St John's wort (Hypericum perforatum): drug interactions and clinical outcomes.

AIMS: The aim of this work is to identify the medicines which interact with the herbal remedy St John's wort (SJW), and the mechanisms responsible. METHODS: A systematic review of all the available evidence, including worldwide published literature and spontaneous case reports provided by healthcare professionals and regulatory authorities within Europe has been undertaken. RESULTS: A number of clinically significant interactions have been identified with prescribed medicines including warfarin, phenprocoumon, cyclosporin, HIV protease inhibitors, theophylline, digoxin and oral contraceptives resulting in a decrease in concentration or effect of the medicines. These interactions are probably due to the induction of cytochrome P450 isoenzymes CYP3A4, CYP2C9, CYP1A2 and the transport protein P-glycoprotein by constituent(s) in SJW. The degree of induction is unpredictable due to factors such as the variable quality and quantity of constituent(s) in SJW preparations. In addition, possible pharmacodynamic interactions with selective serotonin re-uptake inhibitors and serotonin (5-HT(1d)) receptor-agonists such as triptans used to treat migraine were identified. These interactions are associated with an increased risk of adverse reactions. CONCLUSIONS: In Sweden and the UK the potential risks to patients were judged to be significant and therefore information about the interactions was provided to health care professionals and patients. The product information of the licensed medicines involved has been amended to reflect these newly identified interactions and SJW preparations have been voluntarily labelled with appropriate warnings.

[Endometriosis--an inflammatory disease in women. Pain and reduced fertility are serious symptoms]. / Endometrios--en inflammatorisk kvinnosjukdom. Smärta och reducerad fertilitet allvarliga symptom.

Endometriosis is a common disease with serious consequences for the patient and for society. Until now there has been no reliable method for diagnosing endometriosis besides direct visualization, e.g. utilizing laparoscopy. IVF offers the most successful treatment of endometriosis-related infertility, and a patient should be offered that treatment after one year of infertility. Waiting lists are often rather long, and other treatment modalities might be attempted while waiting for IVF. Pharmacological treatment does not increase the chances of pregnancy, while surgical extirpation of mild to moderate endometriosis might well result in a pregnancy earlier than anticipated.

[Current aspects on the treatment of endometriosis]. / Aktuella aspekter på behandling av endometrios.

The aim of pharmacological treatment of endometriosis is to reduce estrogen levels, which may be achieved using gestagens or GnRH-agonists. The effects of the different hormones are mainly the same, while side effects differ. If the GnRH-agonist dose is modified, or if a low dose of estrogen and/or gestagen is given in addition, the hypo-estrogenic side effects of GnRH-agonists can be reduced. Surgical treatment can often be performed in conjunction with diagnostic laparoscopy. Supplementary hormonal treatment may postpone recurrence. Because endometriosis is in many women a chronically recurring disorder, continuity in the doctor-patient relationship is essential.

Development of a new method for the determination of immune responses in the human stomach.

The discovery of the gastric pathogen Helicobacter pylori has created a need for accurate methods to study immune responses locally in the human stomach. Therefore, we have developed a quick and easy method for extraction of antibodies from gastric biopsies using saponin and compared this method with the more laborious analysis of antibody-secreting cells (ASCs) from gastric biopsies. We have also analyzed the antibody content in gastric aspirates, saliva and plasma. There was a strong correlation between the total IgA levels in the biopsy extracts and the frequencies of IgA-secreting cells. In addition, the IgA and IgG levels against a H. pylori whole membrane preparation and purified urease in the biopsy extracts correlated well with the frequencies of specific IgA and IgG secreting cells. However, the antibody levels in gastric aspirates, saliva and plasma specimens did not correlate with the frequencies of corresponding ASC in the gastric biopsies. Thus, the saponin extraction method is suitable for monitoring local antibody responses in the stomach, while analyses of gastric aspirates, saliva or plasma are not appropriate for this purpose.

Antibody responses in serum and lung to intranasal immunization with Haemophilus influenzae type b polysaccharide conjugated to cholera toxin B subunit and tetanus toxoid.

AIM: Cholera toxin B subunit (CTB) has previously been used as a mucosal carrier for various vaccine candidate antigens. The objective of this study was to see if coupling a bacterial polysaccharide, Haemophilus influenzae type b capsular polysaccharide (HibCPS), to CTB, either directly or through prior coupling to tetanus toxoid (TT), would improve the immunogenicity of HibCPS after nasal immunization. METHODS: HibCPS was conjugated to CTB, TT or via TT to CTB, using glutaraldehyde or 1-ethyl-3(3-dimethylaminopropyl)-carbodiimide (EDAC) and N-succinimidyl 3-(2-pyridyldithio) propionate (SPDP). The conjugates were characterized and used for intranasal (IN) and subcutaneous (SC) immunizations of mice. The anti-Hib, -TT and -CTB antibody titers in serum and lungs after the immunizations were measured with ELISA. RESULTS: The HibCTB was poorly immunogenic both given IN and SC compared with HibTT and HibTTCTB, probably because of inefficient coupling. In contrast, the conjugation of CTB to the HibTT conjugate resulted in a preparation which was superior both to the HibTT and the HibCTB conjugates in inducing local IgA and IgG anti-HibCPS antibodies in the lungs. The anti-HibCPS serum IgG titers after IN immunization with the HibTTCTB conjugate were similar to the titers after IN immunization with HibTT, or SC immunization with a commercial HibCRM conjugate vaccine. In contrast to the other conjugates, the HibTTCTB conjugate also gave rise to anti-Hib serum IgA titers. CONCLUSION: We conclude that appropriate conjugation to CTB increases the mucosal immunogenicity of HibCPS, and that intranasal immunization with such a conjugate can give rise to both local and systemic anti-HibCPS antibody responses.

Differential kinetics and distribution of antibodies in serum and nasal and vaginal secretions after nasal and oral vaccination of humans.

Although nasal vaccination has emerged as an interesting alternative to systemic or oral vaccination, knowledge is scarce about the immune responses after such immunization in humans. In the present study, we have compared the kinetics and organ distribution of the antibody responses after nasal and oral vaccination. We immunized female volunteers nasally or orally with cholera toxin B subunit (CTB) and determined the specific antibody levels in serum and nasal and vaginal secretions, as well as the number of circulating antibody-secreting cells, before immunization and 1, 2, 3, 6, and 26 weeks thereafter. Nasal vaccination induced 9-fold CTB-specific immunoglobulin A (IgA) and 56-fold specific IgG antibody increases in nasal secretions, whereas no significant IgA increase was seen after oral vaccination. Both oral and nasal vaccination resulted in 5- to 6-fold CTB-specific IgA and 20- to 30-fold specific IgG increases in vaginal secretions. Strong serum responses to CTB were also induced by both routes of vaccination. A notable difference between nasal and oral vaccination was that the nasal route elicited a specific antibody response with a later onset but of much longer duration than did the oral route. We conclude from this study that the nasal route is superior to the oral route for administering at least nonliving vaccines against infections in the upper respiratory tract, whereas either oral or nasal vaccination might be used for eliciting antibody responses in the female genital tract.

Intranasal vaccination of humans with recombinant cholera toxin B subunit induces systemic and local antibody responses in the upper respiratory tract and the vagina.

Forty-five volunteers were vaccinated twice intranasally with 10, 100, or 1,000 microg of cholera toxin B subunit (CTB). Blood and nasal and vaginal secretions were collected before and 1 week after the second vaccination from all volunteers, and the specific and total immunoglobulin A (IgA) and IgG titers were determined by enzyme-linked immunosorbent assay. Samples were also taken 6 months (n = 16) and 1 year (n = 14) after the vaccination. The 10- and 100-microg doses were well tolerated by the volunteers, but the 1,000-microg dose induced increased secretions from the nose and repetitive sneezings for several hours. The CTB-specific serum IgA and IgG increased 21- and 7-fold, respectively, 1 week after vaccination with the medium dose and increased 61- and 37-fold, respectively, after the high dose. In nasal secretions the specific IgA and IgG increased 2- and 6-fold after the medium dose and 2- and 20-fold after the high dose, respectively. In vaginal secretions the specific IgA and IgG increased 3- and 5-fold after the medium dose and 56- and 74-fold after the high dose, respectively. The lowest dose did not induce any significant antibody titer increases in serum or in secretions. The specific IgA and IgG levels in secretions were still elevated after 6 months but were decreasing 1 year after the vaccination. These results show that intranasal vaccination of humans with CTB induces strong systemic and mucosal antibody responses and suggest that CTB may be used as a carrier for antigens that induce protective immunity against systemic as well as respiratory and genital infections.

Anticarrier immunity suppresses the antibody response to polysaccharide antigens after intranasal immunization with the polysaccharide-protein conjugate.

We have conjugated cholera toxin (CT) B subunit (CTB) to dextran and studied the effect in mice of previous immunization with CT and CTB on the response to dextran after intranasal immunizations with conjugate. Preexisting immunity to CTB was found to inhibit both the lung mucosal response and serum antibody response to dextran, but this effect could be overcome by using a higher dose of conjugate and delaying the conjugate immunization until the CTB antibody titers had declined. The role of anti-CTB antibodies on the mucosal surface was probably to prevent uptake of the conjugate through a mechanism of immune exclusion. Passively transferred serum antibodies against CTB, on the other hand, suppressed both the serum response and the local antibody response against CTB but did not affect the response to dextran after intranasal immunization with conjugate.

Therapeutic efficacy and bone mineral density response during and following a three-month re-treatment of endometriosis with nafarelin (Synarel).

OBJECTIVE: Our goal was to determine the effects of a repeated course of the gonadotropin-releasing hormone agonist nafarelin on symptoms and signs of endometriosis and lumbar and distal radius bone mineral density. STUDY DESIGN: Forty-five women previously treated for 6 months with nafarelin, who had recurrent symptoms and signs of endometriosis, received 400 mcg/day of nafarelin intranasally for 3 months. Efficacy was evaluated by changes in severity of symptoms and signs. Lumbar bone mineral density was measured by dual-energy x-ray absorptiometry and distal radius bone mineral density by single-photon absorptiometry. Bone mineral density was also measured in 10 control volunteers. RESULTS: Repeated 3-month treatment significantly alleviated recurrent symptoms and signs of endometriosis. Lumbar bone mineral density decreased significantly by a mean of 2% at the end of treatment; this loss was restored within 3 to 6 months after treatment completion. No bone mineral density decline occurred in the radius. Bone mineral density changes in the control group were statistically insignificant. CONCLUSIONS: A repeated 3-month course of nafarelin treatment significantly relieved recurrent endometriotic symptoms and signs without sustained loss of bone mineral density.

Immediate postpartum insertion of the norplant contraceptive device.

OBJECTIVE: To determine the safety and efficacy of Norplant (Wyeth-Ayerst Laboratories, Philadelphia, PA) insertion immediately postpartum. DESIGN: Prospective study of 14 women receiving Norplant immediately postpartum compared with controls (n = 6) having a bilateral tubal ligation. Subjects were followed for 3 months postpartum, and data were analyzed by analysis of variance and chi2. SETTING: Academic Health Sciences Center. PATIENTS: Female subjects 18 to 35 years old who had an uncomplicated term pregnancy, normal spontaneous vaginal delivery, and did not breast-feed. INTERVENTION: A brief interview, physical exam, and blood and urine samples were evaluated during a 12-week postpartum period. MAIN OUTCOME MEASURES: Major complaints, serum chemistry panels, hematologic and coagulative measures, serum E2, P, levonorgestrel, PRL, LH, FSH, and urinary estrone-3 conjugates and pregnanediol-3-glucuronide concentrations. RESULTS: Serum levonorgestrel peaked at approximately 2,000 pg/mL (6,400 pmol/L) during the 1st week after Norplant insertion, declining to approximately 250 pg/mL (800 pmol/L) by the 8th week. Significant differences between Norplant and control groups included bleeding irregularities, headaches, alopecia, and abdominal discomfort. Serum electrolytes, metabolic markers, and blood components were within normal limits. Serum E2, P, and urinary steriod biomarkers indicated that steroid secretion was suppressed severely in the Norplant group compared with controls who exhibited normal postpartum ovarian activity. CONCLUSION: Norplant inserted immediately postpartum appears to be a safe and effective method of contraception. However, the long-term hypoestrogenic state and contraceptive efficacy beyond the 3-month postpartum period as observed in this study are concerns that need further clinical evaluation.

PIP: During December 1992 to October 1994, in Texas, clinical researchers conducted a prospective case control study (15 cases receiving Norplant immediately postpartum vs. 6 controls undergoing bilateral tubal ligation immediately postpartum) to determine the safety and efficacy of inserting the contraceptive implant Norplant (6 capsules inserted subdermally, each containing 35 mg levonorgestrel) immediately postpartum. They followed the cases and the controls for three months. The study subjects were 18-35 years old, received prenatal care at one of the Department of Obstetrics and Gynecology's (Texas Tech University Health Sciences Center) community clinics, had an uncomplicated term pregnancy and normal spontaneous vaginal delivery, and did not breast feed. They tended to be poor. During the first week after Norplant insertion, serum levonorgestrel levels peaked at about 2000 pg/ml, then fell abruptly until about the eighth week to about 250 pg/ml. This lower levonorgestrel level concerned the researchers because it is just slightly higher than levels associated with pregnancy. They were also concerned about the possibility of Norplant inducing a hypoestrogenic state in postpartum women. The Norplant group was more likely than the tubal ligation group to experience irregular bleeding (p 0.01), headaches (p 0.01), hair loss (p 0.05), and abdominal discomfort (p 0.05). The various serum metabolic biomarkers, serum electrolytes, and blood components fell into the normal range in both groups. The serum estradiol, progesterone, and urinary steroid biomarkers suggested that the Norplant group experienced very suppressed steroid secretion throughout the three month study period, while the controls had normal postpartum ovarian activity. Thus, ovarian activity was absent in the Norplant group. These findings suggest that postpartum insertion of Norplant is safe and effective. Yet further clinical evaluation is needed to address concerns about the long-term hypoestrogenic state and contraceptive efficacy beyond the three month postpartum period.

Local and systemic antibody responses to dextran-cholera toxin B subunit conjugates.

This study was designed to test local and systemic immunity following mucosal immunization with a polysaccharide-protein conjugate. After preparing and characterizing dextran-cholera toxin B subunit (CTB) conjugates, we studied their immunogenicity in mice following systemic or mucosal immunizations. Dextran was chosen as a model polysaccharide antigen and conjugated via adipic acid dihydrazide and N-succinimidyl-3-(2-pyridyldithio)propionate to CTB. Mice were immunized either subcutaneously, intranasally, or perorally three times, and cholera toxin was used as an adjuvant for the mucosal immunizations. Three conjugates with different molecular weights for dextran (40,000 and 76,000) or varying dextran/CTB molar ratios were tested. Peroral immunizations with all conjugates evoked local immunoglobulin A (IgA) antibody responses against dextran in the small intestine, and intranasal immunizations did the same in the lung. Intranasal immunizations also elicited serum antibody titers that were significantly higher than or equal to those after subcutaneous immunizations. Intranasal immunizations evoked serum IgG antidextran titers which were dependent on the dextran/CTB molar ratio and inversely related to the local IgA response, which was not the case for subcutaneous immunizations. This is the first study of local and systemic immunity following mucosal immunization with a polysaccharide-protein conjugate. The results show that it is possible to evoke a local as well as a systemic antibody response against a polysaccharide by conjugating it to CTB and using an appropriate route of immunization.

Effects of nafarelin versus danazol on lipids and calcium metabolism.

This 6-month clinical trial with an additional 12-month follow-up compared the effects of treatment with the gonadotropin-releasing hormone agonist nafarelin and the androgenic agent danazol on lipids and calcium metabolism in women with endometriosis. Of the 23 women who completed the double-blind, double-dummy study, 15 were treated with nafarelin and 8 with danazol. Investigators observed the effects of both agonists on estradiol levels, American Fertility Society endometriosis scores, and side effects. Results indicate that nafarelin seems to be a good alternative to other medications for the treatment of endometriosis and has an acceptable side-effect profile, including metabolic effects.

No abortion-inducing effect of the ulcer-healing dose of the synthetic prostaglandin E2 analogue enprostil in first trimester.

Milligram-range doses of E2 prostaglandins have long been used to induce labor or abortion in the second and third trimesters of pregnancy. Enprostil, a synthetic dehydroprostaglandin E2 structural analogue, is administered in microgram doses for the treatment of acute duodenal ulcer and acute gastric ulcer. This study examined the effect of the ulcer-healing dose and twice the ulcer-healing dose upon women in the first trimester of pregnancy. Two hundred and seven women who had requested legal abortion in the first trimester participated in two randomized, double-blind, placebo-controlled, parallel studies. They received two doses of enprostil 35 micrograms (the recommended dose for the treatment of duodenal and gastric ulcer) (n = 51), 70 micrograms (twice the recommended dose) (n = 53), or placebo (n = 103) 12 h apart. No drug-induced abortions occurred in any of the first-trimester pregnancies. Vaginal bleeding occurred in 4% of volunteers receiving the lower dose and 4% receiving the higher dose of enprostil. Vaginal bleeding occurred in up to 2% of volunteers on placebo. Although not recommended for pregnant women, if enprostil is given inadvertently to pregnant women with ulcers, it is unlikely to endanger the pregnancy during the first trimester.

Clinical experience treating endometriosis with nafarelin.

The preliminary results from an ongoing multicenter trial further support the efficacy and excellent tolerability of nafarelin in the management of endometriosis.