Formulation development of transdermal dosage forms: quantitative structure-activity relationship model for predicting activities of terpenes that enhance drug penetration through human skin.

Terpenes and terpenoids have been used as enhancers in transdermal formulations for facilitating penetration of drugs into human skin. Knowledge of the correlation between the human skin penetration effect (HSPE) and the physicochemical properties of these enhancers is important for facilitating the discovery and development of more enhancers. In this work, the HSPE of 49 terpenes and terpenoids were compared by the in vitro permeability coefficients of haloperidol (HP) through excised human skin. A first-order multiple linear regression (MLR) model was constructed to link the permeability coefficient of the drug to the lipophilicity, molecular weight, boiling point, the terpene type and the functional group of each enhancer. The Quantitative Structure-Activity Relationship (QSAR) model was derived from our data generated by using standardized experimental protocols, which include: HP in propylene glycol (PG) of 3 mg/ml as the donor solution containing 5% (w/v) of the respective terpene, the same composition and volume of receptor solution, similar human skin samples, in the same set of automated flow-through diffusion cells. The model provided a simple method to predict the enhancing effects of terpenes for drugs with physicochemical properties similar to HP. Our study suggested that an ideal terpene enhancer should possess at least one or combinations of the following properties: hydrophobic, in liquid form at room temperature, with an ester or aldehyde but not acid functional group, and is neither a triterpene nor tetraterpene. Possible mechanisms revealed by the QSAR model were discussed.

Measurement of persistence in 1D diffusion.

Using a novel NMR scheme we observed persistence in 1D gas diffusion. Analytical approximations and numerical simulations have indicated that for an initially random array of spins undergoing diffusion, the probability p(t) that the average spin magnetization in a given region has not changed sign (i.e., "persists") up to time t follows a power law t(-straight theta), where straight theta depends on the dimensionality of the system. Using laser-polarized 129Xe gas, we prepared an initial "quasirandom" 1D array of spin magnetization and then monitored the ensemble's evolution due to diffusion using real-time NMR imaging. Our measurements are consistent with analytical and numerical predictions of straight theta approximately 0.12.

Magnetic resonance imaging of convection in laser-polarized xenon.

We demonstrate nuclear magnetic resonance (NMR) imaging of the flow and diffusion of laser-polarized xenon (129Xe) gas undergoing convection above evaporating laser-polarized liquid xenon. The large xenon NMR signal provided by the laser-polarization technique allows more rapid imaging than one can achieve with thermally polarized gas-liquid systems, permitting shorter time-scale events such as rapid gas flow and gas-liquid dynamics to be observed. Two-dimensional velocity-encoded imaging shows convective gas flow above the evaporating liquid xenon, and also permits the measurement of enhanced gas diffusion near regions of large velocity variation.

Reduced xenon diffusion for quantitative lung study--the role of SF(6).

The large diffusion coefficients of gases result in significant spin motion during the application of gradient pulses that typically last a few milliseconds in most NMR experiments. In restricted environments, such as the lung, this rapid gas diffusion can lead to violations of the narrow pulse approximation, a basic assumption of the standard Stejskal-Tanner NMR method of diffusion measurement. We therefore investigated the effect of a common, biologically inert buffer gas, sulfur hexafluoride (SF(6)), on (129)Xe NMR and diffusion. We found that the contribution of SF(6) to (129)Xe T(1) relaxation in a 1:1 xenon/oxygen mixture is negligible up to 2 bar of SF(6) at standard temperature. We also measured the contribution of SF(6) gas to (129)Xe T(2) relaxation, and found it to scale inversely with pressure, with this contribution approximately equal to 1 s for 1 bar SF(6) pressure and standard temperature. Finally, we found the coefficient of (129)Xe diffusion through SF(6) to be approximately 4.6 x 10(-6) m(2)s(-1) for 1 bar pressure of SF(6) and standard temperature, which is only 1.2 times smaller than the (129)Xe self diffusion coefficient for 1 bar (129)Xe pressure and standard temperature. From these measurements we conclude that SF(6) will not sufficiently reduce (129)Xe diffusion to allow accurate surface-area/volume ratio measurements in human alveoli using time-dependent gas diffusion NMR.

A system for low field imaging of laser-polarized noble gas.

We describe a device for performing MRI with laser-polarized noble gas at low magnetic fields (<50 G). The system is robust, portable, inexpensive, and provides gas-phase imaging resolution comparable to that of high field clinical instruments. At 20.6 G, we have imaged laser-polarized (3)He (Larmor frequency of 67 kHz) in both sealed glass cells and excised rat lungs, using approximately 0.1 G/cm gradients to achieve approximately 1 mm(2) resolution. In addition, we measured (3)He T(2)(*) times greater than 100 ms in excised rat lungs, which is roughly 20 times longer than typical values observed at high ( approximately 2 T) fields. We include a discussion of the practical considerations for working at low magnetic fields and conclude with evidence of radiation damping in this system.

Probing porous media with gas diffusion NMR.

We show that gas diffusion nuclear magnetic resonance (GD-NMR) provides a powerful technique for probing the structure of porous media. In random packs of glass beads, using both laser-polarized and thermally polarized xenon gas, we find that GD-NMR can accurately measure the pore space surface-area-to-volume ratio, S/V rho, and the tortuosity, alpha (the latter quantity being directly related to the system's transport properties). We also show that GD-NMR provides a good measure of the tortuosity of sandstone and complex carbonate rocks.

Chorioamniotic separation after second-trimester genetic amniocentesis: importance and frequency.

PURPOSE: To determine the frequency and importance of chorioamniotic separation (CAS) after second-trimester genetic amniocentesis. MATERIALS AND METHODS: In part 1 of the study, ultrasonography (US) databases were reviewed for cases of CAS. In part 2, a study population of 388 women undergoing amniocentesis underwent directed US examination for assessment of CAS 15 minutes and/or 2 weeks after amniocentesis. CAS, when present, was graded. A control population consisted of 363 women undergoing amniocentesis in whom the membranes were not assessed. RESULTS: In part 1, a review of 23,883 records revealed seven cases of complete CAS, with three deaths, two preterm deliveries, and one emergency cesarean section delivery due to fetal distress. In two of these cases, there were extremity deformities at birth. In part 2, CAS was present in 98 (25%) of 388 women at some point. There was no association between CAS and procedural variables. There was no substantial difference in morbidity between patients with and those without CAS, between patients with different grades of CAS, or between the study and control populations. CONCLUSION: Small degrees of CAS are frequently present after amniocentesis but are not detected because the membranes are not specifically evaluated. Complete CAS is less frequent.

Congenital pseudohypoaldosteronism presenting in utero with acute polyhydramnios.

A case of acute polyhydramnios in a fetus with pseudohypoaldosteronism is presented. Although rare, metabolic causes for polyhydramnios should be considered when no obvious cause is found in workup of the pregnant woman and when structural survey of the fetus is normal.

Low-field MRI of laser polarized noble gas.

NMR images of laser polarized 3He gas were obtained at 21 G using a simple, homebuilt instrument. At such low fields magnetic resonance imaging (MRI) of thermally polarized samples (e.g., water) is not practical. Low-field noble gas MRI has novel scientific, engineering, and medical applications. Examples include portable systems for diagnosis of lung disease, as well as imaging of voids in porous media and within metallic systems.

Deep venous thrombosis treated with an inferior vena cava filter in a pregnant woman after recent neurosurgery. A case report.

A pregnant woman developed iliofemoral thrombosis several weeks after neurosurgery; anticoagulation was contraindicated. The thrombosis was treated successfully with an inferior vena cava filter.

Emergency cervical cerclage: a retrospective review of 51 cases.

Fifty-one patients underwent emergency cervical cerclage using Shirodkar or McDonald suture for incompetent cervix diagnosed during pregnancy. Fifteen patients had only sonographic evidence of cervical incompetence (group I). Eighteen patients had cervical dilation of less than 3 cm (group II), and 18 patients had cervical dilation of 3 cm or more (group III). Perinatal mortality was 0%, 50%, and 55.6%, respectively. The median length of time gained with the cerclage was 16 weeks in group I, 1.8 weeks in group II, and 1 week in group III. Twelve infants required prolonged stay in the neonatal intensive care nursery because of prematurity. Six of 30 surviving infants had some abnormal physical findings at the time of initial discharge from the nursery. Premature rupture of membranes was the most common perioperative and postoperative complication. Chorioamnionitis developed in 17 of the 51 cases. Maternal complications included cervicovaginal fistula, deep vein thrombophlebitis, and pulmonary edema.

Pasteurella multocida chorioamnionitis from vaginal transmission.

A 21 year old primigravida with a twin pregnancy developed Pasteurella multocida chorioamnionitis. Infection occurred at 27 weeks gestational age after prolonged rupture of membranes. The twin in the separate sac presenting proximal to the cervix suffered infection and died shortly after birth whereas the other twin was not infected. The bacterium is believed to have caused ascending infection from asymptomatic colonization of the vaginal tract.

Delayed delivery of second twin: report of four cases and review of the literature.

In four cases of delayed delivery of a twin pregnancy with survival of the second twin, the interval ranged at 41-143 days. Review of the literature and our cases supports the following approach: high ligation of the umbilical cord with an absorbable suture, cervical suture in the presence of cervical dilatation, and serial monitoring of fetal growth and maternal coagulation indices. Disseminated intravascular coagulation has not been reported in such cases.