Enhanced formation of sulfidopeptide-leukotrienes in ulcerative colitis and Crohn's disease: inhibition by sulfasalazine and 5-aminosalicylic acid

Release of sulfidopeptide (SP)-leukotrienes (LT)in vitro from normal human colonic mucosa and from mucosal tissue obtained from patients with Crohn's disease (CD) and ulcerative colitis (UC) was investigated. It was found that inflamed mucosal tissue released significantly more SP-LT than normal colonic mucosa both under control conditions and after addition of calcium ionophore A23187. These results indicate the presence of endogenous stimuli as well as an increased responsiveness to an exogenous stimulus of LT formation in the inflamed mucosa. Sulfasalazine (SASP), a drug used in inflammatory bowel diseases, and its active metabolite 5-aminosalicylic acid (5-ASA) were found to inhibit colonic mucosal SP-LT formation, while only 5-ASA inhibited simultaneously synthesis of another arachidonic acid-derived inflammatory mediator, prostaglandin (PG) E₂. The results suggest that SP-LT might be important mediators of inflammation in CD and UC.     

Oral desensitization to 5-aminosalicylic acid medications.

BACKGROUND: Although hypersensitive subjects have been desensitized to oral sulfasalazine, the feasibility of oral desensitization to the drug's active moiety, 5-aminosalicylic acid has been questioned and never been reported. METHODS: We devised a 5-aminosalicylic acid desensitization protocol and administered the drug to two hypersensitive subjects on three occasions. RESULTS: Both 5-aminosalicylic acid hypersensitive subjects were successfully desensitized without complications and were able to tolerate therapeutic doses. CONCLUSION: Despite changing the drug's properties by crushing it for incrementally increasing administration, we successfully desensitized two patients on three occasions with 5-aminosalicylic acid.     

Therapeutic effectiveness and tolerance of 5-aminosalicylic acid in short term treatment of patients with ulcerative colitis at a low or medium phase of activity

The therapeutic effectiveness and tolerance of 5-aminosalicylic acid (5ASA), compared with Salazosulphapyridine (SASP) in treatment of ulcerative colitis have been evaluated in 86 patients with the disease at a low or medium phase of activity. After a treatment of six weeks, an improvement was noted in 63.6% (5ASA) and 61.3% (SASP) of these patients. However in no case was a complete remission of the disease observed on the basis of endoscopic inspection. In patients with pancolitis the improvement was lower (37.5% with 5ASA, 40% with SASP). The only side-effect was gastric intolerance, which occurred in 18.1% of the 5ASA and in 19% of the SASP patients. In conclusion we can assume that 5ASA and SASP largely overlap each other as regards both therapeutic effectiveness and occurrence of side-effects.     

Positive Coombs' test associated with ulcerative colitis. A prevalence study

Among 112 patients with ulcerative colitis (UC), a positive Coombs' test was detected in two cases. The immunoglobulins were IgG and no complement could be detected on the red cells. None of the two patients showed laboratory evidence of hemolysis, although reduced red cell survival was suspected in one patient with a 6-year history of UC, previous autoimmune hemolytic anemia and a positive in vitro monocyte-macrophage phagocytosis test. The HLA-antigens in the two patients were different except for the common antigen HLA-A1.     

Radioprotection by copper and zinc complexes of 5-aminosalicylic acid: a preliminary study.

The effect of copper and zinc complexes of 5-aminosalicylic acid (hereafter referred to as Cu-5ASA and Zn-5ASA, respectively) against whole-body gamma radiation-induced cytotoxicity was studied in Swiss albino mice. Protection against lethal irradiation was evaluated from 30 day mouse survival (10 Gy) and endogenous spleen colony assay (11 Gy); and against sublethal dose (4 Gy) was assessed from gamma irradiation (RT)-induced formation of micronuclei in the mouse bone marrow 24 h postirradiation. Pretreatment with either Cu-5ASA (2.5-9 mg/kg) or Zn-5ASA (3.5-14 mg/kg) intraperitoneally (i.p.) delayed and reduced percentage mortality in mice exposed to 10 Gy RT. The doses 9 mg/kg for Cu-5ASA and 7 mg/kg for Zn-5ASA were found to be the most effective dose in preventing RT-induced weight loss and reducing percentage mortality. Both the drugs also caused an increase in the endogenous spleen colonies in mouse exposed to 11 Gy RT. At sublethal doses of RT, pretreatment with either Cu-5ASA or Zn-5ASA resulted in a significant decrease in the RT-induced micronucleated polychromatic erythrocytes and normochromatic erythrocytes (MPCEs and MNCEs) and an increase in the ratio of PCE to NCE (P/N), at 24 h postirradiation. These results show that both Cu-5ASA and Zn-5ASA are effective in protecting normal tissues against lethal and sublethal doses of RT. Further pretreatment with either Cu-5ASA or Zn-5ASA enhanced the survival of tumor-bearing mice (Ehrlich's ascites carcinoma) exposed to 7.5 Gy RT. In fact, both the complexes caused an increase in the mean and average survival times (MST and AST) when compared to the irradiated control, suggesting a synergetic effect of these drugs with radiation in causing cytotoxicity to the tumor cells. The data clearly indicate that both Cu-5ASA and Zn-5ASA significantly reduced the deleterious effect of radiation and hence could be useful agents in reducing the side effects of therapeutic radiation.     

Telephone nurse counseling for medication adherence in ulcerative colitis: A preliminary study

Objective

Adherence is challenging in episodic chronic conditions that require medication during both symptomatic and quiescent periods, such as ulcerative colitis (UC). Adherence for these conditions is under-studied. This study was a preliminary test of telephone nurse counseling to address cognitive and emotional barriers to adherence in UC.

Methods

524 people taking mesalamine for UC were referred by their health care providers, and 278 (53%) enrolled. There were no demographic differences between program participants and nonparticipants. Participants reported multiple comorbidities and concomitant medications. All participants received telephone follow-up (M = 2.1 calls) from a registered nurse who used cognitive-behavioral and motivational interviewing counseling techniques. Adherence measured by structured interview was compared to a population baseline using a binomial test.

Results

Attrition was 51% over 6 months but was unrelated to adherence. Participants had better adherence than the expected population rate, with a significant dose-response effect. Reasons for nonadherence were primarily psychological or efficacy-related.

Conclusion

Adherence following intervention was better than typical mesalamine adherence. Self-efficacy predicted adherence, but demographic and clinical variables did not. Adherent participants reported more adverse events.

Practice implications

Attention to patients’ cognitive and emotional reactions may help to improve adherence in episodic chronic diseases such as UC.     

Successful granulocyte transfusion therapy for gram-negative septicemia. A prospectively randomized controlled study.

We prospectively randomized 27 granulocytopenic patients who experienced a total of 30 episodes of gram-negative septicemia. The control group received an appropriate antibiotic regimen alone, whereas the "transfusion" group received infusions of granulocytes in addition to the antibiotics. Five of 14 controls survived, and 12 of 16 in the transfusion group survived, and 12 of 16 in the transfusion group survived (P less than 0.04). An important factor in the outcome of treatment was the recovery of bone-marrow function (return of peripheral granulocyte count greater than or equal to 1000 per microliter). Eighty-three per cent (five of six) of the control group and all (four of four) of the transfusion group with recovery of granulocyte levels survived the episode of sepsis. In contrast, none of the eight control patients, as compared to 67 per cent (eight of 12) of the transfusion group, survived persistent granulocytopenia (P less than 0.005). Granulocyte transfusions appear to complement appropriate antibiotic treatment of gram-negative-septicemia due to granulocytopenia.     

The duration of oral anticoagulation after deep vein thrombosis. A randomized study

Eighty patients with deep vein thrombosis (DVT) were randomized between our routine duration of oral anticoagulation and 50% reduction thereof, in order to evaluate whether shorter therapy could be given without increased risks. The study was stratified, so that 20 patients with the 1st episode of DVT caused by a temporary risk factor were treated for 1.5 or 3 months, 40 patients with the 1st episode of DVT caused by a permanent risk factor for 3 or 6 months, and 20 patients with the 2nd episode of DVT for 6 or 12 months. When warfarin therapy was discontinued, the patients were followed by means of venous occlusion plethysmography every 3 months for 1 year, and clinically for 15-27 months in the different subgroups. Thromboembolic complications were registered and verified by venography and perfusion lung scan. We could not detect any difference between the groups. The rate of rethrombosis and embolism during 12 and 24 months after cessation of anticoagulant therapy was 8 and 10%, respectively, among the patients with reduced duration of treatment and 8 and 14%, respectively, among those with regular duration. One fatal, warfarin-induced hemorrhage occurred. It is important to reduce unnecessary extension of oral anticoagulation after DVT in order to minimize the negative side-effects without increasing the recurrence rate. More extensive trials should be performed to confirm our results and define the optimal duration of treatment.     

A randomized prospective long-term study of two oral appliances for sleep apnoea treatment

Various types of mandibular protrusive appliances have revealed different treatment success in mild-to-moderate obstructive sleep apnoea (OSA). The present study compared the long-term effect of two different appliances in the treatment of OSA. A total of 103 patients with OSA were randomized and treated with an IST^® or Thornton Anterior Positioner (TAP^™) appliance. They were followed-up after a short-term treatment period of 6 months and long-term treatment period of over 24 months. Sleep studies in the sleep laboratory were conducted with and without the appliances, and various questionnaires assessing subjective daytime sleepiness, sleep quality, quality of life and symptom scores were administered at each time interval. Quality of life, sleep quality, sleepiness, symptoms and sleep outcome showed significant improvement in the short-term evaluation with both appliances, but the TAP^™ appliance revealed a significantly greater effect. After more than 2 years of treatment, sleep outcomes revealed an equal effect with both appliances. The subjective benefits achieved initially lessened significantly. This study illustrates that both the IST^® and the TAP^™ appliances are effective therapeutic devices for OSA after a period of over 24 months. Lack of compliance may be due to insufficient improvement in anticipated subjective symptoms and/or a recurrence of symptoms over time.     

A simple method for the purification of 5-aminosalicylic acid. Application of the product as substrate in enzyme-linked immunosorbent assay (ELISA)

Commercially available 5-aminosalicylic acid (5-AS) was recrystallised in the presence of Na2S2O5. A completely colourless solution was obtained when the purified product was dissolved at a concentration of 1 mg/ml in a phosphate buffer containing EDTA and H2O2. No significant increase in absorption was found upon storage for 18 h at 4 degrees C. A 8-fold increase in sensitivity of an enzyme-linked immunosorbent assay for the detection of rotavirus antigens was demonstrated by using the modified substrate solution instead of the conventional substrate solution of crude 5-AS. In addition, P/N values did not significantly change between 2 and 18 h after addition of the substrate, thus rendering the time of reading less critical. No difference in sensitivity of the assay was found between modified 5-AS solution and ortho-phenylenediamine (OPD). However, since OPD requires special care in handling the modified 5-AS solution is preferred for use in routine ELISAs.     

Effects of acetyl-L-carnitine oral administration on lymphocyte antibacterial activity and TNF-alpha levels in patients with active pulmonary tuberculosis. A randomized double blind versus placebo study.

Acetyl-L-carnitine (ALC), a drug for the treatment of ageing-related neuroendocrine dysfunctions, was orally administered--2 gm/day for 30 days--to 10 patients with active pulmonary tuberculosis (TBC). Lymphocyte-mediated antibacterial activity and serum levels of tumor necrosis factor (TNF)-alpha were evaluated before and after treatment, comparing the values with those of 10 TBC patients receiving placebo. Results show that by day 30, antibacterial activity remained unmodified or increased in ALC-treated subjects, while decreased in the placebo group. No influence of ALC on TNF-alpha levels was detectable. These data suggest that the host's immune responses to M. tuberculosis infection can be selectively modulated by drugs acting on the neuroendocrine axis.     

Prospective randomized two-Arm controlled study to determine the efficacy of a specific intervention to improve long-term adherence to highly active antiretroviral therapy

BACKGROUND: Nearly perfect compliance seems to be indispensable to obtain the maximum benefit from highly active antiretroviral therapy (HAART). Interventions to ensure a high level of adherence during a relatively long-term period of therapy are necessary. METHODS: This is a prospective, randomized, two-arm controlled study including patients starting their first-or second-line HAART who were randomized to receive psychoeducative intervention to implement adherence (experimental group [EG]) or a usual medical follow-up (control group [CG]). We aimed to study the efficacy of a psychoeducative intervention to ensure long-term adherence to HAART, its relation with the virologic efficacy of treatment, and to determine the variables related to long-term adherence. Visits were made at weeks 0, 4, 24, and 48 for data collection. Self-reported adherence was registered at each visit and its veracity was tested by randomized blood analyses performed without previous warning to 40% of patients. Appropriate adherence was defined as the consumption of >/=95% of medication prescribed. Statistical analyses were performed both by the as treated (AT) and the intention to treat missing = failure (ITT) methods. RESULTS: In all, 116 patients were included. At week 48, 94% of patients in the EG versus 69% controls achieved adherence >/=95% (p =.008); 89% of patients in the EG versus 66% controls had HIV-1 RNA levels <400 copies/ml (p =.026). Overall, 85% of patients with adherence >/=95% but only 45% of those with adherence <95% had viral load (VL) <400 copies/ml (p =. 008). In multivariate analysis, variables significantly related to adherence were having received a psychoeducative intervention (odds ratio [OR], 6.58; p =.04), poor effort to take medication (OR, 5.38; p =.03), and high self-perceived capacity to follow the regimen (OR, 13.76; p =.04). Self-reported adherence and drug plasma levels coincided in 93% of cases. However, differences in adherence did not reach statistical significance in the ITT analysis although a clear tendency toward benefit was observed in EG. CONCLUSIONS: Specific and maintained psychoeducative interventions based on excellence on clinical practice are useful to keep high levels of adherence as well as high levels of viral suppression. There is a clear relation between high adherence levels and virologic success. Assessment of certain specific variables related to adherence may be helpful to monitor patient's compliance in the clinical setting.     

In vitro susceptibility of diarrhoea producing gram negative enteric bacteria to sulfasalazine, 5-aminosalicylic acid, sulfapyridine and four quinolones. Brief report

The in vitro susceptibility of diarrhoea producing Gram negative enteric bacteria to sulfasalazine, 5-aminosalicylic acid, sulfapyridine and four quinolones was investigated using an agar dilution method. All strains were resistant to 1600 micrograms/ml of sulfasalazine and 5-aminosalicylic acid. MIC range of sulfapyridine for Y. enterocolitica was 3.1-25 micrograms/ml (median:6.2) and for Salmonella 25-100 micrograms/ml (median: 100) Campylobacter jejuni/coli were less susceptible to sulfapyridine with MIC values ranging from 200 to 800 micrograms/ml. Shigella and three of five E. coli strains were resistant to 1600 micrograms/ml of sulfapyridine. Two strains of E. coli were inhibited by 25 micrograms/ml. All strains were fairly susceptible to enoxacin, ciprofloxacin, pefloxacin and ofloxacin. Cirpofloxacin was the most active drug on weight basis.     

A randomized study of maintenance therapy with ranitidine to prevent the recurrence of duodenal ulcer

After an active duodenal ulcer has healed in response to medical therapy, the rate of recurrence during the subsequent year is relatively high. We therefore enrolled 140 patients with healed duodenal ulcers in a two-year randomized, double-blind trial comparing maintenance therapy (ranitidine, 150 mg nightly) with placebo for the prevention of recurrent duodenal ulceration. We performed endoscopy annually and when symptoms suggested the recurrence of ulcers. Verified recurrent ulcers in either group were treated for four or eight weeks with open-label ranitidine (150 mg twice a day). Patients whose ulcers healed within eight weeks resumed randomized treatment. Prophylactic therapy with ranitidine reduced the rate of ulcer relapses from 63 percent in the placebo group to 37 percent in the ranitidine group (P less than 0.05). Treatment with ranitidine extended the median ulcer-free interval from one to two years (P less than 0.05). The first recurrences of ulcer were asymptomatic in half the ranitidine group and in a quarter of the placebo group. Prophylactic therapy with ranitidine also reduced the frequency of recurrent ulcers that were unhealed by eight weeks, that were bleeding, that were in the stomach, or that were the second recurrent ulcer within six months, from 43 percent in the placebo group to 21 percent. Patients who drank alcohol, smoked, had a history of ulcer disease, or had duodenal scarring or erosion at the time of entry into the study were at the greatest risk for recurrence and benefited the most from prophylactic ranitidine. We conclude that prophylactic treatment with ranitidine is effective in preventing the recurrence of duodenal ulceration.     

A randomized prospective study comparing pregnancy rates following clomiphene citrate and human menopausal gonadotrophin therapy.

The anti-oestrogenic effect of clomiphene citrate causes an increased rate of associated cervical factor problems. Theoretically, it may also cause an adverse effect on the endometrium. The hostile mucus may be completely or partially corrected by the use of additional oestrogen after stopping clomiphene, or by intrauterine insemination (IUI). The prospective randomized study presented here was designed to determine whether a higher pregnancy rate might be achieved using human menopausal gonadotrophin (HMG) compared to clomiphene citrate. Thirty-seven women treated with clomiphene citrate for 165 cycles were compared to 33 treated with HMG for 179 cycles. A pregnancy was achieved in 81.1% of clomiphene-treated women (18.2%/cycle) versus 72.7% (13.3% per cycle) of HMG-treated women. The abortion rates of 13.3 and 12.5% respectively, were similar. The data suggest no adverse effect of clomiphene compared to HMG as far as pregnancy rates are concerned. IUI seems to be an effective means of treating cervical factor problems induced by clomiphene.     

A randomized, multicenter, open-label study of poly-L-lactic acid for HIV-1 facial lipoatrophy

BACKGROUND: Facial lipoatrophy can stigmatize and can reduce quality of life, self esteem, and antiretroviral adherence. Poly-L-lactic acid (PLA) injections seem safe and effective, but no randomized study has included objective endpoints. METHODS: HIV-positive adults with moderate/severe facial lipoatrophy were randomized to 4 open-label PLA treatments administered every 2 weeks from week 0 (immediate group, n = 51) or after week 24 (deferred group, n = 50). The primary endpoint was mean change in facial soft tissue volume (FSTV), as assessed by spiral computed tomography. Analyses were by intention to treat. RESULTS: At week 24, mean changes in FSTV were 0 cm3 in the intermediate group and -10 cm3 in the deferred group (between-group difference of 10 [95% confidence interval (CI): -7 to 28] cm3; P = 0.24). The immediate group had a greater mean change in soft tissue depth at the maxilla (2.2 mm [95% CI: 1.6 to 2.9]; P < 0.0001) and base of the nasal septum (1.0 mm [95% CI: 0.3 to 1.6]; P = 0.003) levels. PLA did not have an impact on peripheral fat mass, viral load, or antiretroviral adherence. Patient and physician subjectively assessed facial lipoatrophy severity (P < 0.0001), 2 of 8 Short Form-36 Health Survey and 2 of 5 Multidimensional Body-Self Relations Questionnaire-Appearance Scales, scores improved significantly. The median duration of treatment-related adverse events was 2 (interquartile range: 1 to 3) days. CONCLUSIONS: PLA did not increase FSTV, although tissue thickness in injection planes increased modestly, an improvement observed by patients. PLA was safe and well tolerated. Facial lipoatrophy severity and some quality-of-life domains improved.