Pyostomatitis vegetans associated with inflammatory bowel disease--report of two cases

Pyostomatitis vegetans (PV) is a rare, chronic mucocutaneous disorder associated with inflammatory bowel disease (IBD). Oral lesions of PV are distinct and present as multiple white or yellow pustules with an erythematous base that coalesce and undergo necrosis to form a typical "snail tracks" appearance. Two cases of PV associated with IBD--one with Crohn's disease (CD) and the other with ulcerative colitis (UC) are reported. In the first case, adalimumab therapy brought the oral and gastrointestinal manifestations to complete remission. In the second case, the remission was achieved with systemic steroid therapy, but the disease relapsed after therapy discontinuation. Azathioprine was added leading to sustained remission of PV. Because of persistent active intestinal manifestation of UC, in spite of immunosuppressive therapy, infliximab was introduced. With the therapy remission of intestinal manifestation of UC was achieved as well. Our cases confirm previously reported good experience with immunomodulators and biologics in the treatment of PV. But, before using them we have to exclude an infectious etiology of oral lesions.     

Beclomethasone dipropionate in asthma.

Beclomethasone dipropionate aerosol therapy can replace or diminish systemic corticosteroid therapy in the majority of asthmatics. In a clinical trial of 41 patients with perennial asthma, the 10 who had not required long-term corticosteroid therapy improved symptomatically and in pulmonary function. Of the 31 who had required prolonged systemic corticosteroid therapy 12 were able to discontinue oral prednisone therapy, 15 were able to decrease the maintenance dose of prednisone and only 4 were unable to decrease the dose; all maintained satisfactory lung function and some showed improvement. Discontinuation of systemic corticosteroid therapy was accomplished more readily in patients whose daily maintenance dose was less than 15 mg and who had been taking the drug for less than 3 years. Side effects consisted of a "dry throat" in seven patients, two of whom had throat infections with Candida albicans. Recurrence of rhinitis after discontinuation or reduction of systemic corticosteroid therapy was noted in 11 patients.     

Reasons given by mothers for discontinuing breastfeeding in Iran

Background

We have previously shown that in Iran, only 28% of infants were exclusively breastfed at six months, despite a high prevalence of breastfeeding at two years of age. The primary aim of this study was to investigate the reasons women discontinued exclusive breastfeeding.

Method

This retrospective study was based on questionnaires and interviews with 63,071 mothers of infants up to 24?months of age, divided into two populations: infants younger than six months and six months or older. The data were collected in 2005?C2006 from all 30 provinces of Iran.

Results

Only 5.3% of infants less than six months of age stopped breastfeeding (mean age of 3.2?months); more commonly in urban than rural areas. The most frequently cited reasons mothers gave for discontinuing exclusive breastfeeding were physicians?? recommendation (54%) and insufficient breast milk (self-perceived or true, 28%). Breastfeeding was common after six months of age: only 11% of infants discontinued breastfeeding, at a mean of 13.8?months. The most common reason for discontinuation at this age was insufficient breast milk (self-perceived or true, 45%). Maternal illness or medication (10%), infant illness (6%), and return to work (3%) were uncommon causes. Use of a pacifier was correlated with breastfeeding discontinuation. Maternal age and education was not associated with duration of breastfeeding. Multivariate analysis showed that using a pacifier and formula or other bottle feeding increased the risk of early cessation of breastfeeding.

Conclusions

Physicians and other health professionals have an important role to play in encouraging and supporting mothers to maintain breastfeeding.     

Return of fertility after use of the injectable contraceptive Depo Provera: up-dated data analysis

796 Thai women who stopped using the long-acting injectable contraceptive depot medroxyprogesterone acetate (DMPA, Depo Povera), 437 women who stopped using oral contraceptives and 125 women who had an IUD removed to have a planned pregnancy, were followed up to ascertain the delay to conception after the end of contraception and to determine the proportion of women who did not conceive in the 4 years after discontinuation. The median delay to conception was 5.5 months plus the estimated duration of the effect of the last injection of DMPA, 3 months for oral contraceptives and 4.5 months after discontinuing the IUD. The proportion of women who did not conceive within 9 months after discontinuation of DMPA is similar to that of ex-IUD users, and by 3 years to that of the ex-pill sample. There is no evidence to suggest that prolonged use of DMPA increases the delay to conception. The return of fertility among never pregnant ex-users resembled that of ever pregnant ex-users. There were comparable proportons of live births among ex-DMPA users and ex-pill users and both of these showed higher proportions of live-births than ex-IUD users. There was no evidence to suggest that previous use of DMPA had any significant adverse effect on the outcome of pregnancy of the subsequent births. This study did not show any association between infertility and the previous use of DMPA or other contraceptives.     

Norethisterone oenanthate as an injectable contraceptive: use of a modified dose schedule.

Norethisterone oenanthate (NET-OEN) was given as an injectable contraceptive to 295 healthy women over 1606 woman-months. A modified injection schedule was used. There were no pregnancies, and the 12-month, life-table, use-related discontinuation rate was 39.1/100 users. Menstrual disturbance (10.8/100 women), minor side effects (13.5/100 women), and personal reasons (12.0/100 women) were the main causes of use-related discontinuation. There was no difference in use-related discontinuation rates between women receiving their first injection during a normal menstrual period and those receiving it immediately after a pregnancy. There were no serious side effects. The use of NET-OEN in certain groups of women is recommended, particularly in those in need of highly effective contraception, who cannot or do not wish to take oral contraceptives, who are lactating, or who are awaiting hospital admission for sterilisation.     

Hypertension developing in women using oral contraceptions]

Attention to the problem of hypertension in women using oral contraceptives has been increasing as the use of these preparations has increased. It is estimated that between 1-5% to 15-18% of those women using these preparations suffer from hypertension. Some sources have linked the occurrence of hypertension to a concentration of renin in the blood. It is not clear to this author, though, whether this is the result of some physiological disruption caused by the contraceptive, or caused by some other malfunction of this mechanism. The appearance of hypertension in the course of hormonal contraceptive use is considered to be an indication for the discontinuation of its use.     

Avoidance reactions to painful stimulation of another individual following destruction of the rat amygdala]

Experiments in male albino rats have shown that bilateral lesion of the amygdala does not prevent avoidance conditioning to pain stimulation of another rat, improvement of the reaction after a painful action of the experimental animal and its extinction after the discontinuation of pain stimulation of the partner. Amygdalectomy performed after elaboration of a conditioned avoidance reaction, improves or worsens it, depending on which of the two rivaling motivations (sensitivity to signals of the other animal or fear of an open field) relatively predominanted in the given animal before the operation. The facts obtained suggest that the amygdala may be classified as belonging to the system of brain structures, where the "interrupting function" of emotions is achieved directing the behaviour to meet the predominant need.     

Side effects and discontinuation of oral contraceptive use in southern Brazil

Oral contraceptives have many advantages, but sometimes also have side effects which can cause users to switch appropriately or inappropriately to less effective methods or abandon contraception. In Brazil, 2/3 of married women of childbearing age were using contraception in 1981, and 1/2 of these were using orals. Contraceptive behavior following reported side effects in users of oral contraceptives in Southern Brazil is examined in this study, in relation to diverse factors. Among 2904 currently-married women, aged 15-44, almost 75% reported that they had used the pill at some time, and of these, 45.6% were still doing so. Data on perceived side effects were gathered for all women. There was no independent medical evaluation of the effects, so the data did not necessarily represent actual prevalence of pill related problems. Women who reported problems with the pill were less likely to be current users (25%) than women who did not (65%). However, overall contraceptive prevalence was about the same in both groups (66.2% and 67.0% respectively), indicating that women who stop using oral contraceptives usually switch to another method. However, they are more likely to be using traditional methods than women in the general population, especially if they want more children. Termination of pill use varies little according to the type of problem reported. Women with problems who sought medical attention were more likely to stop using the pill, and 82.4% of women advised to stop by their physician did so, but the major factor affecting discontinuation was the reported experience of a problem. The most frequently reported problems were headaches (38.1%), nausea (34.1%), nervousness (27.9%), and vertigo (18.3%). Physician intervention should help to avoid women's abandoning oral contraceptives unnecessarily.     

Adalimumab serum levels and antidrug antibodies towards adalimumab in peripheral spondyloarthritis: no association with clinical response to treatment or with disease relapse upon treatment discontinuation

Introduction

In this study, we evaluated the clinical relevance of serum drug levels and antidrug antibodies (ADAbs) with regard to response to treatment, as well as to relapse upon treatment discontinuation, in peripheral spondyloarthritis (pSpA) patients treated with adalimumab.

Methods

The study included 26 pSpA patients treated with adalimumab for either 12 weeks (n = 12) or 24 weeks (n = 14) in a randomized controlled trial. Patients achieving inactive disease measured by Ankylosing Spondylitis Disease Activity Score (ASDAS) at the end of the treatment period were classified as responders. Clinical characteristics, serum trough adalimumab levels and ADAbs were assessed at the end of the treatment period and at follow-up (upon relapse or, in absence of relapse, at 16 weeks after discontinuation).

Results

Serum adalimumab levels measured 2 weeks after the last adalimumab administration ranged from <0.002 to 23.0 μg/ml, with a median of 11.5 μg/ml. These levels were associated with neither response to treatment or disease activity measurements at the end of treatment nor with the occurrence of relapse and time to relapse after discontinuation of treatment. Antiadalimumab ADAbs were present in 23% of the patients at end of treatment and in 35% at follow-up after treatment discontinuation, indicating that ADAbs were masked by the presence of the drug in some patients. However, ADAbs at the end of treatment and at follow-up were not different between responders and nonresponders and were not associated with relapse upon discontinuation of treatment.

Conclusions

There is no clear association between adalimumab serum levels or antiadalimumab ADAbs with clinical response to treatment or with relapse upon treatment discontinuation in pSpA.

Trial registration

Netherlands Trial Register ID: NTR1806 (registered 7 May 2009)     

Clinical and radiologic rebound after discontinuation of natalizumab therapy in a highly active multiple sclerosis patient was not halted by dimethyl-fumarate: a case report

Background

The evidence on the use of the oral dimethyl-fumarate after the discontinuation of treatment with natalizumab in people with Multiple Sclerosis is still little. Natalizumab discontinuation may induce the recurrence or rebound of the clinical and neuroradiological disease activity. Currently no therapeutic approach has been established to abolish disease reactivation and rebound after natalizumab interruption.

Case Presentation

We describe a case of a 21-year-old woman affected from a highly active relapsing-remitting Multiple Sclerosis who developed a clinical and radiological rebound 5 months after the last infusion of natalizumab, while she was being treated with dimethyl-fumarate 240 mg twice daily. She had received a bridge “therapy” with Cyclophosphamide before staring dimethyl-fumarate.

Conclusion

We report on this case to stimulate further research to establish whether new current and future drugs available for multiple sclerosis are able to halt the disease rebound after the natalizumab interruption.

     

Determinants of contraceptive discontinuation in six developing countries.

This analysis investigates the determinants of contraceptive discontinuation in six developing countries, using data from Phase I surveys of the DHS programme. Cumulative probabilities of discontinuation at 24 months for reasons other than the desire for another child were examined. By this time, typically about 40% of couples have stopped use and most are subsequently at risk of an unwanted conception. Discontinuation of IUD use was found to be less common than for other methods, partly perhaps because cessation of use requires a deliberate decision to have the device removed. The most important results are negative ones. Neither the schooling of couples nor their type of residence exerted appreciable influence on discontinuation. The policy and programme implications are discussed. Prior use of a method, fertility preferences and the related demographic factors of age and family size emerged as pervasive predictors of discontinuation.     

Nephrotoxicity and neurotoxicity in humans from organogermanium compounds and germanium dioxide

There is no known biological requirement for germanium (Ge), germanates, or any organogermanium compound. Ge deficiency has not been demonstrated in any animal. The estimated average dietary intake of Ge in humans is 1.5 mg/d. Ge is widely distributed in edible foods, all of which, with few exceptions, contain less than 5 ppm Ge, since higher levels are toxic to most plants. Ingestion of Ge compounds has been shown to produce toxic effects in experimental animals. In recent years inorganic germanium salts and novel organogermanium compounds, such as carboxyethyl germanium sesquioxide (Ge-132) and lactate-citrate-germanate (Ge lactate citrate) have been sold as "nutritional supplements" in some countries for their purported immunomodulatory effects or as health-producing elixirs, resulting in intakes of Ge significantly exceeding the estimated average dietary intake. Since 1982, there have been 18 reported cases of acute renal dysfunction or failure, including two deaths, linked to oral intake of Ge elixirs containing germanium dioxide (GeO2) or Ge-132. In these cases, biopsies show vacuolar degeneration in renal tubular epithelial cells, without proteinuria or hematuria, in the absence of glomerular changes. Serum creatinine levels have been well above 400 mumol/L in such patients. In 17 of 18 cases, accumulated elemental Ge intakes reportedly ranged between 16 to 328 g over a 4-36 mo period, or between 100 to 2000 times the average estimated dietary intake for human. In surviving patients, renal function improved after discontinuation of Ge supplementation. However, in no case was recovery complete. One organogermanium compound, an azaspiran organogermanium compound, 2-aza-8-germanspiro[4,5] decane-2-propamine-8,8-diethyl-N,N-dimethyl dichloride (spirogermanium), has been found to cause both neurotoxicity and pulmonary toxicity in phase I and II studies examining its chemotherapeutic potential as an antitumor drug in the treatment of various malignancies. In cancer patients given the drug spirogermanium, 40% experienced marked, yet transient neurotoxicity. Two patients suffered from pulmonary toxicity. Results of phases I and II human cancer trials for spirogermanium have not been favorable, with the exception of moderate benefits for three types of malignancies. It is recommended that patients exposed to long-term (greater than 3 mo) Ge supplementation at levels well above the estimated daily intake be medically supervised and monitored for potential renal-, pulmonary- or neurotoxicity. Further study regarding the mechanism of Ge-induced nephrotoxicity in human is warranted.     

Effect of intravenous infusion of insulin in diabetics with acute myocardial infarction.

Diabetes mellitus is associated with a high mortality after myocardial infarction. To see whether this may be decreased by improved diabetic control the effect of an insulin infusion regimen was studied in patients with acute myocardial infarction. From April 1982 to April 1983, 33 diabetics were admitted with acute myocardial infarction. Those being treated with diet alone or oral hypoglycaemic drugs continued with this unless control was poor, when they were changed to a "sliding scale" regimen of subcutaneous insulin injections thrice daily. Those already receiving insulin were maintained on thrice daily subcutaneous injections. From April 1983 to April 1984, 29 diabetics had acute myocardial infarction. Those receiving treatment with oral hypoglycaemic drugs or insulin were changed to continuous intravenous infusion of insulin, the aim being to maintain the blood glucose concentration at 4-7 mmol/I (72-126 mg/100 ml). Those being treated with diet alone continued with this if blood glucose concentrations were acceptable. Total mortality fell from 42% in the first year to 17% in the second (p less than 0.05). Over the same period mortality among non-diabetic patients with myocardial infarction did not change significantly. There was a significant fall in cardiac arrhythmias (expressed as the percentage of patients in whom arrhythmias were recorded) from 42% to 17% (p less than 0.05). The most significant fall in the incidence of complications occurred in those who had been receiving oral hypoglycaemic drugs on entry to the study (87% to 50%, p less than 0.05).     

MTN-001: Randomized Pharmacokinetic Cross-Over Study Comparing Tenofovir Vaginal Gel and Oral Tablets in Vaginal Tissue and Other Compartments

Background

Oral and vaginal preparations of tenofovir as pre-exposure prophylaxis (PrEP) for human immunodeficiency virus (HIV) infection have demonstrated variable efficacy in men and women prompting assessment of variation in drug concentration as an explanation. Knowledge of tenofovir concentration and its active form, tenofovir diphosphate, at the putative vaginal and rectal site of action and its relationship to concentrations at multiple other anatomic locations may provide key information for both interpreting PrEP study outcomes and planning future PrEP drug development.

Objective

MTN-001 was designed to directly compare oral to vaginal steady-state tenofovir pharmacokinetics in blood, vaginal tissue, and vaginal and rectal fluid in a paired cross-over design.

Methods and Findings

We enrolled 144 HIV-uninfected women at 4 US and 3 African clinical research sites in an open label, 3-period crossover study of three different daily tenofovir regimens, each for 6 weeks (oral 300 mg tenofovir disoproxil fumarate, vaginal 1% tenofovir gel [40 mg], or both). Serum concentrations after vaginal dosing were 56-fold lower than after oral dosing (p<0.001). Vaginal tissue tenofovir diphosphate was quantifiable in ≥90% of women with vaginal dosing and only 19% of women with oral dosing. Vaginal tissue tenofovir diphosphate was ≥130-fold higher with vaginal compared to oral dosing (p<0.001). Rectal fluid tenofovir concentrations in vaginal dosing periods were higher than concentrations measured in the oral only dosing period (p<0.03).

Conclusions

Compared to oral dosing, vaginal dosing achieved much lower serum concentrations and much higher vaginal tissue concentrations. Even allowing for 100-fold concentration differences due to poor adherence or less frequent prescribed dosing, vaginal dosing of tenofovir should provide higher active site concentrations and theoretically greater PrEP efficacy than oral dosing; randomized topical dosing PrEP trials to the contrary indicates that factors beyond tenofovir’s antiviral effect substantially influence PrEP efficacy.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00592124","term_id":"NCT00592124"}}NCT00592124     

The Australian Multiple Sclerosis (MS) Immunotherapy Study: A Prospective,Multicentre Study of Drug Utilisation Using the MSBase Platform

Objective

To prospectively characterise treatment persistence and predictors of treatment discontinuation in an Australian relapsing-remitting multiple sclerosis (RRMS) population.

Methods

Tertiary MS treatment centres participating in the MSBase registry prospectively assessed treatment utilisation, persistence, predictors of treatment discontinuation and switch rates. Multivariable survival analyses were used to compare treatment persistence between drugs and to identify predictors of treatment discontinuation.

Results

1113 RRMS patients were studied. Patients persisted on their first disease-modifying therapy (DMT) for a median of 2.5 years. Treatment persistence on GA was shorter than on all IFNβ products (p<0.03). Younger age at treatment initiation and higher EDSS were predictive of DMT discontinuation. Patients persisted on subsequent DMTs, for 2.3 years. Patients receiving natalizumab (NAT) as a subsequent DMT persisted longer on treatment than those on IFNβ or GA (p<0.000). The primary reason for treatment discontinuation for any drug class was poor tolerability. Annualised switch or cessation rates were 9.5–12.5% for individual IFNβ products, 11.6% for GA and 4.4% for NAT.

Conclusion

This multicentre MS cohort study is the first to directly compare treatment persistence on IFNβ and GA to NAT. We report that treatment persistence in our Australian RRMS population is short, although patients receiving IFNβ as a first DMT persisted longer on treatment than those on GA. Additionally, patients receiving NAT as a subsequent DMT were more likely to persist on treatment than those switched to IFNβ or GA. EDSS and age at DMT initiation were predictive of DMT discontinuation. Treatment intolerance was the principal reason for treatment cessation.     

Modulation of neuropeptide Y and Y1 receptor expression in the amygdala by fluctuations in the brain content of neuroactive steroids during ethanol drinking discontinuation in Y1R/LacZ transgenic mice

Previous studies have shown that GABAergic neuroactive steroids increase Y₁ receptor (Y₁R) gene expression in the amygdala of Y ₁ R / LacZ transgenic mice, harbouring the murine Y₁R gene promoter linked to a LacZ reporter gene. As ethanol is known to increase GABAergic neuroactive steroids, we investigated the relationship between fluctuations in the brain content of neuroactive steroids induced by chronic voluntary ethanol consumption or ethanol discontinuation and both the level of neuropeptide Y (NPY) immunoreactivity and Y₁R gene expression in the amygdala of Y ₁ R / LacZ transgenic mice. Ethanol discontinuation (48 h) after voluntary consumption of consecutive solutions of 3%, 6%, 10% and 20% (v/v) ethanol over 4 weeks produced an anxiety-like behaviour as measured by elevated plus maze. Voluntary ethanol intake increased the cerebrocortical concentration of the progesterone metabolite 3α-hydroxy-5α-pregnan-20-one (3α,5α-TH PROG) that returned to control level 48 h after discontinuation of ethanol intake. Ethanol discontinuation significantly decreased NPY immunoreactivity and concomitantly increased Y ₁ R / LacZ transgene expression in the amygdala, whereas chronic ethanol intake failed to affect these parameters. The 5α-reductase inhibitor finasteride prevented both the increase in the cerebrocortical concentration of 3α,5α-TH PROG apparent after 4 weeks of ethanol intake and the changes in NPY immunoreactivity and transgene expression induced by ethanol discontinuation. Data suggest that 3α,5α-TH PROG plays an important role in the changes in NPY–Y₁R signalling in the amygdala during ethanol discontinuation.     

Determinants of the overall response to furosemide: pharmacokinetics and pharmacodynamics

After an oral or i.v. dose of furosemide, there is considerable interindividual variability in the amount of unchanged drug delivered into the urine. On the average, approximately half as much reaches the intraluminal site of action with an oral compared with an i.v. dose. However, the natriuretic response to the same dose administered by either route is virtually the same. Similarly, after pretreatment with probenecid, the same total amount of furosemide in urine causes a greater overall response. It has been presumed that this paradox is accounted for by differences in rate of delivery of furosemide to the active site such that after an oral dose or after pretreatment with probenecid, amounts of drug are at the "steep" portion of the dose-response curve for longer periods of time. Our analysis shows that this is not the case. For furosemide, the amount of diuretic delivered into the urine that is maximally efficient (21.5 micrograms/min) is considerably less than the amount causing half-maximal response (69.8 micrograms/min). Oral administration or pretreatment with probenecid maintains drug close to this maximally efficient amount more persistently than does i.v. administration. By so doing, total response to an oral dose approaches that of i.v. dosing despite delivering half the amount of drug to the active site, and after probenecid an i.v. dose causes a greater response than i.v. dosing alone despite delivering the same amount of drug to the active site. These data emphasize the importance of the time course of delivery of drug to the active site as an independent determinant of overall response.