Use of follow-on disease-modifying treatments for multiple sclerosis: Consensus recommendations.

BACKGROUND: As patents for multiple sclerosis (MS) therapies expire, follow-on disease-modifying treatments (FO-DMTs) become available at reduced cost. Concerns exist that cheaper FO-DMTs are used simply to reduce healthcare costs. However, the well-being of people with MS should take priority. OBJECTIVES: To identify best practices for FO-DMT development and use by agreeing on principles and consensus statements through appraisal of published evidence. METHODS: Following a systematic review, we formulated five overarching principles and 13 consensus statements. Principles and statements were voted on by a multidisciplinary panel from 17 European countries, Argentina, Canada and the United States. RESULTS: All principles and statements were endorsed by >80% of panellists. In brief, FO-DMTs approved within highly regulated areas can be considered effective and safe as their reference products; FO-DMTs can be evaluated case by case and do not always require Phase III trials; long-term pharmacovigilance and transparency are needed; there is lack of evidence for multiple- and cross-switching among FO-DMTs; and education is needed to address remaining concerns. CONCLUSION: Published data support the use of FO-DMTs in MS. The consensus may aid shared decision-making. While our consensus focused on Europe, the results may contribute to enhanced quality standards for FO-DMTs use elsewhere.

Design of hybrid molecules as antimycobacterial compounds: Synthesis of isoniazid-naphthoquinone derivatives and their activity against susceptible and resistant strains of Mycobacterium tuberculosis.

Isoniazid-naphthoquinone hybrids were synthesized and evaluated against a susceptible (H37Rv) strain and two isoniazid-resistant strains (INHR1 and INHR2) of Mycobacterium tuberculosis. The antimycobacterial activity of the derivatives was determined based on the resazurin microtiter assay and their cytotoxicity in adhered mouse monocyte macrophage J774.A1 cells (ATCC TIB-67). Of the twenty-two compounds evaluated against the three strains of M. tuberculosis, twenty-one presented some activity against the H37Rv and INHR1 (katG S315T) or INHR2 (inhA C(-5)T) strains. Compounds 1a, 2a, and 8a were effective against the INHR1 strain, and compounds 1a, 1b, 2a, 3a, 5a, 5b and 8a were effective against the INHR2 strain, with MICs in the range of 3.12-6.25 µg/mL. Compounds 1b and 5b were the most active against H37Rv, with MIC of 0.78 µg/mL. Based on the selectivity index, 1b and 5b can be considered safe as a drug candidate compounds. These results demonstrate that quinoidal compounds can be used as promising scaffolds for the development of new anti-TB drugs and hybrids with activity against M. tuberculosis-susceptible and INH-resistant strains.

Novel Symmetrical 1,4-Disubstituted-bis-1,2,3-Triazoles: Synthesis by Double CuAAC and Cytotoxicity Evaluation.

BACKGROUND: A series of symmetrical 1,4-disubstituted bis-1,2,3-triazoles was prepared by double copper catalyzed Azide-alkyne Cycloaddition (CuAAC) from aliphatic bis-azides and a tetraethylene glycol bis-azide derivative. The eighteen novel compounds were evaluated in vitro for their cytotoxic activity against two human tumor cell lines: Human breast adenocarcinoma (MDA-MB 231) and ovarian adenocarcinoma (TOV-21G). RESULTS AND CONCLUSION: The results of colorimetric MTT assays showed that compounds 4j and 4q exhibited a better selectivity index and cell viability comparable with the standard drug doxorubicin. These compounds induced apoptosis in both tested cell lines, as assessed by BrdU assay. The results suggest that these structurally simple compounds may be promising prototypes for antitumoral agents.

Familial clustering of systemic lupus erythematosus in the cayman islands.

OBJECTIVE: To describe the unusual clustering of systemic lupus erythematosus (SLE) in a family from the Cayman Islands. METHOD: An observational retrospective study of SLE was done following an index case of mixed connective tissue disease in a 51-year old West Indian woman of African descent. Her two daughters of the same father, who is of Cayman Islands origin, were also diagnosed with SLE. A family tree was subsequently drawn up to 1890 to identify other cases in the same family. RESULTS: There were 13 cases identified and all occurred between the 6th and the 8th generation. A family tree linked all cases to a man from the Cayman Islands who died in 1890. The nine cases with full medical records showed eight females and one male (8:1). The mean age at diagnosis was 29 years; polyarthritis occured in all nine patients (100%), kidney involvement in 6/9 (66.6%), skin rash in 6/9 (66.6%), pleuritis and pericarditis in 6/9 (66.6%) and anaemia in 6/9 (66.6%). The autoantibodies were mainly ANA in all patients (100%) and anti-dsDNA in 8/9 (88.8%). CONCLUSION: The unusual extensive familial clustering in this study represents the first to be described in a West Indian population where SLE is most prevalent and may suggest a genetic predisposition.

The making of a productivity hotspot in the coastal ocean.

BACKGROUND: Highly productive hotspots in the ocean often occur where complex physical forcing mechanisms lead to aggregation of primary and secondary producers. Understanding how hotspots persist, however, requires combining knowledge of the spatio-temporal linkages between geomorphology, physical forcing, and biological responses with the physiological requirements and movement of top predators. METHODOLOGY/PRINCIPAL FINDINGS: Here we integrate remotely sensed oceanography, ship surveys, and satellite telemetry to show how local geomorphology interacts with physical forcing to create a region with locally enhanced upwelling and an adjacent upwelling shadow that promotes retentive circulation, enhanced year-round primary production, and prey aggregation. These conditions provide an area within the upwelling shadow where physiologically optimal water temperatures can be found adjacent to a region of enhanced prey availability, resulting in a foraging hotspot for loggerhead sea turtles (Caretta caretta) off the Baja California peninsula, Mexico. SIGNIFICANCE/CONCLUSIONS: We have identified the set of conditions that lead to a persistent top predator hotspot, which increases our understanding of how highly migratory species exploit productive regions of the ocean. These results will aid in the development of spatially and environmentally explicit management strategies for marine species of conservation concern.

To eat or not to eat an endangered species: views of local residents and physicians on the safety of sea turtle consumption in northwestern Mexico.

Sea turtles have historically been an important food resource for many coastal inhabitants of Mexico. Today, the consumption of sea turtle meat and eggs continues in northwestern Mexico despite well-documented legal protection and market conditions providing easier access to other more reliable protein sources. Although there is growing evidence that consuming sea turtles may be harmful to human health due to biotoxins, environmental contaminants, viruses, parasites, and bacteria, many at-risk individuals, trusted information sources, and risk communicators may be unaware of this information. Therefore, we interviewed 134 residents and 37 physicians in a region with high rates of sea turtle consumption to: (1) examine their knowledge and perceptions concerning these risks, as a function of sex, age, occupation, education and location; (2) document the occurrence of illness resulting from consumption; and (3) identify information needs for effective risk communication. We found that 32% of physicians reported having treated patients who were sickened from sea turtle consumption. Although physicians believed sea turtles were an unhealthy food source, they were largely unaware of specific health hazards found in regional sea turtles, regardless of location. By contrast, residents believed that sea turtles were a healthy food source, regardless of sex, age, occupation, and education, and they were largely unaware of specific health hazards found in regional sea turtles, regardless of age, occupation, and education. Although most residents indicated that they would cease consumption if their physician told them it was unhealthy, women were significantly more likely to do so than men. These results suggest that residents may lack the necessary knowledge to make informed dietary decisions and physicians do not have enough accurate information to effectively communicate risks with their patients.

Lack of effects of acemetacin on signalling pathways for leukocyte adherence may explain its gastrointestinal safety.

BACKGROUND AND PURPOSE: Acemetacin is a non-steroidal anti-inflammatory drug which is rapidly bioconverted to indomethacin, but produces significantly less gastric damage than indomethacin. This study was performed to investigate several possible mechanisms that could account for the gastrointestinal tolerability of acemetacin. EXPERIMENTAL APPROACH: The gastric and intestinal damaging effects of acemetacin and indomethacin were examined in the rat. Effects of the drugs on blood levels of leukotriene B(4) and thromboxane B(2), on leukocyte-endothelial adherence in post-capillary mesenteric venules, and on gastric expression of tumour necrosis factor-alpha (TNF-alpha) were determined. The two drugs were also compared for gastric toxicity in rats pretreated with inhibitors of COX-2 and NOS. KEY RESULTS: Acemetacin induced significantly less gastric and intestinal damage than indomethacin, despite markedly suppressing COX activity. Indomethacin, but not acemetacin, significantly increased leukocyte adherence within mesenteric venules, and gastric expression of TNF-alpha. Pretreatment with L-nitro-arginine methyl ester or lumiracoxib increased the severity of indomethacin-induced gastric damage, but this was not the case with acemetacin. CONCLUSIONS AND IMPLICATIONS: The increased gastric and intestinal tolerability of acemetacin may be related to the lack of induction of leukocyte-endothelial adherence. This may be attributable to the reduced ability of acemetacin to elevate leukotriene-B(4) synthesis and TNF-alpha expression, compared to indomethacin, despite the fact that acemetacin is rapidly bioconverted to indomethacin after its absorption.

Suppressive effects of nitric oxide-releasing prednisolone NCX-1015 on the allergic pleural eosinophil recruitment in rats.

BACKGROUND: The addition of a nitric oxide (NO)-releasing moiety to prednisolone was shown to enhance the anti-inflammatory activity of this glucocorticoid in some experimental conditions, but its effectiveness in the context of eosinophilic inflammation remains to be elucidated. OBJECTIVE: This study compared the anti-inflammatory effect of prednisolone to a NO-releasing derivative of prednisolone, NCX-1015, using a model of allergen-evoked eosinophil recruitment in rats. The efficacy of a NO-donor compound, DETA-NONOate, was also assessed for comparison. METHODS: Wistar rats were actively sensitized with Al(OH)(3) plus ovalbumin and 14 days later challenged with antigen intrapleurally. Treatments were performed locally 1 h before challenge. Cysteinyl-leucotrienes (Cys-LT) and eotaxin were measured by ELISA. RESULTS: Antigen challenge induced an eosinophil infiltration at 12 h, maximal at 24 h. It also caused an increase in the levels of Cys-LTs in the pleural exudate and in the expression of 5-lipoxygenase (5-LO) in infiltrated leucocytes at 6 h, peaking at 12 h and persisting for at least 24 h. Treatment with equimolar doses of prednisolone and NCX-1015 inhibited the late eosinophil infiltration, although the dose required to produce maximal inhibition was about one-tenth that of prednisolone. Cys-LT generation and 5-LO expression were inhibited by NCX-1015 but not by prednisolone. Treatment with prednisolone combined with the NO-donor DETA-NONOate led to a greater inhibition of the eosinophilia and Cys-LT generation as compared with either drug alone. Administration of the steroid receptor antagonist RU 486, 1 h before prednisolone and NCX-1015, abolished the inhibitory effect of the former, under conditions where it only partially affected the latter. CONCLUSIONS: Our findings indicate that NCX-1015 provided a greater anti-inflammatory effect than prednisolone on the allergic eosinophil recruitment in rats, suggesting that NO-releasing steroids can be considered as a promising therapeutic approach to allergic diseases.

Mechanisms underlying the anti-inflammatory activity and gastric safety of acemetacin.

BACKGROUND AND PURPOSE: Acemetacin is regarded as a pro-drug of indomethacin and induces significantly less gastric damage but the reasons for this greater gastric safety of acemetacin are unclear. The anti-inflammatory effects of acemetacin have been attributed, at least in part, to its hepatic biotransformation to indomethacin. The aim of this study was to determine the effects of acemetacin and indomethacin in an in vivo model of acute inflammation and to examine the importance of biotransformation of acemetacin (to indomethacin) to its anti-inflammatory actions. EXPERIMENTAL APPROACH: The zymosan airpouch model was used in rats. Indomethacin or acemetacin (2.7-83.8 micromol kg(-1)) were administered orally or directly into the pouch. Leukocyte infiltration, prostaglandin (PG) E(2) and leukotriene (LT) B(4) levels in exudates, and whole blood thromboxane (TX) B(2) synthesis were measured. KEY RESULTS: Acemetacin was rapidly converted to indomethacin after its administration. Both acemetacin and indomethacin elicited comparable, dose-dependent reductions of leukocyte infiltration and of PGE(2) and TXB(2) synthesis. However, indomethacin induced more gastric damage than acemetacin and elevated LTB(4) production in the airpouch. CONCLUSIONS AND IMPLICATIONS: The similar effects of acemetacin and indomethacin on leukocyte infiltration and PG synthesis are consistent with rapid biotransformation of acemetacin to indomethacin. Some of this biotransformation may occur extra-hepatically, for instance in inflammatory exudates. Acemetacin probably exerts actions independent of conversion to indomethacin, given the different effects of these two drugs on LTB(4) production. Such differences may contribute to the relative gastric safety of acemetacin compared to indomethacin.

An in vitro study to determine the effectiveness of a patellar ligament/fascia lata graft and new tibial suture anchor points for extracapsular stabilization of the cranial cruciate ligament-deficient stifle in the dog

OBJECTIVE-(1) To determine whether an extracapsular patellar ligament/fascia lata graft would provide stability in the cranial cruciate ligament (CrCL)-deficient stifle comparable with that of the intact. (2) To determine if different tibial anchor points would enhance stability of the CrCL-deficient stifle when compared with the standard fabellar-tibial suture (FTS) placement. STUDY DESIGN-Experimental. ANIMALS-Twenty-eight canine cadaver hind limbs. METHODS-Stifles were mounted in a jig and tested between loads of -65 and 80 N. After testing the intact CrCL, 4 stabilization techniques were tested after CrCL transection: lateral graft technique (LGT) and 3FTS with different tibial anchor points. RESULTS-There were no significant differences in displacement between the LGT and standard FTS between the LGT and the intact CrCL, or between the FTS and the intact CrCL, in either the Securos or the Screw-washer experiments. Stiffness of the intact CrCL was significantly greater than that of any stabilization techniques. Differences in stiffness were not significant between the suture stabilization techniques. CONCLUSIONS-Securely anchored, the LGT results in a reduction in drawer motion similar to that of the intact CrCL and the standard FTS. Altering the tibial anchor point of the FTs does not improve stiffness or enhance stabilization of the CrCL-deficient Stifle. CLINICAL RELEVANCE-The LGT could be used for the treatment of CrCL ruptures in the dog. A clinical study is recommended (AU)

Vasorelaxant effects of a nitric oxide-releasing aspirin derivative in normotensive and hypertensive rats.

1. Nonsteroidal anti-inflammatory drugs have been reported to exacerbate hypertension and to interfere with the effectiveness of some anti-hypertensive therapies. In this study, we tested the effects of a gastric-sparing, nitric oxide-releasing derivative of aspirin (NCX-4016) on hypertension in rats. 2. Hypertension was induced by administering L-NAME in the drinking water (400 mg l(-1)). Groups of rats were treated daily with aspirin, NCX-4016 or vehicle. 3. NCX-4016 significantly reduced blood pressure relative to the aspirin-treated group over the 2-week period of treatment. Aspirin and, to a lesser extent, NCX-4016 suppressed whole blood thromboxane synthesis. 4. In anaesthetized rats, acute intravenous administration of NCX-4016 caused a significant fall in mean arterial pressure in hypertensive rats, but was devoid of such effects in normotensive controls. 5. In vitro, NCX-4016 relaxed phenylephrine-pre-contracted aortic rings obtained from both normotensive and hypertensive rats, and significantly reduced their responsiveness to the contractile effects of phenylephrine. 6. These results suggest that NCX-4016 reduces blood pressure in hypertensive rats, not simply through the direct vasodilatory actions of the nitric oxide released by this compound, but also through possible interference with the effects of endogenous pressor agents. These properties, added to its anti-thrombotic effects, suggest that NCX-4016 may be a safer alternative to aspirin for use by hypertensive patients.

Underlying mechanisms of portal hypertensive gastropathy.

Gastric mucosal lesions are frequently observed in patients with liver cirrhosis and portal hypertension. Similar lesions can be observed in experimental portal hypertension. This review summarizes our current knowledge of the pathophysiology of portal hypertensive gastropathy, with a particular focus on the microcirculatory disturbances that characterize this condition. The stomach of cirrhotic patients exhibits an increased susceptibility to injury induced by several irritants. Similarly, the stomach of portal hypertensive animals is less resistant to injury. One of the most important factors contributing to the increased susceptibility to damage is an impaired hyperemic response when the epithelium is exposed to irritants. This appears to be related to a reduction in mucosal prostaglandin production and to altered microcirculatory responsiveness to nitric oxide. Nitric oxide overproduction in portal hypertension may have direct effects on gastric blood flow regulation. Elevated production of tumor necrosis factor-alpha by gastric mucosa in portal hypertensive rats has also been shown to contribute to mucosal injury. A better understanding of the pathogenesis of portal hypertensive gastropathy may lead to development of specific therapeutic interventions for this condition.

Endodontic therapy and root submersion of an impacted maxillary canine. A case report and review of the root submergence concept.

A case report of root submersion of a maxillary canine after endodontic therapy is presented. A review of the rationale and validity of the root submersion concept is also presented.

Intestinal platelet-activating factor synthesis during Nippostrongylus brasiliensis infection in the rat.

Infection of rats with the parasite Nippostrongylus brasiliensis results in severe intestinal pathology and dysfunction. Much of the damage that occurs within the intestinal tract may be the direct result of the production of potent inflammatory mediators. PAF is one such lipid mediator that may lead to the altered motility and secretory changes that occur during N. brasiliensis infection. Male, Sprague-Dawley rats were subcutaneously infected with 3000 third stage larvae, while control groups were injected with phosphate buffered saline. At various times post infection (4-42 days) groups of four or more infected and control rats were killed and samples of ileum and jejunum were removed for determination of PAF and leukotriene synthesis (LTB4 and LTC4), myeloperoxidase (MPO) activity and tissue eosinophil and mast cell numbers. Separate groups of rats were killed at similar times for the determination of intestinal worm burden and serum rat mast cell protease II (RMCP-II) levels. Significant elevation in PAF synthesis was not seen until day 15, a time when the intestinal worm burden was no longer evident. Furthermore, this elevation was restricted to the jejunum. The elevation in PAF synthesis correlated with a significant elevation in histologically detectable eosinophils and mast cells in the jejunum. Mast cell activity, as detected through serum concentrations of RMCP-II, was significantly elevated at day 8 post-infection and remained elevated until day 18 post-infection. However, despite significant changes in ileal eosinophil and mast cell numbers, PAF synthesis in the ileum did not differ significantly over the course of the infection. LTB4 and LTC4 production and MPO activity, were significantly elevated in both ileum and jejunum only following worm loss. These results demonstrate that PAF synthesis is altered following primary infection with N. brasiliensis. Changes in PAF synthesis paralleled changes in synthesis of other inflammatory mediators and were associated with hyperplasia of various inflammatory cells. Nevertheless, elevated PAF production is not simply a consequence of intestinal eosinophil and mast cell hyperplasia, as ileal PAF production did not significantly change despite hyperplasia of these cell types.

Racial/Ethnic differences in smoking, drinking, and illicit drug use among American high school seniors, 1976-89.

BACKGROUND: This paper reports racial/ethnic differences in the use of licit and illicit drugs by high school seniors in the United States. METHODS: The study uses questionnaire data from annual, nationally representative surveys of seniors from 1976 through 1989. Combined sample sizes were 57,620 for 1976-79; 75,772 for 1980-84; and 73,527 for 1985-89. RESULTS: Native American had the highest prevalence rates for cigarettes, alcohol, and most illicit drugs; White students had the next highest rates for most drugs. Asian Americans had the lowest prevalence rates, and Black students had levels nearly as low except for marijuana. Prevalence rates for the Hispanic groups were mostly in the intermediate ranges except for relatively high cocaine use among the males. Trend patterns for most forms of drug use were similar across subgroups, although cigarette use declined more sharply for Black than White seniors, resulting in greater Black-White differences in recent years. CONCLUSIONS: This study, other school-based studies, and general population surveys all show relatively low levels of drug use by most non-White youth, especially Black Americans and Asian Americans. Multivariate analyses indicate that such subgroup differences in high school seniors' drug use are not primarily attributable to family composition, parents' education, region, or urban-rural distinctions.

Alterations in regional blood flow in rats following sensitization to the nematode Nippostrongylus brasiliensis: effects of PAF antagonists.

1. Changes in tissue and organ blood flow associated with sensitization of rats to the nematode parasite, Nippostrongylus brasiliensis, were studied 30 to 35 days after infection, a time when very few worms remain in the animal. 2. Neither active nor passive sensitization modified heart rate, mean arterial blood pressure, cardiac output or total peripheral resistance. Passive sensitization and administration of non-immune sera did not modify blood flow to any of the tissues studied. 3. Active sensitization increased hepatic arterial blood flow, but decreased blood flow to the stomach, duodenum, jejunum and the submandibular glands. These effects cannot be attributed to residual nematode infections as treatment with the anthelmintic, thiabendazole, did not alter blood flow relative to untreated, actively sensitized rats. 4. The effects of active sensitization on blood flow were probably due to an action of platelet-activating factor (PAF) since treatment of actively sensitized animals with the selective antagonists, WEB-2086 and BN 52021, reversed the decrease in flow seen to the intestinal regions. The PAF antagonists increased blood flow to the kidneys and the trachea of sensitized animals. 5. These results suggest that the PAF released from undetermined sources in nematode-sensitized rats, produces altered blood flow, primarily to the stomach and proximal small bowel.

A family approach to cardiovascular risk reduction: results from the San Diego Family Health Project.

The effectiveness of a family-based cardiovascular disease risk reduction intervention was evaluated in two ethnic groups. Participants were 206 healthy, volunteer low-to-middle-income Mexican-American and non-Hispanic white (Anglo-American) families (623 individuals), each with a fifth or a sixth-grade child. Families were recruited through elementary schools. Half of the families were randomized to a year-long educational intervention designed to decrease the whole family's intake of high salt, high fat foods, and to increase their regular physical activity. Eighty-nine percent of the enrolled families were measured at the 24-month follow-up. Both Mexican- and Anglo-American families in the experimental groups gained significantly more knowledge of the skills required to change dietary and exercise habits than did those in the control groups. Experimental families in both ethnic groups reported improved eating habits on a food frequency index. Anglo families reported lower total fat and sodium intake. There were no significant group differences in reported physical activity or in tested cardiovascular fitness levels. Significant differences for Anglo-American experimental vs. control adult subjects were found for LDL cholesterol. Significant intervention-control differences ranging from 2.2 to 3.4 mmHg systolic and/or diastolic blood pressure were found in all subgroups. Direct observation of diet and physical activity behaviors in a structured environment suggested generalization of behavior changes. There was evidence that behavior change persisted one year beyond the completion of the intervention program. It is concluded that involvement of families utilizing school based resources is feasible and effective. Future studies should focus on the most cost-effective methods of family involvement, and the potential for additive effects when family strategies are combined with other school health education programs.