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Unlabelled: We investigated the contribution of bicarbonate ion, gamma-aminobutyric acid-A (GABA(A)) receptors, and N-methyl-D-aspartate (NMDA) receptors to pentobarbital-induced enhancement of excitatory synaptic transmission in the hippocampal slice. Transverse hippocampal slices (400 microm thick) were prepared from 20- to 30-day-old Sprague-Dawley rats and maintained in an interface chamber perfused with warmed (35 degrees C) oxygenated artificial cerebrospinal fluid. Extracellular field potentials, evoked by orthodromic paired-pulse stimulation of the Schaffer collateral CA1 pathway, were analyzed for the population spike (PS) amplitude. Pentobarbital had a concentration-dependent, biphasic effect on PS amplitudes, which were increased approximately twofold (P < 0.001) when the slice was exposed to pentobarbital concentrations of 1 and 5 microM and depressed at drug concentrations larger than 10 microM. Pentobarbital (5 microM) did not increase the PS amplitude when stimulation was stopped during exposure to the drug. The enhancement of PS amplitude was suppressed in the presence of 10 microM acetazolamide, a nonselective carbonic anhydrase inhibitor, and when the slice was bathed in CO(2)/HCO(3)(-)-free artificial cerebrospinal fluid. Pretreatment with 1 microM picrotoxin, a GABA(A) receptor antagonist, or 5 microM 2-amino-5-phosphopentanoic acid, a specific NMDA receptor antagonist, also suppressed enhancement of PS amplitude by 5 microM pentobarbital. The results suggest that small concentrations of pentobarbital (1 and 5 microM) enhance synaptic transmission through mechanisms involving GABA(A) and NMDA receptors and the HCO(3)(-) ion., Implications: Enhanced hippocampal synaptic transmission after exposure to subanesthetic concentrations of pentobarbital persists during drug washout. This finding may help to explain why some patients experience excitation and enhanced pain during emergence from anesthesia.

Purpose: To determine whether preserved amniotic membrane can be used to reconstruct the ocular surface after excision of the invading granulation material typical of LOGIC syndrome (laryngeal and ocular granulation tissue in children from the Indian subcontinent)., Methods: Granulation tissue was dissected and excised from both eyes of a 10-year-old boy with LOGIC syndrome. This procedure was followed by coverage of the corneal, scleral, and subtarsal regions of each eye with amniotic membrane, which had been stored for 6 months at -70 degrees C., Results: Initial 2.5-month follow up demonstrated complete disappearance of granulation tissue. The fornices were patent, there was no recurrence of symblepharon, ocular inflammation was suppressed, and the patient reported markedly increased comfort. Both eyelids remained ptotic because of levator muscle atrophy secondary to many years of inability to open either eye. No residual scarring or evidence of granulation tissue was observed in that period. The 10-month follow up demonstrated limited recurrence, particularly where there was an intraoperative break in the amniotic membrane., Conclusions: After 24 operations to treat the ocular complications induced by LOGIC syndrome, amniotic membrane transplantation was the first effective treatment. In the early follow up period (2-3 months), there was complete cessation of the proliferation of granulation tissue and reepithelialization of the corneal surface. Longer follow up (10 months) demonstrated limited recurrence, which will require retreatment.

New contraceptive modalities that are being introduced into the US marketplace reflect many changes in the delivery of existing steroidal products. These products are available now not only as oral medications but also as transdermal, intravaginal, intrauterine, and implantable or injectable devices. Each of these has its own unique profile and enhances the ability of consumers to pick and choose the product that is most acceptable to them. However, development of new barrier contraceptives, particularly those that have the potential to reduce the heterosexual transmission of HIV or to reduce a bacterial infection such as Chlamydia or Neisseria gonorrhea, continues to be moving forward in clinical trials. These products can have a lower efficacy compared with the steroidal products but, because of their other benefits, may be of significant medical use.

Background: Neuronal excitation may result from stimulation of gamma-aminobutyric acid A (GABA(A)) receptors that prolong the channel opening, depolarizing the postsynaptic membrane. Drugs such as acetazolamide or amiloride can block GABA depolarization. Barbiturates facilitate nociceptive reflexes and also prolong the GABA(A) channel open-time. To evaluate the possible mechanism, the authors studied the impact of acetazolamide and amiloride on pentobarbital-induced nocifensive reflex facilitation. Because nitric oxide (NO) is a mediator of reflex facilitation, the authors evaluated the effects of NO synthase inhibition., Methods: Nocifensive reflex thresholds were quantified with the hind paw withdrawal latency from radiant heat (HPW latency) in the rat. Nocifensive reflexes were facilitated with intraperitoneal injection of pentobarbital (30 mg/kg). The authors tested the roles of GABA-mediated depolarization and NO in reflex facilitation by pretreatment with acetazolamide and amiloride and inhibition of NO synthase with L-NAME and 7-NI, respectively. Sedative effects of pentobarbital were evaluated with the righting reflex, the response to vibrissal stimulation, and plasma drug concentrations., Results: Pentobarbital decreased the hind paw withdrawal latency from 11.2+/-1 to 8.3+/-1 s (P < 0.001). Pretreatment with each of the four test drugs limited the reduction in reflex facilitation after pentobarbital to 1.3 s or less, similar to the reduction seen after saline injection, without altering sedation. L-NAME increased plasma pentobarbital concentrations by 10% without changing the concentration associated with return of responsiveness., Conclusions: Pentobarbital-induced nocifensive reflex facilitation was inhibited by all four tested drugs without evidence of increased sedation. The results are consistent with a role for GABA(A) receptor-mediated depolarization in barbiturate-induced hyper-reflexia.

This randomized prospective study measured the effects of an intravenous opioid bolus on cerebrospinal fluid pressure (CSFP), mean arterial pressure (MAP), and cerebral perfusion pressure (CPP) during skull-pin insertion. Twenty-two adult patients scheduled for elective craniotomy for supratentorial lesions were studied. Outcome variables were MAP, heart rate (HR), and lumbar CSFP. The standardized anesthetic regimen included fentanyl (2 microg/kg), thiopental (5-7 mg/kg), lidocaine (1.5 mg/kg), isoflurane (0.3-0.7 minimum alveolar anesthetic concentration), and vecuronium (0.1 mg/kg). During stable anesthesia, sufentanil (0.8 microg/kg) or fentanyl (4.5 microg/kg) was given as a bolus before skull-pin insertion. The hemodynamic effects of the opioid injection were modified with phenylephrine and/or atropine when indicated. CSFP remained unchanged in both treatment groups. MAP and CPP increased approximately 10 mm Hg after skull-pin insertion (P<0.001). In the sufentanil group, HR decreased approximately 10 bpm after opioid injection and remained decreased throughout the study. In fentanyl-treated patients, HR decreased 8 bpm after opioid injection but returned to preopioid rates after skull-pin insertion. In conclusion, in anesthetized patients, an intravenous bolus of fentanyl or sufentanil prior to skull-pin insertion results in stable values of CSFP, CPP, BP, and HR when the hemodynamic effects of the opioid are modified with phenylephrine and atropine.

Use of standard estrogen-progestin contraception remains problematic in several subgroups of patients (e.g., those in whom exogenous estrogens are contraindicated, such as survivors of hormone-dependent cancer, or patients with endometriosis or uterine fibroids). In addition, the postcoital contraception, even if already available, remains at least underused. Additionally, continuous intake of contraceptive steroids is under increasing scrutiny. Would antiprogestins, and specifically the applications of mifepristone such as the ones reviewed in this article offer significant improvements at such problematic occasions? The most attractive novel contraceptive application of mifepristone is that of emergency postcoital contraception after unprotected intercourse. In addition, various options in the endometrial category, specifically those requiring drug administration only during a limited time, might be used in the future. Mifepristone might offer contraceptive and therapeutic relief to patients suffering from endometriosis or uterine fibroids, both conditions that have been shown to benefit from mifepristone therapy. However, the use of mifepristone in contraceptive preparations that are widely available would pose an additional problem of possible misuse of the compound, the reason for currently limiting access to mifepristone. However, such risk should be easily avoidable in the case of postcoital contraception in which only one dose of mifepristone is needed. Regarding the future of mifepristone, and more broadly that of antiprogestins in contraception, the authors believe that they will have a place in the future contraceptive armament. As already emphasized, the strongest clinical areas are those of immediate postcoital and endometrial contraception. Additional studies evaluating parenteral modes of administration, the long-term endometrial effects, and safety and metabolic effects of prolonged antiprogestin administration are needed before mifepristone can be considered a part of the contraceptive arena.

In many studies reporting an increase in cerebrospinal fluid pressure (CSFP) after opioid administration, concomitant decreases in mean arterial pressure (MAP) have been observed. Autoregulatory cerebral vasodilation may therefore have been a factor in the CSFP increases. We tested the hypothesis that increases in CSFP after bolus injection of opioids could be minimized by modifying concomitant decreases in MAP with phenylephrine. Thirty-three patients with supratentorial mass lesions were studied in a randomized, prospective, double-blind, saline-controlled comparative trial. The principal outcome measures were lumbar CSFP, MAP, and heart rate (HR). Study drugs, sufentanil 0.8 micrograms/kg (n = 12), fentanyl 4.5 micrograms/kg (n = 11), or normal saline (n = 10), were injected intravenously (IV) during stable general anesthesia with 0.3-0.7 minimum alveolar anesthetic concentration (MAC) of isoflurane in oxygen and controlled ventilation (end-tidal carbon dioxide 32-35 mm Hg). Phenylephrine 50-100 micrograms was injected IV when MAP decreased by more than 15% of initial values, and atropine 0.5 mg IV when HR decreased to less than 45 bpm. Opioid administration was associated with significant decreases in MAP, 21 +/- 9 mm Hg (mean +/- SD) in the sufentanil group and 16 +/- 7 mm Hg in the fentanyl group; P < 0.001. These decreases in MAP were of short duration (i.e., corrected with 1-2 min). Patients in the sufentanil group needed more phenylephrine than patients in the fentanyl group (170 +/- 89 micrograms vs 100 +/- 47 micrograms; P < 0.05). No significant change in the CSFP was seen in either the sufentanil (1 +/- 6 mm Hg) or fentanyl-treated patients (O +/- 2 mm Hg). No significant changes in MAP or CSFP were observed in the saline-treated patients. HR decreased after injection of either study drug (P < 0.01) but remained unchanged in the saline group. In summary, during stable anesthesia with isoflurane in oxygen, bolus injections of fentanyl or sufentanil, despite producing rapidly corrected mean decreases in MAP of 18% and 25%, respectively, were not associated with any change in CSFP.

Background: Recent studies have suggested that supraspinal structures are involved in barbiturate-induced enhancement of nociceptive processing. The goal of the study was to determine whether cortical and subcortical regions involved in nociception were relatively activated or depressed by noxious stimulation during infusion of small doses of thiopental., Methods: Local cerebral glucose utilization (LCGU) was measured with the 14C-2-deoxyglucose radioautographic technique in 14 rats. During the LCGU experiment, pressure was applied to the tail every 2 min, and the somatic motor response threshold was recorded. Seven animals received thiopental infusions to produce a steady-state plasma concentration (target concentrations of 10 micrograms/ml), and seven untreated animals served as controls., Results: A steady-state plasma thiopental concentration (11.1 +/- 1.8 to 13.0 +/- 2.1 micrograms/ml) was accompanied by a decrease in the somatic motor response threshold from 277 +/- 32 g (before thiopental) to 215 +/- 41 g (P < 0.001). The somatic motor response threshold remained unchanged in the control group. Average LCGU was 29% less in the thiopental-treated animals than in the untreated controls (P < 0.001). In cortical regions associated with nociception, LCGU was relatively increased (+3% +/- 14%) during the thiopental infusion in comparison to the visual and auditory cortices (-18% +/- 13%; P < 0.001). Individual structures that showed relative changes during thiopental infusion included the nucleus accumbens (+17%, P < 0.05) and the habenula (-17%, P < 0.05). Heterogenous relative changes (P < 0.05) in LCGU were observed in the auditory system: auditory cortex (-22%), medial geniculate (-16%), lateral lemniscus (+26%), superior olive (+38%)., Conclusions: Noxious stimulation during low-dose thiopental infusions relatively increased LCGU in cortical regions postulated to be responsible for processing of noxious stimuli. Nuclei in the descending pain modulating system were not relatively depressed.

Microvascular pericytes contain predominantly endothelin A (ET(A))-like binding sites and also a smaller number of ETB binding sites. In this study we verified the expression of both receptors in these cells. We then examined the effect of insulin, a potent mediator of vasodilatation, on the expression of these receptors in pericytes by Northern hybridization. Northern hybridization studies showed that ET(A) mRNA levels were not influenced by exposure to insulin (1 x 10(-7) M). By contrast, ETB receptor mRNA, which was minimal under basal conditions, was significantly increased by 4 h after exposure to insulin.

Objective: To compare the bleeding patterns obtained with two continuous combined and two sequential regimens of conjugated estrogens with medroxyprogesterone acetate (MPA) and conjugated estrogens alone., Methods: This was a 1-year double-blind, randomized study done with 1724 postmenopausal women at 99 sites in the United States and Europe. All five treatment groups received 0.625 mg/day of conjugated estrogens. Groups A and B also took continuous daily doses of 2.5 and 5.0 mg of MPA, respectively. Groups C and D took 5.0 and 10.0 mg of MPA, respectively, for the last 14 days of each 28-day cycle. Group E took continuous daily doses of placebo to match MPA., Results: The two continuous combined regimens (A and B) produced amenorrhea in 61.4 and 72.8%, respectively, of all evaluable cycles. Generally, the incidence of amenorrhea increased and irregular bleeding decreased with longer duration of treatment. In addition, amenorrhea occurred for at least the last seven consecutive cycles of the treatment year for about 40% of the patients taking the lower-dose continuous combined regimen (A), about 50% of the patients taking the higher-dose continuous combined regimen (B), and about 50% of the patients taking conjugated estrogens alone. About 5% of the patients who took either of the sequential regimens (C or D) had amenorrhea during that time. Most of the cycles (81.3 and 77.0% in groups C and D, respectively) for patients taking the sequential conjugated estrogens-MPA regimens had regular withdrawal bleeding or withdrawal spotting. There was no bleeding or spotting in 75.5% of the cycles for patients who took conjugated estrogens alone., Conclusions: Approximately half of the women who took the continuous combined conjugated estrogens-MPA regimens had amenorrhea, and the incidence tended to increase during the study. Women who took the sequential regimens had good cycle control with minimal irregular bleeding. More than half of those who took conjugated estrogens alone had amenorrhea.

Background: Although low doses of barbiturates are widely believed to increase sensitivity to pain, studies of the electrophysiologic effects of these drugs on the neurons involved in nociception in the spinal cord have detected only depressant effects. The goal of the studies reported here was to quantify the hyperalgesia resulting from low-dose thiopental infusions and to measure the associated concentrations of thiopental in the plasma, brain, and spinal cord., Methods: Nociception was measured using the threshold for motor response to pressure stimulation of the tail (nociceptive threshold) and tail flick latency in the rat. Thiopental was administered by intravenous infusions designed to produce plasma concentrations that either slowly increased or remained at a steady state. Plasma and tissue thiopental concentrations were measured by high-performance liquid chromatography., Results: We observed a reduction in nociceptive threshold that was correlated with the plasma thiopental concentration over the range 2-20 micrograms.ml-1 (7.6-76 microM). The relationship was nonlinear. Nociceptive threshold reached a nadir (36% less than control values) at a mean plasma thiopental concentration of 13.7 micrograms.ml-1 (51.9 microM). The steady-state study showed a similar reduction in nociceptive threshold, with an equilibrium plasma thiopental concentration of 7.6 +/- 1.3 micrograms.ml-1 (28.8 +/- 4.9 microM). Concentrations of thiopental in brain and spinal cord samples were 1.7 +/- 0.03 and 3.5 +/- 1.7 micrograms.g-1, respectively., Conclusions: These studies confirm previous reports of hyperalgesia in association with small doses of thiopental. Reductions in nociceptive threshold and tail flick latency were observed in association with spinal cord concentrations of thiopental in a range reported by others to depress the electrophysiologic activity of neurons involved in nociception.

Background: Previous studies have suggested that focal cryogenic brain lesions that cause functional cerebral depression may increase anesthetic potency. To determine whether this effect was caused by changes in nociception, this study prospectively evaluated the influence of an experimental focal brain injury on the analgesic effects of the opioids, fentanyl and alfentanil, in rats., Methods: The cortical freezing lesion was made with a brass probe cooled to -50 degrees C, applied through a craniotomy to the intact dura for 5 s. The analgesic effects of the opioids were quantified by tail-flick latency 3 days after the injury. The prolongation of tail-flick latency by infusions of each opioid in animals injured with a standardized cortical freezing lesion was compared with the results obtained from sham-operated control animals., Results: At the endpoint of the experiment, prolongation of the tail-flick latency to 10 s, the mean serum concentrations (EC50) of both fentanyl and alfentanil were approximately 25% less in the brain-injured animals than in the controls (EC50 fentanyl; injured: 10.2 +/- 2.6 ng/ml, controls: 13.6 +/- 5.2 ng/ml [P < 0.02]; EC50 alfentanil; injured: 54.7 +/- 9.2 ng/ml, controls: 74.3 +/- 18.4 ng/ml [P < 0.02]). For alfentanil, no significant differences in pharmacokinetics between injured and control animals were observed., Conclusions: These results support the hypothesis that reductions in anesthetic requirements in this animal model of brain injury may be caused, in part, by alterations in nociception.

Methods of reversible contraception, oral contraceptives, intrauterine devices, and Norplant (systemic progestin-only contraceptive; Wyeth-Ayerst, Radnor, PA), can be used for women over 35 years of age. Oral contraceptive formulations are safe and effective for healthy women up to the age of menopause. Oral contraceptives in women who do not smoke cigarettes do not result in a significant increased risk for cardiovascular disease. The incidence of breast cancer is not increased in women who have used oral contraceptives. A slight increase was found in younger women who had been on oral contraceptives based on a reanalysis of the contraceptive and steroid hormone study of the Centers for Disease Control. A reduction in the incidence of ovarian epithelial neoplasia by 40% was found in three European case-control studies. Two intrauterine devices are currently available on the US market: Paragard (GynoPharma, Somerville, NJ) and Progestasert (Alza Corp., Palo Alto, CA). Both of these provide highly effective contraception. A World Health Organization prospective randomized study found that there was an increase in pelvic inflammatory disease rates in the first 20 days after intrauterine device insertion. The intrauterine device itself did not increase the pelvic inflammatory disease incidence rates. The Norplant system exerts its contraceptive action through ovulation inhibition and alteration of cervical mucus. The major consumer complaint is irregular or prolonged uterine bleeding, which can be controlled by oral estrogen.