based on problematic meta-analysis.
Explore the source record for details and available documents.
Anti-Inflammatory Agents↗
Central airway compression. Anaesthetic and intensive care consequences.
Explore the source record for details and available documents.
Adult↗
Olanzapine. A review of its pharmacological properties and therapeutic efficacy in the management of schizophrenia and related psychoses.
Olanzapine is a thienobenzodiazepine derivative which displays efficacy in patients with schizophrenia and related psychoses. It has structural and pharmacological properties resembling those of the atypical antipsychotic clozapine and an improved tolerability profile compared with the classical antipsychotic haloperidol. In several large, well controlled trials in patients with schizophrenia or related psychoses, olanzapine generally 5 to 20 mg/day was at least as effective as haloperidol (5 to 20mg) and more so than placebo, as assessed by overall rating scales for psychoses. Olanzapine improved negative symptoms to a greater extent than haloperidol in 2 of 3 comparative trials, including the largest trial. Efficacy of olanzapine has a rapid onset (within 1 to 2 weeks). Its clinical benefits appear to be maintained for treatment periods of up to 1 year, as shown by analysis of the extension phase of several trials demonstrating decreased probability of hospitalisation over this period compared with haloperidol. Preliminary data suggest the drug may also improve quality of life. Olanzapine was associated with significantly fewer adverse movement disorders (e.g. akathisia, dystonia, hypertonia, extrapyramidal symptoms) than haloperidol. There have been no reports of agranulocytosis (as occurs with clozapine) or any other haemotoxicity attributed to olanzapine, and the drug has shown minimal effect on prolactin levels. Transient increases in levels of hepatic transaminases seem to be clinically important. The only events recorded more frequently during olanzapine than during haloperidol therapy were weight gain, dry mouth and increased appetite. Although the antipsychotic activity of olanzapine has been well demonstrated. Its efficacy in refractory schizophrenia and its place relative to other atypical antipsychotics remain to be determined. Nevertheless, if the long term tolerability profile of olanzapine is confirmed, the drug should provide a valuable therapeutic alternative in the management of schizophrenia and related psychoses.
Animals↗
Insufficient stocking of poisoning antidotes in hospital pharmacies.
OBJECTIVE: To determine whether antidotes for poisoning and overdose are available in hospitals that provide emergency department care. DESIGN: Written survey of hospital pharmacy directors, each of whom reported the amount currently in stock of 8 different antidotes: antivenin (Crotalidae) polyvalent, cyanide kit, deferoxamine mesylate, digoxin immune Fab, ethanol, naloxone hydrochloride, pralidoxime chloride, and pyridoxine hydrochloride. PARTICIPANTS: Pharmacy directors of all hospitals with emergency departments in Colorado, Montana, and Nevada. MAIN OUTCOME MEASURES: Proportions of hospitals with insufficient stocking of each antidote, defined as complete lack of the antidote or an amount inadequate to initiate treatment of 1 seriously poisoned 70-kg patient. RESULTS: Questionnaires were mailed to 137 hospital pharmacy directors and 108 (79%) responded. Only 1 (0.9%) of the 108 hospitals stocked all 8 antidotes in adequate amounts. The rate of insufficient stocking for individual antidotes ranged from 2% (for naloxone) to 98% (for digoxin immune Fab). In a multiple regression analysis, smaller hospital size and lack of a formal review of antidote stocking were independent predictors of the number of antidotes stocked insufficiently. CONCLUSIONS: Insufficient stocking of antidotes is a widespread problem in Colorado, Montana, and Nevada. Although these states are served by a certified regional poison center, potentially lifesaving antidotes are frequently not available when and where they might be needed to treat a single poisoned patient.
Analysis of Variance↗
Galanthamine.
Galanthamine is a selective acetylcholinesterase inhibitor which has shown potential for the treatment of Alzheimer's disease. Galanthamine is selective for acetylcholinesterase versus butyrylcholinesterase; however, the drug produces greater enzyme inhibition in human erythrocytes than in human brain tissue. Galanthamine attenuates drug-and lesion-induced cognitive deficits in animal models of learning and memory. Preliminary results in patients with Alzheimer's disease have reported galanthamine to be associated with a reduction in cognitive deterioration on some neuropsychiatric rating scales. Nausea and vomiting are the most commonly reported adverse effects; liver toxicity has not been reported to date.
Alzheimer Disease↗
Mycophenolate mofetil. A review of its pharmacodynamic and pharmacokinetic properties and clinical efficacy in renal transplantation.
Mycophenolate mofetil is an ester prodrug of the active immunosuppressant mycophenolic acid. It is a noncompetitive, selective and reversible inhibitor of inosine monophosphate dehydrogenase, an important enzyme in the de novo synthesis of guanosine nucleotides in T and B lymphocytes. Mycophenolate mofetil and/or mycophenolic acid inhibit the proliferation of lymphocytes and the production of antibodies induced by a variety of mitogens and antigens. Mycophenolate mofetil is also active in several animal models of transplantation and has produced effects in animals that indicate that it may inhibit the chronic rejection process. Mycophenolate mofetil has been compared with azathioprine or placebo in 3 large, randomised, double-blind, multicentre trials as part of combination immunosuppression therapy with cyclosporin and corticosteroids. Compared with either placebo or azathioprine (1 to 2 mg/kg/day or 100 to 150 mg/day), mycophenolate mofetil 2 or 3 g/day was associated with a significantly lower proportion of patients experiencing acute rejection or treatment failure during the first 6 months after transplantation. Mycophenolate mofetil also tended to be associated with a lower proportion of patients who required a full course of antirejection therapy. However, the proportion of patients who died or who had graft loss was similar between all of the treatment groups. There are currently no data regarding the effects of mycophenolate mofetil on long term patient or graft survival, which are important clinical outcomes in assessing its place in the management of renal transplantation. Clinical trials are also needed to evaluate mycophenolate mofetil in specific patient populations (e.g. repeat renal transplant patients or highly sensitised patients), to determine its efficacy in alternative immunosuppressive protocols and to investigate its use in the transplantation of other solid organs. In summary, mycophenolate mofetil appears to be an attractive new agent in the prevention of graft rejection in renal transplant recipients that has shown superior efficacy to azathioprine. Although long term clinical outcome data are required, mycophenolate is a potentially important advance in transplant immunosuppression.
Animals↗
Docetaxel. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in the management of metastatic breast cancer.
Docetaxel is a member of the taxoid class of antineoplastic agents. Its mechanism of action is primarily related to its ability to enhance microtubule assembly and to stabilise microtubules by preventing their depolymerisation, thus disrupting normal cell division. Docetaxel has significant cytotoxic activity against human breast cancer cell lines and freshly explanted human breast cancer cells in vitro. It has also shown activity in mice against mammary tumours and human mammary tumour xenografts. Docetaxel has been investigated in the treatment of patients with advanced and/or metastatic breast cancer in European and North American phase II trials using an initial dose of 100 mg/m2 infused over 1 hour every 3 weeks. As first-line treatment, monotherapy with docetaxel was associated with complete and partial response rates of 5 to 16% and 49 to 53%, respectively, with an overall (complete plus partial) response rate of 54 to 68%. The median overall survival time of patients in one study was > or = 71 weeks. Docetaxel monotherapy has shown impressive activity as second-line therapy in patients with metastatic breast cancer who had relapsed while receiving adjuvant therapy or who had progressive disease following previous treatment, with overall response rates of 53 and 58% reported in 2 studies. A number of issues need to be addressed before the ultimate place of docetaxel in the management of metastatic breast cancer is fully established. The efficacy of docetaxel compared with standard agents and in combination regimens and its effect on quality-of-life aspects require further evaluation. Nevertheless, docetaxel is a promising new agent which has produced impressive clinical results and should be considered an alternative second-line treatment of patients with metastatic breast cancer.
Animals↗
Moclobemide. An update of its pharmacological properties and therapeutic use.
Unlike older monoamine oxidase inhibitors, which irreversibly and nonselectively bind monoamine oxidase (MAO), moclobemide is a reversible and selective inhibitor of the MAO-A isozyme. Moclobemide only weakly potentiates the pressor response induced by tyramine or other indirectly acting sympathomimetics; therefore, there is no need to avoid dietary tyramine or over-the-counter decongestants with moclobemide as there is with older MAO inhibitors. Recent clinical trials and meta-analyses have confirmed the efficacy of moclobemide in the treatment of depressive disorders. Moclobemide has been shown to have similar efficacy to tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs) and nonselective, irreversible MAO inhibitors. Long term follow-up studies of 6 to 12 months' duration have demonstrated that the antidepressant efficacy of moclobemide is maintained. Moclobemide, given alone or in combination with another antidepressant, has shown some efficacy in patients with refractory depression; however, comparative trials are required to confirm these findings. Data are also available to show clinical efficacy of moclobemide in the management of social phobia. Comparative studies have established that moclobemide is better tolerated at therapeutic dosages and has less toxicity in overdose than TCAs and nonselective, irreversible MAO inhibitors. Moclobemide lacks the anticholinergic, sedative and cardiovascular effects associated with many of the older antidepressants. Compared with SSRIs, moclobemide has a similar overall tolerability, although it tends to cause fewer gastrointestinal effects than the SSRIs and has not been reported to interfere with sexual function. In summary, recent data which confirm and extend its comparative therapeutic efficacy and low potential for adverse effects have established moclobemide as an effective treatment in depressive disorders. The drug is also effective in patients with a primary diagnosis of social phobia. Its lack of adverse anticholinergic, cardiovascular, cognitive and psychomotor effects makes moclobemide a particularly useful option in the elderly or patients with cardiac disease.
Age Factors↗
Riluzole. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in amyotrophic lateral sclerosis.
Riluzole, a benzothiazole, affects neurons by 3 mechanisms: by inhibiting excitatory amino acid release, inhibiting events following stimulation of excitatory amino acid receptors and stabilising the inactivated state of voltage-dependent sodium channels. It has demonstrated neuroprotective activity in vivo and in vitro. Results from 2 randomised double-blind placebo-controlled trials in patients with amyotrophic lateral sclerosis (ALS; motor neuron disease) have demonstrated that riluzole can extend survival and/or time to tracheostomy. After 18 months, the relative risk of death or tracheostomy with riluzole 100 mg/day was reduced by 21%. Although riluzole slowed the rate of deterioration in muscle strength in the first trial, this was not confirmed in the second, larger trial. Riluzole had no effect on any other functional or secondary variable. Gastrointestinal effects, anorexia, asthenia, circumoral paraesthesia and dizziness were reported more frequently with riluzole than placebo. Elevated alanine aminotransferase levels were observed in 10.6 versus 3.8% of patients treated with riluzole 100 mg/day versus placebo, leading to treatment withdrawal in 3.8 versus 2.1% of patients. In conclusion, riluzole is the first drug that has been shown to have an effect on survival in patients with ALS. Although the effect of riluzole was modest, it has allowed some insight into the pathogenesis of ALS from which future gains may be made.
Administration, Oral↗
Propofol. A pharmacoeconomic appraisal of its use in day case surgery.
Propofol is an intravenous anaesthetic agent that has become widely used in day case surgery. It induces anaesthesia rapidly and 'smoothly', is associated with a quick recovery and has a lower incidence of postoperative nausea and vomiting (PONV) than other agents. In studies comparing propofol with other intravenous anaesthetics (most commonly thiopental sodium) in day case surgery, the use of propofol as induction and/or maintenance anaesthesia was associated with a shorter time to intermediate recovery (street fitness or time to discharge), although the mean time difference was generally less than 1 hour. However, when compared with volatile anaesthetics (particularly desflurane), the differences in time to discharge were smaller. Propofol is also associated with less PONV than barbiturates, volatile anaesthetics or barbiturate/volatile anaesthetic combinations in the immediate postoperative period. The faster recovery time and the decreased incidence of PONV have potential pharmacoeconomic implications. Delayed recovery can increase the use of hospital resources and decrease patient throughput and PONV can incur costs due to an increase in adjunctive medications usage (e.g. antiemetics), nursing time or unintended admissions. The pharmacoeconomic significance of these properties of propofol requires formal evaluation. Pharmacoeconomic investigations, such as cost-effectiveness, cost-benefit and cost-minimisation studies, which include clinical outcome parameters are difficult to conduct in anaesthesia since there are no objective measures of equipotency between anaesthetic agents and because there is no specific health outcome associated with the delivery of anaesthesia. At present, cost-utility studies are not possible because there are no validated instruments for measuring utility in the provision of anaesthesia. To date, pharmacoeconomic analyses of propofol (and other anaesthetic agents) in day case surgery have been restricted to partial cost analyses. Only 2 of these have included the cost of drug wastage, an important consideration since propofol contains no preservative. With 1 exception, these studies have only included drug acquisition costs and propofol was reported to be approximately 1- to 3-fold as costly as other intravenous/inhalational agents. However, these limited analyses have little applicability since they do not include all relevant costs. In addition to drug acquisition costs, pharmacoeconomic studies should also include other direct costs such as the cost of adjunctive medications (including treatment necessary for adverse events), equipment and staff time, indirect costs such as loss of productivity and/or wages and intangible costs such as patient satisfaction and quality of life. A few studies have attempted to quantify some of these factors. Based on differences in recovery time, 2 studies have estimated a decreased demand for nursing staff time associated with the use of propofol compared with thiopental sodium/isoflurane. In addition, informal patient satisfaction assessments show propofol to be equal to or better than other anaesthetic agents. With these broader considerations, it thus remains for future studies to quantify the intangible and indirect costs associated with propofol anaesthesia, to determine whether differences in recovery between propofol and other agents (especially the newer inhalational anaesthetics) are of economic importance, and to identify those instances where propofol use provides the greatest value for available funds.
Ambulatory Surgical Procedures↗
Interactive effects of fluoride and aluminum uptake and accumulation in bones of rabbits administered both agents in their drinking water.
Fluoride (F) and aluminum (Al), which are known to form a strong complex, are both present in finished drinking water. The effect of F and AI on one another's tissue accumulation was determined using adult male New Zealand white rabbits. Thirty-six rabbits (three per group) were given Purina Rabbit Chow and drinking water containing no F or AI, F alone (1, 4, or 50 ppm F as NaF), Al alone, (100 or 500 ppm Al as AlCl3), or a combination of F and Al, ad libitum for 10 wk. None of these treatments altered food intake or weight gain in these rabbits. However, rabbits treated with 1 ppm F and 500 ppm Al consumed significantly less water than control rabbits. The F accumulation in plasma, urine, incisors, and tibia was increased as the F addition to the drinking water increased within groups receiving a single concentration of Al. In contrast, F accumulation in plasma, urine, incisors, and tibia decreased as the Al concentration increased within groups receiving a single F concentration, indicative of decreased intestinal absorption. Importantly, Al levels in tibia were significantly increased by the addition of F to the drinking water, even in animals receiving no Al in their drinking water. The effect of F on Al accumulation in bone was confirmed by our evaluating Al levels in sterna harvested from rats treated with 0 or 79 ppm F (as NaF in the drinking water) in a study conducted by the National Toxicology Program (Bucher et al., 1991). Therefore, some of the osteotoxicity seemingly associated with high F levels in bone may be due to the accumulation of Al or an Al-F complex.
Aluminum↗
Doxazosin. An update of its clinical pharmacology and therapeutic applications in hypertension and benign prostatic hyperplasia.
Doxazosin is a long-acting alpha 1-adrenoceptor antagonist structurally related to prazosin and terazosin. Its antihypertensive effect is produced by a reduction in the smooth muscle tone of peripheral vascular beds resulting in a decrease in total peripheral resistance without significant effect on cardiac output or heart rate. In benign prostatic hyperplasia, doxazosin's effect of relieving bladder outflow obstruction is produced through a reduction in prostatic tone mediated via alpha 1-adrenoceptor blockade. In most comparative trials doxazosin has proven to be equally effective as the comparator drug in the treatment of mild to moderate hypertension. It has been used in a variety of patient populations including the elderly, Blacks, smokers, and patients with concomitant disease states such as renal dysfunction, hypercholesterolaemia, non-insulin dependent diabetes mellitus (NIDDM) and respiratory disease. Doxazosin has also been used successfully in combination with beta-adrenoceptor antagonists, diuretics, calcium channel antagonists, and angiotensin-converting enzyme inhibitors in patients with hypertension that is uncontrolled with monotherapy. Doxazosin has a beneficial effect on some of the risk factors associated with coronary heart disease including elevated serum lipid levels, impaired glucose metabolism, insulin resistance and left ventricular hypertrophy. Modest decreases in total cholesterol, low density lipoprotein cholesterol and triglycerides are seen with doxazosin therapy while small increases in high density lipoprotein cholesterol and the high density lipoprotein cholesterol/total cholesterol ratio are consistently reported. Some studies have reported an improvement in glucose tolerance although this effect has been more consistently seen in nondiabetic patients than in patients with NIDDM. Additionally, doxazosin produces a similar reduction in left ventricular hypertrophy to other antihypertensive agents. Modelling-based calculations suggest that doxazosin significantly reduces the risk of developing coronary heart disease in patients with mild to moderate hypertension, although this remains to be confirmed in long term prospective studies. Doxazosin appears to be a promising agent in the treatment of urinary symptoms associated with benign prostatic hyperplasia. Similar to other alpha 1-adrenoceptor antagonists, doxazosin treatment produces increases in peak and mean urinary flow rates and improves other objective and symptomatic measures.(ABSTRACT TRUNCATED AT 400 WORDS)
Carbohydrate Metabolism↗
Trimetrexate. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in the treatment of Pneumocystis carinii pneumonia.
Trimetrexate is a folinic acid analogue structurally related to methotrexate, whose primary mechanism of action is believed to be inhibition of dihydrofolate reductase. This reduces the production of DNA and RNA precursors and leads to cell death. Trimetrexate is lipophilic and can passively diffuse across cell membranes including those of Pneumocystis carinii and its mammalian host. To minimise toxicity, trimetrexate must be coadministered with calcium folinate (leucovorin calcium), a reduced folate coenzyme, which is transported into, and protects, mammalian host cells but not P. carinii cells. In noncomparative trials trimetrexate was effective in the treatment of P. carinii pneumonia (PCP) in patients with AIDS who were intolerant of or refractory to cotrimoxazole (trimethoprim/sulfamethoxazole) and pentamidine treatment. In these patients, 2- to 4-week survival rates of 48 to 69% were reported. In a comparative trial in the initial therapy of PCP, trimetrexate was less effective than cotrimoxazole in moderate to severe disease as evidenced by a significantly higher failure rate. Trimetrexate was better tolerated than cotrimoxazole when used in this setting, however. Significantly fewer patients receiving trimetrexate plus calcium folinate discontinued treatment because of adverse events than did patients receiving cotrimoxazole. The most common adverse effect associated with trimetrexate is myelosuppression (neutropenia and thrombocytopenia); this is mitigated by coadministration of calcium folinate and is generally reversible upon dosage reduction or discontinuation. Other adverse effects include increases in serum aminotransferase levels, anaemia, fever, rash/pruritus, and increased alkaline phosphatase or serum creatinine levels. Further research into the use of trimetrexate, including its efficacy as prophylaxis, in combination with other agents and as an oral formulation, is needed to clearly define its role in the treatment of PCP and to identify patients most likely to benefit. Currently, trimetrexate should be considered as an alternative treatment option in immunocompromised patients with moderate to severe PCP who have not responded to or are intolerant of first-line therapy.
AIDS-Related Opportunistic Infections↗
Propofol. An overview of its pharmacology and a review of its clinical efficacy in intensive care sedation.
Propofol is a phenolic derivative that is structurally unrelated to other sedative hypnotic agents. It has been used extensively as an anaesthetic agent, particularly in procedures of short duration. More recently it has been investigated as a sedative in the intensive care unit (ICU) where it produces sedation and hypnosis in a dose-dependent manner. Propofol also provides control of stress responses and has anticonvulsant and amnesic properties. Importantly, its pharmacokinetic properties are characterised by a rapid onset and short duration of action. Noncomparative and comparative trials have evaluated the use of propofol for the sedation of mechanically ventilated patients in the ICU (postsurgical, general medical, trauma). Overall, propofol provides satisfactory sedation and is associated with good haemodynamic stability. It produces results similar to or better than those seen with midazolam or other comparator agents when the quality of sedation and/or the amount of time that patients were at adequate levels of sedation are measured. Patients sedated with propofol also tend to have a faster recovery (time to spontaneous ventilation or extubation) than patients sedated with midazolam. Although most studies did not measure time to discharge from the ICU, propofol tended to be superior to midazolam in this respect. In a few small trials in patients with head trauma or following neurosurgery, propofol was associated with adequate sedation and control of cerebral haemodynamics. The rapid recovery of patients after stopping propofol makes it an attractive option in the ICU, particularly for patients requiring only short term sedation. In short term sedation, propofol, despite its generally higher acquisition costs, has the potential to reduce overall medical costs if patients are able to be extubated and discharged from the ICU sooner. Because of the potential for hyperlipidaemia and the development of tolerance to its sedative effects, and because of the reduced need for rapid reversal of drug effects in long term sedation, the usefulness of propofol in long term situations is less well established. While experience with propofol for the sedation of patients in the ICU is extensive, there are still areas requiring further investigation. These include studies in children, trials examining cerebral and haemodynamic outcomes following long term administration and in patients with head trauma and, importantly, pharmacoeconomic investigations to determine those situations where propofol is cost effective. In the meantime, propofol is a well established treatment native to benzodiazepines and/or other hypnotics or analgesics when sedation of patients in the ICU is required. In particular, propofol possesses unique advantages over these agents in patients requiring only short term sedation.
Adolescent↗
The temporal relationship between hepatic GSH loss, heme oxygenase induction, and cytochrome P450 loss following intraperitoneal aluminum administration to mice.
The time- and dose-dependent accumulation of aluminum (Al) in liver and its effect on several hepatic systems were investigated in female Swiss-Webster mice given intraperitoneal (ip) Al lactate. A single dose of 50, 75, or 100 mg Al/kg produced significant depletion of hepatic glutathione (GSH) and cytochrome P450 (P450) and an increase in heme oxygenase (HO) activity when measured at 6 hr. However, no increase in hepatic malondialdehyde (MDA) was seen at this time. Using a dose of 100 mg Al/kg, Al rapidly accumulated in liver (0.29 +/- 0.03 vs 0.12 +/- 0.04 micrograms Al/mg protein at 6 hr). Hepatic GSH was significantly depleted at 2, 4, and 6 hr postdosing, HO activity was significantly increased at 6, 12, 24, 48, and 96 hr postdosing, hepatic cytochrome P450 was decreased at 12, 18, 24, and 48 hr postdosing, while hepatic MDA was not significantly elevated until 24 hr postdosing. Twenty-four hours following three daily doses of 50 mg Al/kg, HO activity was increased, P450 levels were depleted, and hepatic Al content was significantly increased, although hepatic MDA was unaffected. We conclude that parenteral Al produces a course of hepatic damage that begins with GSH depletion and proceeds through a sustained increase in HO activity, with cytochrome P450 loss being an early event and production of hepatic MDA being a late event.
Aluminum↗
Heme oxygenase induction. A possible factor in aluminum-associated anemia.
The effect of repeated parenteral administration of aluminum (Al) was investigated to determine if a relationship exists between the severity of anemia and increase in hepatic heme oxygenase activity. Female Swiss Webster mice were dosed for 11 d with 50 mg Al/kg, as Al lactate, and sodium lactate was given to control mice. On d 12, hematocrit, hemoglobin, blood smears, hepatic heme oxygenase activity, and cytochrome P450 levels were assessed. Significant decreases in hematocrit (39.1 +/- 0.7 vs 43.1 +/- 0.3% in controls) and hemoglobin (13.1 +/- 0.4 vs 14.2 +/- 0.2 g/dL in controls) were produced by Al administration. Blood smears from Al-treated mice consistently showed smaller, more irregular red cells. Cytochrome P450 content was significantly decreased (0.443 +/- 0.043 vs 0.665 +/- 0.055 nmol/mg) whereas hepatic heme oxygenase activity was significantly increased (2.75 +/- 0.34 vs 1.66 +/- 0.20 nmol/mg/h) in Al-treated animals. The production of mild anemia by parenteral aluminum correlated significantly with the increase in heme oxygenase activity, which, although only 66% greater than in control, preceded a significant loss of cytochrome P450. The increased heme oxygenase activity, with subsequent increased destruction of heme and/or heme proteins is discussed as a possible mechanism for the microcytic, hypochromic anemia associated with Al overload.
Aluminum↗