High-frequency EPR study of the ferrous ion in the reduced rubredoxin model.

High-frequency (94-371 GHz) EPR data are reported for powdered samples of [PPh4]2[Fe(SPh)4], an accurate model for the reduced site of rubredoxins. This is the first HFEPR investigation of an S = 2 ferrous complex, illustrating the utility of this technique for the investigation of integer-spin systems. A full-matrix diagonalization approach is used to simulate spectra over the 94-371 GHz frequency range, providing the spin-Hamiltonian parameters g, D, and E. It is observed that g is anisotropic, characterized by gx = gy = 2.08 and gz = 2.00, and that D = +5.84 cm(-1) and E = +1.42 cm(-1), where the uncertainty in each parameter is estimated as +/- 2%. The spin-Hamiltonian for [PPh4]2[Fe(SPh)4] is related to fundamental properties, such as the crystal-field splitting and the spin-orbit coupling of Fe2+. It is shown that the conventional spin-Hamiltonian accurately represents the electronic structure of the Fe2+ ion in this molecule. Through a comparison with Fe(SPh)4(PPh4)2, the zero-field splitting of the Fe2+ site in reduced rubredoxin is estimated to be D = +5.3 cm(-1) and E = +1.5 cm(-1). This is one of the few HFEPR investigations of a rhombic, high-spin system; as such, it is a step toward the eventual investigation of similar Fe2+ sites in proteins.

Caffeine based measures of CYP1A2 activity correlate with oral clearance of tacrine in patients with Alzheimer's disease.

AIMS: To study the potential utility of caffeine based probes of CYP1A2 enzyme activity in predicting the pharmokinetics of tacrine in patients with Alzheimer's disease. METHODS: The pharmokinetics of a single 40 mg oral dose of tacrine were measured in 19 patients with Alzheimer's disease. Each patient also received 2 mg kg(-1) [13C-3-methyl] caffeine orally and had breath and urine samples collected. RESULTS: Tacrine oral clearance (CL F(-1) kg(-1)), which varied 15-fold among the patients, correlated significantly with the 2 h total production of 13CO2 in breath (r=0.56, P=0.01), and with each of two commonly used urinary caffeine metabolite ratios: the 'paraxanthine/caffeine ratio' (1,7X + 1, 7U)/1,3,7X) (r=0.76, P=0.0002) and the 'caffeine metabolic ratio' (AFMU + 1X + 1U)/1, 7U)(r=0.76, P=0.0001). CONCLUSIONS: These observations support a central role for CYP1A2 in the in vivo disposition of tacrine and the potential for drug interactions when tacrine treated patients receive known inducers or inhibitors of this enzyme. The magnitude of the correlations we observed, however, are probably not sufficient to be clinically useful in individualizing tacrine therapy.

Safety of tacrine: clinical trials, treatment IND, and postmarketing experience.

The safety of tacrine (Cognex), a centrally active, reversible acetylcholinesterase inhibitor approved in 1993 for the treatment of mild to moderate dementia of the Alzheimer type, was evaluated in 2,706 patients with Alzheimer disease (AD) in clinical trials and in 9861 patients with AD in a treatment investigational new drug (TIND) program. More than 190,000 patients in the United States received tacrine during the first 2 years following marketing approval. The most common tacrine-associated adverse events were elevated liver transaminase levels [alanine aminotransferase (ALT) and, to a lesser degree, aspartate aminotransferase] and peripheral cholinergic events involving primarily the digestive system (nausea, vomiting, diarrhea, dyspepsia, anorexia, and weight loss). Based on clinical trial experience, potentially clinically significant (>3 x upper limit of normal) ALT elevations occurred in 25% of patients, requiring routine monitoring early in treatment. The elevations were almost always asymptomatic, rarely accompanied by significant increases in bilirubin, and related to time on drug rather than to dose (90% occurred within the first 12 weeks of treatment). Gastrointestinal events were related to dose and generally of mild to moderate intensity. Tacrine-associated events, including ALT elevations, were reversible. Cholinergic events were manageable with dosage adjustment. Tacrine was not associated with permanent liver injury in clinical trials or a TIND setting.

The caffeine breath test does not identify patients susceptible to tacrine hepatotoxicity.

Therapy with tacrine, a promising new treatment for Alzheimer's disease, must be discontinued in up to 15% of patients because of hepatocellular toxicity. Recent studies using human liver microsomes have suggested that a single liver enzyme, cytochrome P450 1A2 (CYP1A2), catalyzes the major route of metabolism and elimination of tacrine, and also catalyzes the pathway(s) involved in the generation of reactive metabolites capable of covalent protein binding and cytotoxicity. Because CYP1A2 activity has been shown to vary up to 60-fold among patients, we proposed that a convenient measure of CYP1A2 activity, the [(13)C 3-methyl] caffeine breath test (CBT), might be clinically useful in identifying patients most susceptible to tacrine liver toxicity. To test this hypothesis, we administered the CBT to 37 patients with Alzheimer's disease before they began treatment with tacrine. Twenty patients received 2 mg/kg of [(13)C 3-methyl] caffeine. The remaining 17 patients received the commercially available CBT kit, which employs a constant 200-mg dose. The activities of two other major drug-metabolizing enzymes (cytochrome P450 3A4 and 2D6 [CYP3A4 and CYP2D6]) were also measured in these 17 patients. We found that the results obtained from the CBT protocol did not predict the peak serum alanine transaminase (ALT) observed in the patients. The measured CYP3A4 and CYP2D6 activities also failed to predict the susceptible patients. However, the result of the standardized-dose CBT correlated well with the logarithm of the steady-state plasma tacrine level obtained in 10 patients (R(2) = .69, P = .003). We conclude that the CBT will not be clinically useful in determining the subset of patients most susceptible to tacrine hepatotoxicity. However, the correlation we observed between CBT results and tacrine blood levels is the first evidence supporting a critical role for CYP1A2 activity in the disposition of the drug in vivo.

Glutathione S-transferase mu genotype (GSTM1*0) in Alzheimer's patients with tacrine transaminitis.

1. Tacrine (1,2,3,4-tetrahydro-9-aminoacridine) which is used in Alzheimer's disease, causes elevation of liver transaminases ('tacrine transaminitis') in 40-50% of patients. This may be related to the formation of a chemically reactive metabolite from tacrine, which can be detoxified in vitro by glutathione. 2. Glutathione-S-transferase mu (GSTM1), a detoxication enzyme, is polymorphically expressed being absent in about 50% of patients. Its role in the detoxication of the reactive metabolite of tacrine is not known. 3. The frequency of the enzyme deficiency (GSTM1*0) has been investigated in patients with tacrine transaminitis using polymerase chain reaction (PCR) to determine whether the GSTM1 status can be used as an absolute predictive factor for susceptibility to tacrine transaminitis. 4. The frequency of the GSTM1*0 genotype in patients with tacrine transaminitis (n = 33; 45.5%) was not significantly different from that in patients treated with tacrine without liver dysfunction (n = 37; 43%), and when compared with all the controls used in the study (n = 167; 56%). 5. The frequency of the GSTM1*0 genotype in patients with Alzheimer's disease (n = 79; 46%) was not significantly different from that in healthy volunteers (n = 121; 59.5%). 6. Our results indicate that the GSTM1 status cannot be used clinically to predict individual susceptibility to tacrine transaminitis, and that patients with the GSTM1*0 genotype are unlikely to have an increased risk of tacrine-induced liver damage. Furthermore, the GSTM1 status was not associated with Alzheimer's disease.

Progressive alveolar septal injury in primates exposed to 60% oxygen for 14 days.

Moderate exposures to hyperoxia are becoming increasingly common in clinical medicine as advancing technology allows O2 to be more effectively delivered to nonintubated patients. The sensitivity of the lung to injury by a subchronic exposure to 60% O2 was investigated, using baboons and serial lobar biopsies. Because results obtained from different regions of the lung were compared, the alveolar architecture of different lung lobes of three controls was studied, with the use of electron microscopic morphometric analyses, to assess possible lobar differences in volume, surface, and numerical densities of cells and tissues. In animals exposed to 60% O2, the same techniques were used to assess specific tissue changes in the epithelial, interstitial, and endothelial compartments of the alveolar septa. All six lobes of the normal baboon lung were found to be identical with respect to alveolar architecture. Thus, for gases of low reactivity and given in high concentrations, such as O2, cross-comparisons between different lobes are appropriate. Exposure to 60% O2 was found to cause proliferation of alveolar type II epithelium, suggesting a low-grade, chronic epithelial injury. Animals allowed to recover for 8 wk in room air showed progressive changes in the alveolar interstitium, involving increases in both cells and matrix. Because sequential lobar resections were done, animals were exposed both to 60% O2 and to the effects of general anesthesia and thoracotomies. The exposure to 60% O2 for 2 wk in this experimental setting leads to an alveolar septal injury that includes a progressive interstitial fibrotic response.

The Clinician Interview-Based Impression (CIBI): a clinician's global change rating scale in Alzheimer's disease.

Global assessments are Food and Drug Administration-required primary outcome measures in trials of putative antidementia drugs. Global ratings are intended to provide an index of clinical importance of change that cannot be obtained from quantitative assessment measures such as mental status examinations. We examined the performance of a global assessment of change instrument, the Clinician Interview-Based Impression (CIBI), in the placebo group of a 30-week, randomized, double-blind clinical trial of tacrine in patients with Alzheimer's disease. Initially there were 184 placebo patients, of whom 125 completed the 30-week study. Descriptive statistics, correlations with changes on other assessment instruments, and test-retest reliability were determined for the CIBI. At week 30, clinicians rated more than 40% of patients on the CIBI as unchanged. The CIBI ratings were weakly but significantly correlated, in the expected direction, with change scores on the quantitative cognitive assessments. The CIBI was modestly reliable on test-retest at weeks 22 and 24 but less reliable compared with other quantitative outcome measures. Modifications of the CIBI that might improve its reliability and acceptance include (1) no restrictions on the form of the bedside mental status assessment, (2) inclusion of caregiver input, and (3) better definition of ratings on the global scale. Global instruments, if properly constructed, can provide an index of clinically important change for the assessment of dementia patients.

A 30-week randomized controlled trial of high-dose tacrine in patients with Alzheimer's disease. The Tacrine Study Group.

OBJECTIVE: To evaluate the efficacy and safety of high-dose tacrine hydrochloride over 30 weeks in patients with probable Alzheimer's disease. DESIGN: A 30-week randomized, double-blind, placebo-controlled, parallel-group trial. SETTING: Outpatients at 33 US centers. PATIENTS: Men and women at least 50 years of age with mild to moderate Alzheimer's disease and otherwise in good health. INTERVENTIONS: Group 1 received placebo; group 2 received 40 mg/d of tacrine for 6 weeks, then 80 mg/d for 24 weeks; groups 3 and 4 received 40 mg/d of tacrine for 6 weeks, 80 mg/d for 6 weeks, and 120 mg/d for 6 weeks. Group 3 remained on a dosage of 120 mg/d for a total of 18 weeks; after 6 weeks at 120 mg/d, group 4 titrated to 160 mg/d for the last 12 weeks. PRIMARY OUTCOME MEASURES: Clinician Interview-Based Impression (CIBI), Alzheimer's Disease Assessment Scale--Cognitive subscale (ADAS-Cog), and Final Comprehensive Consensus Assessment (FCCA). RESULTS: A total of 663 patients entered the study; 653 patients were included in an intent-to-treat (ITT) analysis; 263 had evaluable data at 30 weeks. The results of the ITT analysis revealed significant (P < or = .05) dose-response trends and between-group comparisons on CIBI and ADAS-Cog. In evaluable patients, significant dose-response trends were observed for all three primary measures (P < or = .001). Significant differences in favor of 160 mg/d of tacrine vs placebo were observed on the CIBI (P < or = .002) and ADAS-Cog and FCCA (P < or = .001), as well as caregiver-global and quality-of-life assessments (P < or = .05). On the CIBI, 23% and 42% of tacrine-treated patients in the ITT and evaluable-patient populations, respectively, were rated improved compared with 17% and 18% of placebo patients, respectively. The primary reasons for withdrawal of tacrine-treated patients were asymptomatic liver transaminase elevations (28%) and gastrointestinal complaints (16%). These adverse events were reversible on discontinuation of treatment, and many patients were able to restart tacrine. CONCLUSIONS: Tacrine produced statistically significant, dose-related improvements on objective performance-based tests, clinician- and caregiver-rated global evaluations, and measures of quality of life. There was no evidence that the large number of patient withdrawals biased the overall conclusions of the study.

Hepatotoxic effects of tacrine administration in patients with Alzheimer's disease.

OBJECTIVE: To characterize the hepatic effects of tacrine treatment in patients with Alzheimer's disease. DESIGN: Controlled trials of tacrine therapy consisting of two blinded, parallel-group trials; three blinded, enrichment-design trials; and their respective open-label extensions. SETTING: Multicenter clinical trials in the United States, France, and Canada. PATIENTS: A total of 2446 men and women at least 50 years of age with a diagnosis of probable Alzheimer's disease of mild to moderate severity and in good health without significant hepatic, cardiovascular, or renal disease. INTERVENTION: Administration of tacrine vs placebo, with weekly measurement of serum hepatic enzymes. MAIN OUTCOME MEASURES: Incidence, maximum severity, and timing of event for serum alanine aminotransferase (ALT) elevation. RESULTS: Among the 2446 patients who received tacrine in clinical trials, ALT levels greater than the upper limit of normal (ULN) occurred on at least one occasion in 1203 patients (49%), ALT levels greater than three times the ULN occurred in 621 patients (25%), and ALT levels greater than 20 times the ULN occurred in 40 patients (2%). The elevated ALT levels were generally asymptomatic and occurred more frequently in women than men. The mean time from initiation of tacrine treatment to first ALT level greater than three times the ULN was 50 days, and 90% of all initial ALT levels greater than three times the ULN occurred during the first 12 weeks of treatment. Of 145 patients who discontinued tacrine treatment because of an ALT level greater than three times the ULN and were rechallenged, 127 (88%) were able to resume long-term therapy with the drug. In all instances, discontinuing tacrine completely reversed elevations in ALT levels, and no deaths related to hepatotoxicity occurred. CONCLUSIONS: These data suggest that the potential for serious hepatic toxicity can be reduced through careful monitoring of ALT levels in patients who may benefit from tacrine therapy.

In vivo interaction of ketoconazole and sucralfate in healthy volunteers.

Absorption of ketoconazole is impaired in subjects with an increased gastric pH due to administration of antacids, H2-receptor antagonists, proton pump inhibitors, or the presence of hypochlorhydria. Sucralfate could provide an attractive alternative in patients receiving ketoconazole who require therapy for acid-peptic disorders. Twelve healthy human volunteers were administered a single 400-mg oral dose of ketoconazole in each of three randomized treatment phases. In phase A, ketoconazole was administered orally with 240 ml of water. In phase B, ketoconazole and sucralfate (1.0 g) were administered simultaneously with 240 ml of water. In phase C, ketoconazole was administered with 240 ml of water 2 h after administration of sucralfate (1.0 g) orally with 240 ml of water. A 680-mg oral dose of glutamic acid hydrochloride was administered 10 min prior to and with each dose of ketoconazole, sucralfate, or ketoconazole plus sucralfate. Simultaneous administration of ketoconazole and sucralfate led to a significant reduction in the area under the concentration-time curve and maximal concentration of ketoconazole in serum (78.12 +/- 12.20 versus 59.32 +/- 13.61 micrograms.h/ml and 12.34 +/- 3.07 versus 8.92 +/- 2.57 micrograms/ml, respectively; P < 0.05). When ketoconazole was administered 2 h after sucralfate, the observed ketoconazole area under the concentration-time curve was not significantly decreased compared with that of ketoconazole alone. The time to maximal concentrations in serum and the ketoconazole elimination rate constant were not significantly different in any of the three treatment phases. In patients receiving concurrent administration of ketoconazole and sucralfate, doses should be separated by at least 2 h.

Endobronchial brachytherapy.

Endobronchial brachytherapy is a palliative treatment primarily used for individuals with lung cancer. This article describes the brachytherapy and presents the nurse's role before, during, and after the procedure. Coordination between hospital staff--endoscopy department, pulmonologist, radiation oncologist, and radiology department--is important to assure the success of this procedure.

Responses of baboons to prolonged hyperoxia: physiology and qualitative pathology.

Cardiopulmonary responses to prolonged hyperoxia and their relationships to the development of lung pathology have not been fully characterized in primates. In this study, circulatory hemodynamics and pulmonary function, vascular permeability, and leukocyte sequestration were measured in male baboons after 100% O2 exposure and related to ultrastructural changes of lung injury by electron microscopy. Three groups of animals were exposed to 100% O2 in an exposure cage for 40, 66, and 80 h, respectively. A fourth group of animals was exposed in a cage for 80 h and then anesthetized and ventilated with 100% O2 for additional time. These animals were exposed for a total duration of 110 h or until death from the injury. Physiological responses to hyperoxia were characterized by decreases in total lung capacity and inspiratory capacity at 80 and 110 h. A significant increase in pulmonary leukocyte accumulation was noted by 80 h. Extravascular lung water and permeability surface-area product increased at 80 and 110 h. Cardiac output and stroke volume also decreased, and systemic vascular resistance increased after 80 and 110 h of hyperoxia. Histopathological changes were present in the lungs of all but the 40-h exposure group. Animals exposed for 66 h showed endothelial injury and neutrophil accumulation. By 80 h, animals showed endothelial cell destruction, interstitial edema, and type I cell injury. At 110 h, animals showed substantial destruction of endothelial and type I epithelial cells, exposure of alveolar basement membrane, congestion of capillaries, and substantial interstitial edema. The data indicate that histological changes by electron microscopy precede physiological responses to hyperoxic pulmonary injury in baboons by as much as 14 h and that the physiological responses to early hyperoxic injury are relatively insensitive to the pathological injury.

Modification of gastric pH with oral glutamic acid hydrochloride.

The extent to which oral glutamic acid hydrochloride decreases mean gastric pH in fasting persons with and without simulated hypochlorhydria was studied. Healthy nonsmoking men were randomly assigned to one of two drug regimens followed by the other regimen after a one-week washout period. In regimen 1 the fasting subjects received two 680-mg doses of glutamic acid hydrochloride given 10 minutes apart. Regimen 2 was the same, except that an oral dose of ranitidine 300 mg (as the hydrochloride salt) was administered one to two hours before the first dose of glutamic acid hydrochloride to simulate hypochlorhydria. Gastric pH was monitored radiotelemetrically before and after glutamic acid hydrochloride administration by using the Heidelberg capsule technique. Six men 20 to 28 years of age participated in the study. For regimen 1, the gastric pH before glutamic acid hydrochloride was given was not significantly different from that after administration (grand medians, 1.4 and 1.3, respectively). In regimen 2, the median gastric pH increased to greater than 4.0 within two hours after ranitidine treatment. Median gastric pH after the second dose of glutamic acid hydrochloride was significantly lower than before the first dose (grand medians, 1.6 and 6.2, respectively). The time to minimum pH was 2 to 15 minutes, and pH remained less than 3.0 for a mean of 45 minutes. Glutamic acid hydrochloride alone did not decrease fasting gastric pH, but it significantly reduced pH in subjects with simulated hypochlorhydria produced by orally administered ranitidine.

Adult respiratory distress syndrome from sulfuric acid fume inhalation.

A 23-year-old man had adult respiratory distress syndrome (ARDS) caused by acute exposure to sulfuric acid fumes. The patient survived the initial hospitalization to be readmitted later with a lung abscess. After therapy, his chest roentgenogram and pulmonary function tests revealed no abnormalities except a marginally decreased DLCO, and he was without functional deficit. Noncardiogenic pulmonary edema probably resulted from direct alveolar injury caused by sulfuric acid.

Clinical uses of intravenous immune globulin.

The preparation, pharmacokinetics, clinical uses, dosage and administration, and adverse effects of intravenous immune globulin (IVIG) are reviewed. IVIG, which consists primarily of immunoglobulin G (IgG), is initially prepared from pooled human plasma by using the Cohn-Oncley fractionation procedure. Secondary treatments render the preparation suitable for i.v. use. The specific antibody content of IVIG depends on the geographic location of the plasma donors, the product, and the product lot. The metabolism of IgG appears to follow a multicompartmental, first-order process. The half-life of IgG is dependent on the half-lives of the IgG subclasses; three of the four subclasses have half-lives in the range of 23-25 days. IVIG is indicated in the treatment of idiopathic thrombocytopenic purpura (ITP) and as replacement therapy in primary humoral immunodeficiencies (PHI). IVIG has also been used for antimicrobial prophylaxis in bone marrow transplant and burn patients and in patients with malignancies. Patients with HIV infection, cystic fibrosis, neonatal sepsis, and respiratory syncytial virus infection may also benefit from prophylaxis or treatment with IVIG. The recommended dosage of IVIG in ITP is 400 mg/kg/day for two to five days. For the treatment of PHI, the usual dosage is 100-400 mg/kg every three or four weeks. Adverse reactions are often mild and are usually related to the infusion rate. Intravenous immune globulin is a valuable therapeutic tool in several immunodeficiency and autoimmune states, but IVIG products are expensive, and conclusive data on their efficacy in the treatment of many disorders remain to be obtained.

Nontraumatic prehospital sudden death in young adults.

The clinical and/or autopsy records of 83 consecutive adults presenting with nontraumatic prehospital sudden death (NPSD) in a single county were reviewed. Coronary artery disease (CAD) was the primary cause of death in individuals 36 to 45 years old. Non-CAD cardiac disease was the second most common cause of NPSD in this age group. Between the ages of 18 and 35 years, non-CAD cardiac disease was the primary cause and toxic ingestions were the second most common. Patients with rhythms other than ventricular fibrillation/tachycardia, asystole, or electromechanical dissociation on presentation to the emergency room (ER) were more likely to survive. Patients with asystole in the ER were more likely to die in the ER than were patients with other rhythms. Patients with toxic ingestions tended to have a better prognosis for successful resuscitation and for ultimate survival. Age, sex, bystander cardiopulmonary resuscitation, and time in the field were not significant prognostic variables. Patients with abdominal hemorrhage (eight of 83) as the cause of NPSD may represent a subgroup for whom a special approach is warranted. None of these patients survived. Early detection by culdocentesis or paracentesis in female patients of reproductive age and nasogastric lavage or stool occult blood testing could lead to more vigorous fluid resuscitation and early surgical intervention in abdominal hemorrhage.

Patterns of progression and markers of lung injury in rodents and subhuman primates exposed to hyperoxia.

Exposure to high concentrations of oxygen causes injury throughout the respiratory tract. Good markers for the earliest stages of injury are not available although the course of tissue and cell responses to injury has been well characterized in a variety of animal models including rats and subhuman primates. Exposure to subacute levels of hyperoxia (40%-60% O2) causes lung injury that is difficult to detect even after exposures of up to 7 days in duration unless animals are subsequently stressed with a second form of lung injury. Rats preexposed to 40% and 60% O2 die sooner when exposed to 100% O2 than do control animals, suggesting an increased susceptibility to a second injury. Rats exposed to 60% O2 are more susceptible to development of pulmonary edema during high tidal volume mechanical ventilation, suggesting an increased susceptibility to mechanical stress. Exposures to 60% O2 may set up chronic progressive inflammatory reactions in the lung interstitium manifested by an increase in interstitial cells and matrix occurring weeks after the hyperoxic exposure. Both rats and baboons show similar responses to acute lethal exposures to hyperoxia, although the time course is more prolonged in the baboon. Both species demonstrate increased numbers of neutrophils in the lung microvasculature as one of the earliest structural evidences of lung injury. Both species demonstrate an increase in interstitial cells, quantitative evidence of injury to alveolar epithelial cells, and a significant fall in the number of capillary endothelial cells during the late phases of hyperoxic lung injury. These changes are associated with significant decreases in the total lung capacity and residual volume, increases in pulmonary artery pressure and pulmonary vascular resistance, and tachycardia. Baboons develop a 30% reduction in cardiac output after 80 h of 100% oxygen exposure because of a diminished ejection fraction. The primary difference in the progression of lung injury between species is in the time course rather than in the basic pattern of morphologic and physiologic responses.

Pleural amyloidosis.

Pleural amyloidosis has been reported rarely, and the diagnosis of this disease by Cope needle biopsy has, to our knowledge, been reported only once previously. We report two patients in whom the diagnosis of pleural amyloidosis was made by biopsy specimens obtained in the examination of large, unilateral pleural effusions. In one patient, the diagnosis was made by Cope needle biopsy. The clinical and diagnostic significance of these cases are discussed.