Prodrugs for targeting hypoxic tissues: regiospecific elimination of aspirin from reduced indolequinones

We report the cases of three patients with anorexia nervosa (AN) who each recovered rapidly after experiencing a life-threatening episode with severe thrombocytopenia. All three cases were the typical restricting-type of AN, occurring in adolescence. They refused to be admitted to a hospital until their general condition had been severely deteriorated. Their lowest platelet counts were 2.9, 4.6, and 2.3 x 10(4)/mm3, respectively. Apparent hemorrhagic tendencies, such as purpura, gingival and nasal bleeding, and gastrointestinal bleeding were observed. The bone marrow examination showed apparent hypoplasia in two patients. No evidence of disseminated intravascular coagulation or autoantibody to platelets was detected. The platelet counts recovered rapidly by water and nutritional supplementation. The recovery from the AN itself was excellent in all three patients without specific psychotherapy.     

Clinical utility of human polymerized hemoglobin as a blood substitute after acute trauma and urgent surgery

We have previously documented the safety of 1 unit (50 gram) of human polymerized hemoglobin (Poly SFH-P) in healthy volunteers. This report describes the first patient trial to assess the therapeutic benefit of Poly SFH-P in acute blood loss. Thirty-nine patients received 1 (n = 14), 2 (n = 2), 3 (n = 15), or 6 (n = 8) units of Poly SFH-P instead of red cells as part of their blood replacement after trauma and urgent surgery. There were no safety issues related to the infusion of Poly SFH-P. The plasma hemoglobin concentration ([Hb]) after the infusion of 6 units (300 gram) of Poly SFH-P was 4.8 +/- 0.8 g/dL (mean +/- SD). Although the red cell [Hb] fell to 2.9 +/- 1.2 g/dL, the total [Hb] was maintained at 7.5 +/- 1.2 g/dL. Poly SFH-P maintained total [Hb], despite the marked fall in red cell [Hb] due to blood loss. The utilization of O2 (extraction ratio) was 27 +/- 16% from the red cells and 37 +/- 13% from the Poly SFH-P. Twenty-three patients (59%) avoided allogeneic transfusions during the first 24 hours after blood loss. Poly SFH-P effectively loads and unloads O2 and maintains total hemoglobin in lieu of red cells after acute blood loss, thereby reducing allogeneic transfusions. Poly SFH-P seems to be a clinically useful blood substitute.     

Social phobia: long-term treatment outcome and prediction of response--a moclobemide study

In this open, prospective, structured, naturalistic study of the efficacy of long-term treatment in social phobia 93 consecutive outpatients suffering from severe generalized or circumscribed social phobia (median Liebowitz Social Anxiety Scale score 83) and a high degree of concomitant psychiatric disease were administered treatment with moclobemide (712 +/- 75 mg/day at steady state). Fifty-nine patients who responded (Clinical Global Impression for Change: very much/much improved) completed 2 years of treatment. Patients then entered a drug-free period of at least 1 month during which 88% of the patients deteriorated. In a further 2-year treatment period with moclobemide those patients who had deteriorated became responders again. Symptoms recurred in a substantial number of the patients at the end of the study when the dose was reduced and then discontinued. Post-study follow up at 6-24 months after study completion found that 63.2% of patients were almost asymptomatic or had only mild symptoms, 15.8% were off all treatment, 28.1% were back on moclobemide, 10.6% were taking another psychotropic drug and 8.8% were in psychotherapy. All previous non-responders to moclobemide and mostly alcohol abusers (36.9%), had moderate or severe social phobia and were off all treatment (13.3%), on psychotherapy (15.9%) or on another psychotropic drug (8.8%). Discriminant analysis correctly predicted outcome in 93.5% of all patients. Alcohol abuse was by far the strongest predictor of negative outcome. Coexisting generalized anxiety disorder and dysthymia were less potent in this regard, whereas high baseline Hamilton anxiety or depression scale scores, circumscribed social phobia, or social phobia unassociated with avoidant personality disorder were predictors of a positive outcome. In conclusion, severe social phobia can be successfully treated in the long-term but many patients may need medication or psychotherapy for many years. Treatment should start as early as possible because complications such as alcohol abuse make treatment difficult.     

Neutral endopeptidase activity in newborn and adult rabbit tracheas

Neutral endopeptidase (NEP, E.C. 3.4.24.11), a widely distributed ectoenzyme, cleaves and inactivates a variety of biologically active peptides, including the tachykinin, substance P (SP). This study was undertaken to determine whether the modulation of SP airway smooth muscle contraction by NEP is age-dependent. We studied the contractile response of isolated tracheal rings from newborn and 120 day old New Zealand white rabbits. We measured NEP activity and determined immunoreactive NEP content in tracheal membrane preparations. NEP activity was then localized histochemically in sections of rabbit tracheas. In the presence of the NEP inhibitor, SCH 32615, the contractile response of isolated tracheal rings to SP was increased both in the newborn and 120 day old rabbits. However, the increase was greatest in the newborn animals. NEP activity in tracheal membrane preparations increased fivefold between the newborn and 120 day old rabbits. Western blot analysis also revealed a significant increase in the immunoreactive NEP content of these tracheal membrane preparations between the newborn and 120 day old rabbits. NEP activity, localized histochemically, was most intense in the epithelial region of the newborn animals, with a shift of activity to the subepithelial region with age. The prominent epithelial localization of neutral endopeptidase in the tracheas of these 1 day old rabbits, which we have shown to have relatively low neutral endopeptidase activity, suggests that the location of neutral endopeptidase in the airway, including proximity to relevant substance P receptors, may be critical to its function.     

Computerized medication instruction for psychiatric inpatients admitted for acute care

We studied the efficacy and feasibility of using computer-based instruction to provide medication information to hospitalized patients with acute psychotic conditions. Patients were randomly assigned to receive computer-based (n = 21) or personal instruction (n = 21); for the final analyses the computer group was expanded to include 13 patients from a pilot study. Outcome measures were knowledge retention (indicated by changes in test scores) and compliance with medication regimens after discharge (indicated by telephone follow-up at one week, one month, and three months). The subjects reacted positively to the computer program. Knowledge retention and compliance were similar in the computer and control groups. We conclude that psychiatric inpatients admitted for acute care can participate in, and learn from, computerized medication instruction.     

Lack of association between antiphospholipid antibodies and first-trimester spontaneous abortion: prospective study of pregnancies detected within 21 days of conception

OBJECTIVE: To determine the role of antiphospholipid antibodies and anticardiolipin antibodies in first-trimester losses, addressing experimental pitfalls that preclude excluding the possibility that these antibodies reflect merely the selection bias of studying couples only after they have already experienced losses. DESIGN: Given that retrospective studies cannot exclude the possibility that such antibodies arise as a result of the fetal death, blood samples were obtained either before pregnancy or very early in pregnancy. Sera were obtained within 21 days of conception. SETTING: Multicenter university-based hospitals (National Institute of Child Health and Human Development collaborative study). PATIENT(S): Subjects for the current study were 93 women who later experienced pregnancy loss (48 diabetic; 45 nondiabetic), matched 2:1 with 190 controls (93 diabetic and 97 nondiabetic) who subsequently had normal live-born offspring. INTERVENTION(S): Sera from these 283 women were analyzed for antiphospholipid antibodies by enzyme immunoassay. In 260 of the 283 women (87 with pregnancy losses; 173 with live-born infants), sera were also available to perform assays for anticardiolipin antibodies by enzyme immunoassay. MAIN OUTCOME MEASURE(S): Pregnancy losses. RESULT(S): No association was observed between pregnancy loss and the presence of antiphospholipid antibodies or anticardiolipin antibodies. Levels of antiphospholipid antibodies were 6-19 PL/mL in 62.4% of the pregnancies that ended in losses and > or = 20 PL/mL in 5.4%; among pregnancies resulting in live-born infants, the percentages were 56.8% and 6.8%, respectively. Of the pregnancies that ended in a loss, 5.7% had anticardiolipin antibodies > or = 16 GPL/mL, compared with 5.2% of those ending in a live birth. CONCLUSION(S): This prospective study suggests that anticardiolipin antibodies and antiphospholipid antibodies are not associated with an increased risk for first-trimester pregnancy loss.     

Isolated lung perfusion with tumor necrosis factor for pulmonary metastases

BACKGROUND: A phase I trial was initiated to define the feasibility and safety of single-lung isolation perfusion with tumor necrosis factor-alpha, interferon-gamma, and moderate hyperthermia for patients with unresectable pulmonary metastases. METHODS: Twenty patients with lung metastases (Ewing's, 2; sarcoma, 8; melanoma, 6; other, 4) were considered for single-lung isolation perfusion with 0.3 to 6.0 mg of tumor necrosis factor-alpha and 0.2 mg interferon-gamma delivered through an oxygenated pump circuit. Sixteen perfusions were performed in 15 patients (bilateral in 1). Metastases were completely resected (no single-lung isolation perfusion) in 3 patients, 1 patient had extrapulmonary disease, and one single-lung isolation perfusion was aborted for mechanical reasons. RESULTS: There were no significant changes in systemic arterial blood pressure or cardiac output during perfusion. Systolic pulmonary artery pressure increased with isolation, but returned to pre-single-lung isolation perfusion levels after clamp release. The maximum systemic tumor necrosis factor-alpha level was 8 ng/mL, whereas pump-circuit levels ranged from 200 to 10,976 ng/mL. There were no deaths, and the mean hospitalization period was 9 days (range, 5 to 34 days). A short-term (6 to 9 month) unilateral decrease in perfused nodules was noted in 3 patients (melanoma in 1, adenoid cystic carcinoma in 1, renal cell carcinoma in 1). CONCLUSIONS: Future studies using a combination of biologic modifiers, chemotherapy, and hyperthermia should be pursued to define active cytotoxic agents that will preserve underlying pulmonary function.