Long-Term Low-Dose Pyrimethamine Use for the Prevention of Ocular Toxoplasmosis Recurrences: A Cohort Study.

PURPOSE: To describe the effect of long-term, low-dose pyrimethamine for the prevention of ocular toxoplasmosis (OT) recurrences. METHODS: Sixty-three consecutive patients with inactive ocular toxoplasmosis and positive toxoplasma IgG serology were included. Pyrimethamine (25 mg) + folinic acid (15 mg) were administered every other day (three times weekly) for 12 months. Eighteen patients received the treatment for an additional six months as part of an extension study. RESULTS: Thirty-eight patients (60.3%, n = 63) were female; 38 (60.3%) had a previous history of recurrence and 37 (58.7%) had active OT within the preceding 12 months. Three (4.8%) patients had unilateral recurrences at 8, 12 and 18 months after starting intermittent pyrimethamine treatment. Five patients (7.9%) were discontinued due to hematological, renal and hepatic changes. Treatment was considered successful in 42 patients (84%). CONCLUSION: Long-term, low-dose pyrimethamine can be considered as a treatment option for the prevention of ocular toxoplasmosis recurrence in selected patients, with only a few, mild and reversible systemic adverse events.

Effectiveness of Treatments for Ocular Toxoplasmosis.

Purpose: To evaluate the effectiveness of treatments for ocular toxoplasmosis (OT).Methods: A review of charts was conducted from patients who experienced an active episode of OT treated at the Federal University of São Paulo and associated sites. OT charts were reviewed to determine treatment effectiveness based on clinical judgment, taking clinical course and outcome into consideration in addition to change in best-corrected visual acuity. Treatment emergent adverse events (TEAEs) were used to assess safety.Results: Overall, 451/1200 patient charts met the inclusion criteria. The most commonly prescribed treatment was trimethoprim + sulfamethoxazole (52.3%) followed by pyrimethamine + sulfadiazine (28%). Treatment was successful in 96.9% of patients. Irrespective of the treatment, active lesions were resolved in 63.9% of patients within 6 weeks. Vision improved in 56.3% of patients. The incidence of TEAEs was low (10%).Conclusions: All treatments were effective for active episodes of OT, with few side effects.

Adverse Event Profile of Pyrimethamine-Based Therapy in Toxoplasmosis: A Systematic Review.

INTRODUCTION: Approximately a third of the population worldwide is chronically infected with Toxoplasma gondii. Pyrimethamine-based regimens are recommended for the treatment of toxoplasmosis. OBJECTIVE: The aim was to evaluate the safety profile of pyrimethamine-based treatment for the three main Toxoplasma manifestations: toxoplasmic encephalitis (TE), ocular toxoplasmosis, and congenital toxoplasmosis. METHODS: PubMed, Cochrane Library, and Google Scholar databases were searched through August 1, 2016. Randomized, observational, prospective/retrospective, and cohort studies were eligible. Thirty-one studies were included with a total of 2975 patients. Of these, 13 were in congenital toxoplasmosis (n = 929), 11 in ocular toxoplasmosis (n = 1284), and seven in TE (n = 687). Across manifestations, adverse event (AE)-related treatment discontinuation and/or change in therapy involved ≤37% of patients and occurred in >55% of studies: 100% for ocular toxoplasmosis, 57.1% for TE, and 61.5% for congenital toxoplasmosis. The most commonly observed AEs were bone marrow suppression, dermatologic, and gastrointestinal (GI). The prevalence of bone marrow suppression-related AEs was ≤50% in congenital toxoplasmosis, ≤42.7% in TE, and ≤9.0% in ocular toxoplasmosis. The frequency of GI and dermatologic AEs were ≤100 and ≤11.1%, respectively, for ocular toxoplasmosis, ≤10.7 and ≤17.9% for TE, and ≤10.8 and ≤2.1% for congenital toxoplasmosis. Steven-Johnson syndrome was reported in two patients with ocular toxoplasmosis and one with TE. CONCLUSION: The AE profile associated with pyrimethamine-based treatments differed by each manifestation of toxoplasmosis and within a given manifestation. Hematologic AEs occurred across all manifestations indicating the importance of monitoring the blood of patients administered pyrimethamine-based regimens.

The effect of pycnogenol on patients with dysmenorrhea using low-dose oral contraceptives.

OBJECTIVE: Menstrual symptoms such as dysmenorrhea usually occur during the hormone-free interval in oral contraceptive users. Progestin withdrawal activates NF-κB transcription factor, which upregulates both vascular endothelial growth factor (VEGF) and Cox-2 expression in the endometrium. The use of natural NF-κB inhibitors such as pycnogenol may block this response, improving dysmenorrhea. PATIENTS AND METHODS: Twenty-four patients with severe dysmenorrhea were allocated to one of two treatment groups. In Group A (n=13), women were treated with an oral contraceptive containing 15 µg of ethinyl estradiol and 60 mg of gestodene (Adoless(®)) in a 24/4 regimen for three consecutive cycles. Women in Group B (n=11) used the same contraceptive regimen together with 100 mg of pycnogenol (Flebon(®)) continuously for 3 months. Pain scores were graded using a visual analog scale (VAS) before and during the hormone-free interval at the end of the third treatment cycle. RESULTS: Before treatment, VAS pain scores for dysmenorrhea were 8 and 9 in Groups A and B, respectively. However, by the end of the third treatment cycle, pain scores had decreased significantly (P<0.05) both in groups A and B. The final pain scores were 6 in Group A and 2 in Group B, a difference that was statistically significant (P<0.0001). In Group B, 27% of the patients became pain-free, while in Group A, none of the women reported complete disappearance of this symptom. The number of bleeding days was also lower in Group B. DISCUSSION: Pycnogenol effectively decreased pain scores and the number of bleeding days when administered concomitantly with a low-dose 24/4 oral contraceptive containing gestodene.

Impact of long-acting injectable antipsychotics on medication adherence and clinical, functional, and economic outcomes of schizophrenia.

Schizophrenia is a debilitating chronic disease that requires lifelong medical care and supervision. Even with treatment, the majority of patients relapse within 5 years, and suicide may occur in up to 10% of patients. Poor adherence to oral antipsychotics is the most common cause of relapse. The discontinuation rate for oral antipsychotics in schizophrenia ranges from 26% to 44%, and as many as two-thirds of patients are at least partially nonadherent, resulting in increased risk of hospitalization. A very helpful approach to improve adherence in schizophrenia is the use of long-acting injectable (LAI) antipsychotics, although only a minority of patients receive these. Reasons for underutilization may include negative attitudes, perceptions, and beliefs of both patients and health care professionals. Research shows, however, significant improvements in adherence with LAIs compared with oral drugs, and this is accompanied by lower rates of discontinuation, relapse, and hospitalization. In addition, LAIs are associated with better functioning, quality of life, and patient satisfaction. A need exists to encourage broader LAI use, especially among patients with a history of nonadherence with oral antipsychotics. This paper reviews the impact of nonadherence with antipsychotic drug therapy overall, as well as specific outcomes of the schizophrenia patient, and highlights the potential benefits of LAIs.

The effect of oral contraceptives on aromatase and Cox-2 expression in the endometrium of patients with idiopathic menorrhagia or adenomyosis.

BACKGROUND: The presence of aromatase and cyclooxygenase-2 (Cox-2) expression was investigated in the endometrium of patients with idiopathic menorrhagia or adenomyosis. The effect of oral contraceptives administered in extended regimens on the endometrial expression of these enzymes was also investigated. METHODS AND RESULTS: Aromatase expression was detected by immunohistochemistry in the endometrial glands and stroma of patients with idiopathic menorrhagia or adenomyosis. There was no difference in the percentage of aromatase expression in the endometria between the two groups. The mean intensity of Cox-2 expression in the glandular epithelium also did not differ significantly between the groups. Among the patients using oral contraceptives in extended regimens, the relative decrease in both aromatase and Cox-2 expression was significantly greater in amenorrheic patients compared with those who were experiencing breakthrough bleeding. CONCLUSION: The presence of aromatase expression in the endometrium is associated with the occurrence of menorrhagia, irrespective of the presence of adenomyosis. Continuous expression of these enzymes in the endometrium of users of oral contraceptives in extended regimens is positively associated with the presence of breakthrough bleeding. This suggests a role for both aromatase and Cox-2 in the etiology of abnormal uterine bleeding.

Combining oral contraceptives with a natural nuclear factor-kappa B inhibitor for the treatment of endometriosis-related pain.

Endometriosis is a chronic disease in which a persistent state of heightened inflammation is maintained by nuclear factor-kappa B (NF-κB) activation. The progestins present in oral contraceptives are potent inhibitors of NF-κB translocation to cell nuclei, while Pycnogenol® (Pinus pinaster) acts by blocking post-translational events. In this study, the effects of Pycnogenol on pain scores were investigated in patients with endometriosis using oral contraceptives containing either gestodene or drospirenone in extended regimens. Pain scores were determined using a visual analog scale before and after 3 months of treatment. Oral contraceptives, used alone (groups 1 and 3) or in association with Pycnogenol (groups 2 and 4), resulted in significant decreases in pain scores after 3 months of treatment; however, this reduction was significantly greater in the groups using oral contraceptives + Pycnogenol (groups 2 and 4) compared with those using oral contraceptives alone (groups 1 and 3). In the groups using oral contraceptives alone, 50% of patients became pain-free by the end of the third month of treatment. These results suggest that Pycnogenol increases the efficacy of oral contraceptives for the treatment of endometriosis-related pain.

Role of inflammation and aromatase expression in the eutopic endometrium and its relationship with the development of endometriosis.

Epigenetic changes favoring the transcription of the aromatase gene in the endometrium allow endometrial cells to survive in ectopic locations by producing estrogens that spare them from destruction through activated macrophages. Local estrogen production hastens prostaglandin synthesis by stimulating COX-2 activity, thus creating a self-perpetuating sequence of augmented estrogen formation and enhanced inflammation. Repetitive retrograde menstruation reintroduces aromatase-positive endometrial cells endowed with the capacity to implant and invade the peritoneum. In order to control endometriosis, an effective medication must inhibit aromatase, block COX-2, decrease fibrosis and induce amenorrhea. Within this framework, progestins, either alone or in the form of oral contraceptives, appear as first-line treatment for endometriosis owing to their capacity to block enzymes such as aromatase and COX-2.

Advantages of the association of resveratrol with oral contraceptives for management of endometriosis-related pain.

BACKGROUND: The effect of resveratrol on the management of endometriosis-related pain was investigated in 12 patients who failed to obtain pain relief during use of an oral contraceptive containing drospirenone + ethinylestradiol. METHODS AND RESULTS: The addition of 30 mg of resveratrol to the contraceptive regimen resulted in a significant reduction in pain scores, with 82% of patients reporting complete resolution of dysmenorrhea and pelvic pain after 2 months of use. In a separate experiment, aromatase and cyclo-oxygenase-2 expression were investigated in the endometrial tissue of 42 patients submitted to laparoscopy and hysteroscopy for the management of endometriosis. Sixteen of these patients were using oral contraceptives alone prior to hospital admission, while the remaining 26 were using them in combination with resveratrol. Inhibition of both aromatase and cyclo-oxygenase-2 expression was significantly greater in the eutopic endometrium of patients using combined drospirenone + resveratrol therapy compared with the endometrium of patients using oral contraceptives alone. CONCLUSION: These results suggest that resveratrol potentiates the effect of oral contraceptives in the management of endometriosis-associated dysmenorrhea by further decreasing aromatase and cyclo-oxygenase-2 expression in the endometrium.

Effect of a hormone-releasing intrauterine system (Mirena(®)) on aromatase and Cox-2 expression in patients with adenomyosis submitted or not, to endometrial resection.

OBJECTIVE: To investigate the effect of a levonorgestrel-releasing intrauterine system (Mirena(®)) on aromatase and cyclooxygenase-2 (Cox-2) expression in the endometrium of patients with adenomyosis who were submitted to endometrial resection at the time of insertion, compared to a group not submitted to endometrial resection and a group of controls with adenomyosis not submitted to any previous hormonal treatment. PATIENTS AND METHODS: Patients with adenomyosis (n = 89) were included in this study. Twenty- two patients had been using Mirena(®) for 5 years but had not been submitted to endometrial resection prior to insertion of the device. Twenty-four patients were submitted to endometrial resection at the time of Mirena(®) insertion. The remaining 43 patients with adenomyosis had undergone no previous hormonal treatment and served as a control group. Cox-2 and aromatase expression were determined in the endometrium by immunohistochemistry. RESULTS: Use of Mirena(®) for 5 years reduced aromatase expression in the endometrium; however, this reduction was significantly greater in the uteri previously submitted to endometrial resection. The reduction in Cox-2 expression was significant only in the uteri submitted to endometrial resection followed by the insertion of Mirena(®). CONCLUSION: Endometrial resection followed by the insertion of Mirena(®) was associated with greater rates of amenorrhea in patients with adenomyosis, which in turn were associated with a more effective inhibition of aromatase and Cox-2 expression in the endometrium.

Correlation between aromatase expression in the eutopic endometrium of symptomatic patients and the presence of endometriosis.

OBJECTIVE: To investigate whether aromatase expression in the eutopic endometrium correlates with the presence and severity of endometriosis in patients with infertility and/or dysmenorrhea undergoing laparoscopy and hysteroscopy. PATIENTS: The study involved 106 patients of reproductive age with symptoms of dysmenorrhea and infertility. Sixteen endometriosis-free asymptomatic patients were used as a control group. METHODS: Concomitant laparoscopy and hysteroscopy was carried out in all cases. An endometrial biopsy was taken to determine aromatase p450 expression by immunohistochemistry. Endometriosis was staged according to the American Society of Reproductive Medicine classification. RESULTS: Endometriosis was diagnosed by laparoscopy in 92/106 symptomatic patients. In this group, aromatase expression was detected in the eutopic endometrium of 66/92 patients with endometriosis (72%) and in 13/14 (95%) patients in the symptomatic, endometriosis-free group (P = 0.09). Aromatase expression was not detected in any patients from the control group. In the endometriosis group, aromatase expression was detected in the eutopic endometrium of 28/45 patients (62%) with American Society of Reproductive Medicine classification stage 1 of the disease, in 11/14 patients (78%) with stage II, 14/20 patients (70%) with stage III, and in 12/13 patients (92%) with stage IV; however, the difference was only statistically significant between stages I and IV (P = 0.04). CONCLUSION: Aromatase expression in the endometrium was associated with the presence of dysmenorrhea and infertility irrespective of the presence of endometriosis. When endometriosis was present, however, there was a tendency for aromatase expression to be positively correlated with dysmenorrhea severity.

The effect of a continuous regimen of drospirenone 3 mg/ethinylestradiol 30 microg on Cox-2 and Ki-67 expression in the endometrium.

OBJECTIVE: To study Cox-2 expression in relation to bleeding patterns in patients using an oral contraceptive containing 3 mg of drospirenone and 30 microg of ethinylestradiol (DRSP/EE). METHODS: Forty-three patients of reproductive age with symptoms of menorrhagia and dysmenorrhoea, who were submitted to endometrial resection, were enrolled. Twelve patients were in the proliferative phase and the remaining 31 were either currently using DRSP/EE or had discontinued its use four to eight days prior to hysteroscopy. Cox-2 and Ki-67 expression were determined in the endometrium using immunohistochemistry. RESULTS: Cox-2 expression was significantly inhibited in the glandular epithelium of patients who became amenorrhoeic during DRSP/EE use; however, in patients with breakthrough bleeding and in those who had stopped oral contraceptive use, a significant increase occurred in Cox-2 expression in the endometrium. Ki-67 expression decreased significantly during DRSP/EE use, but returned to proliferative phase values four to eight days after discontinuation of treatment. CONCLUSION: These results suggest that endometrial bleeding during DRSP/EE use is associated with an increase in Cox-2 expression in the endometrium. A similar increase was also seen four to eight days following discontinuation of the oral contraceptive.

Activation of NF-kappaB and COX-2 expression is associated with breakthrough bleeding in patients using oral contraceptives in extended regimens.

The objective of the present study was to determine whether there is an increase in endometrial inflammation associated with the occurrence of breakthrough bleeding in patients using an oral contraceptive in extended regimens. The presence of nuclear factor NF-kappaB and Cox-2 expression was determined by immunohistochemistry in endometrial samples removed by hysteroscopy from patients with breakthrough bleeding during continuous use of an oral contraceptive containing gestodene. All patients had a history of menorrhagia associated or not with the presence of uterine pathology. The percentage of endometria showing a positive staining reaction for NF-kappaB in cell nuclei was significantly higher in patients with breakthrough bleeding than in those with amenorrhea. Cox-2 expression in the endometrium was also significantly more frequent in patients with breakthrough bleeding. The occurrence of breakthrough bleeding in patients with uterine pathology using combined oral contraceptives is associated with the activation of endometrial inflammation through the NF-kappaB pathway.

Is aromatase expression in the endometrium the cause of endometriosis and related infertility?

Aromatase expression in the endometrium seems to play a pivotal role in the development of endometriotic lesions. Because inflammatory mediators such as prostaglandin E2 appear to activate aromatase in the cells of the endometrial stroma, it was hypothesised that the ensuing inflammation caused by the arrival of aromatase-positive cells in the peritoneal cavity would stimulate local estrogen production, which would in turn facilitate the development of endometriotic lesions by suppressing macrophage phagocytosis. Aromatase expression in the eutopic endometrium will also hamper ovum nidation, thus causing infertility. Progestins, such as gestodene and danazol, are potent inhibitors of aromatase expression in the endometrium, and the use of vaginal rings with danazol in doses that do not block ovulation is associated with the occurrence of pregnancy in patients with severe endometriosis without the need for surgery. A local effect on the endometrium suppressing aromatase expression has been suggested as a possible mechanism of action for the danazol ring.

Testosterone replacement therapy in the climacteric: benefits beyond sexuality.

Testosterone therapy during menopause has a wide range of benefits that reach beyond the realm of human sexuality. This is a consequence not only of the widespread distribution of androgen receptors in various extragonadal tissues but also of the conversion of androgens to estrogens in the tissues in which aromatase expression is present. For this reason, testosterone therapy during the climacteric years will not only supply androgens but will also stimulate estrogen production in tissues that express aromatase. Furthermore, the bioavailability of androgens to the tissues depends not only on the rate of their production by the postmenopausal ovaries and adrenals but also on the circulating levels of sex hormone-binding globulin (SHBG). Tibolone inhibits SHBG production in the liver, thus increasing free testosterone levels. The association of tibolone with testosterone as a form of androgen replacement therapy during the climacteric is discussed, as is the use of low-dose testosterone, tibolone or the association of both in perimenopausal patients with signs of androgen deficiency. Testosterone treatment has a boosting effect not only on human sexuality but also on the sensation of well-being, a stimulatory effect conferred by the increase in beta-endorphins.

Effect of oral contraceptives on vascular endothelial growth factor, Cox-2 and aromatase expression in the endometrium of uteri affected by myomas and associated pathologies.

BACKGROUND: The study was conducted to evaluate vascular endothelial growth factor (VEGF), Cox-2 and aromatase expression in the endometrium of uteri with myomas and other associated pathologies. STUDY DESIGN: Hysteroscopy was performed in 118 women of reproductive age with myomas and menorrhagia, 40 of whom were using a pill containing 75 mcg gestodene+30 mcg ethinylestradiol. Aromatase p450, VEGF and Cox-2 expression was detected using immunohistochemistry. Fisher's Exact Test and the Mann-Whitney test were used in the statistical analysis, with significance established at p<.05. RESULTS: In patients with myomas and menorrhagia, associated pathologies such as adenomyosis, endometrial polyps and endometriosis were found in 32%, 12% and 17% of cases, respectively. Aromatase, Cox-2 and VEGF expression was greater during the proliferative phase compared to the luteal phase of the cycle or following oral contraceptive use. CONCLUSION: Endogenous progesterone or combined oral contraceptives are potent inhibitors of VEGF, aromatase and Cox-2 expression in the endometrium of patients with myomas and menorrhagia.

The effect of oral contraceptives on aromatase expression in the eutopic endometrium of patients with endometriosis.

OBJECTIVE: To determine the effect of oral contraceptives containing gestodene on aromatase expression in the endometrium of patients diagnosed with endometriosis. PATIENTS AND METHODS: Endometrial biopsies were taken at the time of laparoscopy in 40 patients with endometriosis, 16 of whom were using an oral contraceptive containing gestodene at the time of laparoscopy. The remaining 24 patients were receiving no form of treatment for endometriosis. Endometrial biopsies taken from 23 patients with normal echographic signs and no symptoms were used as controls. Aromatase expression was evaluated in endometrial samples using immunohistochemistry. RESULTS: In the untreated, symptomatic endometriosis patients, aromatase expression was detected during the proliferative phase in 92% of cases, while in the symptom-free control patients aromatase was expressed in only 9% of cases. In patients with endometriosis who were using oral contraceptives, there were significantly fewer cases of positive endometria compared with the untreated patients with endometriosis (6%). CONCLUSION: Oral contraceptives containing gestodene are effective in decreasing aromatase expression in the eutopic endometrium of patients with endometriosis.

Non-contraceptive health benefits of oral contraceptives.

The use of combined oral contraceptives (COCs) is associated with a reduced risk of developing endometriosis, myomas, and endometrial and ovarian carcinoma. The mechanisms involved are multiple; next to ovulation suppression, a reduction in inflammation in the genital tract is involved. This is accomplished through inhibition of the endometrial expression of enzymes related to the biosynthesis of prostaglandin and oestrogen, particularly cyclooxygenase type II (Cox-2) and aromatase. The blockade of these enzymatic systems by COCs explains the beneficial effects of these compounds in treating the symptoms, and halting the progression of myomas, endometriosis and adenomyosis, all of which are characterized by increased inflammation. Inhibition of aromatase and Cox-2 expression in the endometrium by COCs may explain their efficacy in controlling the pain and excessive uterine bleeding caused by these pathologies. The reduction of inflammation in the endometrium may also be the mechanism behind the lower incidence of endometrial carcinoma in COC users. The blockade of ovulation and ovarian steroidogenesis, on the other hand, may explain the lesser incidence of ovarian cancer and the improvement of acne in users. In conclusion, inflammation appears to play a pivotal role in the development of various benign and malignant gynecological diseases. COCs reduce inflammation in the female genital tract by blocking enzymes such as Cox-2 and aromatase.

Aromatase expression in the eutopic endometrium of myomatous uteri: the influence of the menstrual cycle and oral contraceptive use.

AIMS: To detect aromatase expression in the endometrium of myomatous uteri and to correlate it with the location of the myoma, phase of the menstrual cycle, the presence of menorrhagia and oral contraceptive use. METHOD: Aromatase p450 expression was measured using immunohistochemical methods in the endometrium of 116 patients. Sixty-one patients had menorrhagia associated with intramural/submucous myomas and nine had subserous myomas and no excessive bleeding. Forty-six patients had no uterine pathology and served as controls. Nineteen out of 61 patients with menorrhagia were oral contraceptive users at the time of the examination. Endometrial samples were obtained by hysteroscopy in all cases. RESULTS: Aromatase p450 expression was detected more frequently in the eutopic endometrium of patients with submucous or intramural myomas than in those in the subserous group, and was significantly greater during the proliferative phase than during the luteal phase or following the use of oral contraceptives. In normal uteri, aromatase expression was detected in the endometrium in less than 10% of users. CONCLUSIONS: Aromatase expression in the endometrium was affected by the location of the myoma, the presence of symptoms, and the phase of the menstrual cycle. Oral contraceptives, on the other hand, inhibited aromatase expression in the eutopic endometrium of patients with submucous/intramural myomas.