Human antibodies can cross guinea pig placenta and bind its neonatal Fc Receptor: implications for studying immune prophylaxis and therapy during pregnancy.

Despite increased use of monoclonal and polyclonal antibody therapies, including during pregnancy, there is little data on appropriate animal models that could humanely be used to understand determinants of protection and to evaluate safety of these biologics in the mother and the developing fetus. Here, we demonstrate that pregnant guinea pigs can transport human IgG transplacentally at the end of pregnancy. We also observe that human IgG binds to an engineered soluble variant of the guinea pig neonatal Fc receptor in vitro in a manner similar to that demonstrated for the human variant, suggesting that this transplacental transport mirrors the receptor-based mechanism seen in humans. Using an intravenous antihepatitis B-specific immune globulin preparation as an example, we show that this transport results in neutralizing activity in the mother and the newborn that would potentially be prophylactic against hepatitis B viral infection. These preliminary data lay the groundwork for introducing pregnant guinea pigs as an appropriate model for the evaluation of antibody therapies and advancing the health of women and neonates.

Increased levels of IgE and autoreactive, polyreactive IgG in wild rodents: implications for the hygiene hypothesis.

To probe the potential role of Th1 versus Th2 reactivity underlying the hygiene hypothesis, intrinsic levels of Th1-associated and Th2-associated antibodies in the serum of wild rodents were compared with that in various strains of laboratory rodents. Studies using rat lung antigens as a target indicated that wild rats have substantially greater levels of autoreactive, polyreactive immunoglobulin G (IgG), but not autoreactive, polyreactive IgM than do laboratory rats, both on a quantitative and qualitative basis. Increased levels of serum IgG and IgE were observed in both wild rats and wild mice relative to their laboratory-raised counterparts, with the effect being most pronounced for IgE levels. Further, wild rats had greater intrinsic levels of both Th1- and Th2-associated IgG subclasses than did lab rats. The habitat (wild versus laboratory raised) had a more substantial impact on immunoglobulin concentration than did age, strain or gender in the animals studied. The presence in wild rodents of increased intrinsic, presumably protective, non-pathogenic responses similar to both autoimmune (autoreactive IgG, Th1-associated) and allergic (IgE, Th2-associated) reactions as well as increased levels of Th1-associated and Th2-associated IgG subclasses points toward a generally increased stimulation of the immune system in these animals rather than a shift in the nature of the immunoreactivity. It is concluded that, at least to the extent that feedback inhibition is a controlling element of immunoreactivity, an overly hygienic environment may affect the threshold of both types of immune responses more so than the balance between the different responses.

Exposure of mice to topical bovine thrombin induces systemic autoimmunity.

Bovine thrombin is used as an aid to hemostasis in medical and surgical procedures. At least 500,000 Americans are exposed to this therapeutic annually and reports suggest that exposure is associated with the development of autoreactive antibodies. To determine whether bovine thrombin can induce pathological autoimmunity we exposed nonautoimmune-prone galactose-alpha1-3-galactose-deficient mice to the two bovine thrombin preparations currently approved for use in the United States. We found that, like humans exposed to bovine thrombin, mice developed an immune response against the therapeutic and the xenogeneic carbohydrate galactose-alpha1-3-galactose, and some mice developed autoantibodies against clotting factors. Further, unexpectedly, a single exposure to this therapeutic also induced autoimmunity with features characteristic of systemic lupus erythematosus including antibodies against nuclear antigens, native DNA, double-stranded DNA, and cardiolipin. High levels of these autoantibodies correlated with glomerulonephritis in all mice evaluated. This autoimmune syndrome was detected in mice 15 weeks after a secondary exposure to bovine thrombin and female mice were found to develop the syndrome at a significantly greater frequency than males. Thus, these studies indicate that exposure to bovine thrombin preparations can induce a pathological systemic autoimmune syndrome with lupus-like serology.

Cesarean section in a severely traumatized patient.

Massive trauma in a near-term pregnant patient challenges the emergency physician with very difficult treatment choices. We present the case of a severely traumatized pregnant female, near term, in whom the decision to proceed with a perimortem cesarean section in the Emergency Department produced a viable infant. We discuss the guidelines that are used in making such a decision and their rationale. The physiologic changes of pregnancy that may complicate maternal assessment and the effect of shock on the fetus are also discussed.

Hepatoblastoma in a patient with familial polyposis coli.

Two cases of hepatocellular carcinoma in patients with familial polyposis coli (FPC) have recently been reported in the literature. Hepatoblastoma was also reported in five children with maternal ancestors with FPC. We report a case of hepatoblastoma in a female infant whose father has FPC as further evidence of an association between hepatoblastoma and FPC.

Dissecting aneurysm of the hepatic artery.

Aneurysms of the hepatic artery are rare and frequently diagnosed only at autopsy. First described by Wilson over 250 years ago, less than 400 cases have been reported in the literature (1,2). Dissection of these aneurysms is documented even less frequently, with only 11 cases reported in a review by Larson et al. (3). A case of sudden death from dissection and rupture of such an aneurysm was seen at the Westchester County Medical Examiner's Office, New York.

Bioequivalence of carbamazepine chewable and conventional tablets: single-dose and steady-state studies.

Single-dose and steady-state studies were carried out on separate occasions to examine the bioequivalence of the newly formulated carbamazepine chewable tablet. In the single-dose study, the plasma levels resulting from 2 X 200-mg conventional tablets (CT), 4 X 100-mg chewable tablets swallowed whole (SW), and 4 X 100-mg chewable tablets chewed before swallowing (CHEW) were compared. A randomized 3 X 3 Latin-square design balanced for residual effects, with a 3-week washout period, was used (n = 6). Plasma samples were analyzed by a specific GC method for carbamazepine. The following parameters were used for evaluation: AUC, Cmax, tmax, and t1/2. None of the parameters were significantly different except Cmax and t1/2 values for CHEW and CT. The Cmax was 25% higher and t1/2 was 11% shorter for CHEW than CT. The impact of differences in the peak plasma levels at steady state were examined by pharmacokinetic projection (400 mg b.i.d.) based on the single-dose data and with simulated induction equal to a 50% reduction in t1/2. The projected steady-state CT and CHEW plasma concentrations were similar, with a difference of only 4%. The results demonstrate the bioequivalence of the dosage forms with respect to the extent of absorption, and similar steady-state concentrations of carbamazepine in plasma can be expected. To test the conclusion from the projected study, a separate bioequivalence study to compare CHEW relative to CT was performed at steady state in normal volunteers (200 mg b.i.d.).(ABSTRACT TRUNCATED AT 250 WORDS)

Kinetics of hydrochlorothiazide absorption in humans.

The kinetics of absorption of hydrochlorothiazide was studied in four adult male volunteers. Plasma levels were monitored for 48 h after a 100-mg dose. Food, electrolyte, and water intake were regulated as far as possible. The plasma level data were fitted to a two-compartment open model with either first-order or zero-order absorption, using the pharmacokinetic computer program AUTOAN. A better fit of the data, both graphically and statistically, was obtained with zero-order absorption kinetics. Additional confirmation of absorption kinetics was obtained by treating the plasma level results by the Loo-Riegelman method. Cartesian graphs of the amount absorbed verus time afforded linear plots, which indicate a zero-order process.

Bioavailability and kinetics of maprotiline.

Six male subjects received simultaneously single 50-mg oral doses of a maprotiline hydrochloride tablet and a trideuterated maprotiline hydrochloride aqueous solution. No side effects or other problems were encountered. The blood levels of unlabeled and isotope-labeled maprotiline for each subject were essentially superimposable. Peak levels, averaging about 50 ng/ml, were attained between 8 and 24 hr after drug. The biologic t1/2 (beta-phase) averaged 58 hr for the unlabeled and 60.5 hr for the labeled drug. The total areas under the curves (extended to time infinity) averaged 3,862 and 3,944 ng . hr/ml for maprotiline and trideuterated maprotiline, respectively (differences between the two are not significant). At the 95% degree of confidence the Westlake confidence limits show less than 10% differences between the formulations with respect to area under the curve data (calculated both to 168 hr and extended to time infinity), peak blood levels, and biologic t1/2s. There were no differences between formulations with respect to times of peak concentrations. Estimates were made for apparent volumes of distribution (about 1,000 l), apparent blood clearance (about 14 l/hr), lag times (about 1.42 hr for tablets and 1.31 hr for solution), and absorption rate constants (about 0.34 hr-1 for the tablets and 0.42 hr-1 for the solution).