Ernesto Palazzini

Rifaximin versus Ciprofloxacin for the Treatment of Traveler's Diarrhea: A Randomized, Double-Blind Clinical Trial

Rifaximin is a poorly absorbed rifamycin derivative under investigation for treatment of infectious diarrhea. Adult students from the United States in Mexico and international tourists in Jamaica were randomized to receive either rifaximin (400 mg twice per day) or ciprofloxacin (500 mg twice per day) for 3 days, following a double-blinded model, from June 1997 to September 1998. A total of 187 subjects with diarrhea were studied. Time from initiation of therapy to passage of last unformed stool was comparable for those receiving rifaximin or ciprofloxacin (median, 25.7 hours versus 25.0 hours, respectively). There was no significant difference in the proportion of subjects in the 2 groups with respect to clinical improvement during the first 24 hours (P=.199), failure to respond to treatment (P=.411), or microbiological cure (P=.222). The incidence of adverse events was low and similar in each group. Rifaximin is a safe and effective alternative to ciprofloxacin in the treatment of travelers diarrhea.

In Vitro Activity and Fecal Concentration of Rifaximin after Oral Administration

ABSTRACT Rifaximin showed moderately high MICs (the MIC at which 90% of the isolates tested were inhibited = 50 μg/ml) for 145 bacterial enteropathogens from patients with travelers diarrhea acquired in Mexico during the summers of 1997 and 1998. Rifaximin concentrations in stool the day after oral administration (800 mg daily for 3 days) were high (average, 7,961 μg/g), proving the value of the drug.

Rifaximin: a nonabsorbed antimicrobial in the therapy of travelers' diarrhea.

Background/Aims: Bacterial enteropathogens, the major cause of travelers’ diarrhea, are customarily treated with antibacterial drugs. Rifaximin, a nonabsorbed antimicrobial was examined as treatment for travelers’ diarrhea. Methods: A randomized, prospective, double-blind clinical trial was carried out in 72 US adults in Mexico. Patients with acute diarrhea received one of three doses of rifaximin (200, 400 and 600 mg t.i.d.) or trimethoprim/sulfamethoxazole (TMP/SMX, 160 mg/800 mg b.i.d.) for 5 days. Results were compared with data from 2 placebo-treated historical control populations. Results: The shortest duration of treated diarrhea was seen in the group receiving 200 mg rifaximin t.i.d (NS). Clinical failure to respond to treatment occurred in 6 of 55 (11%) rifaximin-treated subjects versus 5 of 17 (29%) of TMP/SMX-treated subjects (NS). Sixteen of twenty (80%) of the enteropathogens isolated from the rifaximin-treated subjects and 7 of 7 (100%) from the TMP/SMX group were eradicated by treatment (NS). Sixteen of twenty-four (67%) enteropathogens identified were susceptible to TMP and all 24 were inhibited by ≤50 µg/ml of rifaximin. Rifaximin reduced the number of unformed stools passed during the first 24 h of treatment when compared with 2 control placebo groups (3.3 versus 5.1; p = 0.008 and 0.0001) and led to a reduced duration of post-enrollment diarrhea (mean values of 43.1 versus 68.1 and 81.9 h; p = 0.001). Conclusions: Rifaximin shortened the duration of travelers’ diarrhea compared with TMP/SMX and 2 earlier studied placebo-treated groups. A poorly absorbed drug if effective in treating bacterial diarrhea has pharmacologic and safety advantages over the existing drugs.

Inhibition of intestinal bacterial translocation with rifaximin modulates lamina propria monocytic cells reactivity and protects against inflammation in a rodent model of colitis.

Background: A modification of the intestinal flora and an increased bacterial translocation is a common finding in patients with inflammatory bowel disease as well as in animal model of colitis. Rifaximin, a non-absorbable derivative of rifamycin, is an effective antibiotic that acts by inhibiting bacterial ribonucleic acid synthesis. Aims: In the present study, we investigated the effect of the administration of rifaximin (10, 30 and 50 mg/kg/day) or prednisolone (10 mg/kg/day) in 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in mice. Methods: Colitis was induced in mice by intrarectal administration of TNBS (1.5 mg/mouse in 50% ethanol) and disease severity assessed clinically and by histologic scoring of colon damage, determination of interleukin (IL)-2, IL-12, interferon (IFN)-γ and tumor necrosis factor (TNF)-α (protein and mRNA and myeloperoxidase (MPO) activity in the colon. Cytokines production by the lamina propria mononuclear cells (LPMC) and luminal bacteria were also measured. Results: Rifaximin administration (30 or 50 mg/kg/day) increased survival rates of colitic mice and reduced colitis severity as demonstrated by improvement of wasting syndrome, histologic scores, decrease in colon IL-2, IL-12, IFN-γ and TNF-α (protein and mRNA) levels, and diminished colon MPO activity. Rifaximin administration caused a significant reduction of colon bacterial translocation towards mesenteric lymph nodes. LPMC obtained from rifaximin-treated mice released significantly lower amount of IFN-γ in response to ex vivo stimulation with agonistic anti-CD3 and anti-CD28 antibodies. Rifaximin (50 mg/kg/day) significantly accelerates recovery in mice with established colitis. Conclusions: Luminal bacterial microflora plays a role in the pathogenesis of TNBS-induced colitis in mice. Rifaximin administration reduces the development of colitis and accelerates healing of established disease by preventing bacterial translocation.

Relative contribution of acetylated cyclo-oxygenase (COX)-2 and 5-lipooxygenase (LOX) in regulating gastric mucosal integrity and adaptation to aspirin.

In addition to inhibiting formation of prothrombotic eicosanoids, aspirin causes the acetylation of cyclooxygenase (COX)‐2. The acetylated COX‐2 remains active, and upon cell activation, initiates the generation of 15R‐HETE, a lipid substrate for 5‐lipoxygenase (LOX) leading to the formation of 15‐epi‐LXA4 (also termed “aspirin‐triggered lipoxin,” or ATL). Because ATL potently inhibits polymorphonuclear cell (PMN) function, we assessed the relative contribution of this lipid mediator in conjunction with another 5‐LOX product, the leukotriene (LT)B4, to the pathogenesis of acute damage and gastric adaptation to aspirin. Data presented herein indicate that acute injury and gastric adaptation to aspirin is associated with ATL generation. Administration of COX inhibitors (celecoxib, indomethacin, ketoprofen) to aspirin‐treated rats exacerbated acute injury and abolished adaptation to aspirin. Moreover, it inhibited ATL formation and caused a four‐ to fivefold increase in LTB4 synthesis. In contrast, licofelone, a COX/5‐LOX inhibitor, did not exacerbate acute gastric injury nor did it interfere with gastric adaptation to aspirin. Although licofelone blocked ATL and LTB4 formation in aspirin‐treated rats, it attenuated aspirin‐induced gastric PMN margination. These findings indicate that the balance between the production of LTB4 and ATL modulates PMN recruitment/function and gastric mucosal responses to aspirin.

Evaluation of the effects of human leukocyte IFN-α on the immune response to the HBV vaccine in healthy unvaccinated individuals

HBV vaccine needs 3 injections over 6 months to induce immunity. Thus, the use of adjuvants capable of inducing earlier immune protection would be highly desirable. Most adjuvants may act by inducing cytokines, and among them, type I interferons (IFNs), deserve a special attention in view of the potent immunomostimulatory activity observed in mouse models and on dendritic cell functions. The aim of the present trial was to evaluate the effects of IFN-alpha administered as an adjuvant of HBV vaccine in healthy unvaccinated individuals. No significant enhancing effect on the antibody response was observed, in spite of an early and transient upregulation of costimulatory molecule expression on peripheral blood mononuclear cells, which may be suggestive of an IFN-mediated activation of antigen presenting cells. We conclude that, under the conditions used in this trial, natural IFN-alpha does not act as an adjuvant of the HBV vaccine in healthy unvaccinated individuals.

Pharmacology of Desmin (low molecular weight Dermatan sulphate) in healthy volunteers following intravenous bolus administration of different dosages (200, 400, 800 mg)

Eight healthy volunteers (6 males, 2 females, mean age 31.6 yrs), were administered--on three separate days--200, 400 and 800 mg of a new low molecular weight Dermatan sulphate (Desmin), given as a single i.v. bolus (2 min.) injection. Before each administration and 10, 20, 30 min., 1, 2, 4, 8, 12, 24 hours after, blood samples were drawn and the following coagulative assays performed: aPTT (activated Partial Thromboplastin Time), TT (Thrombin Time), anti Xa (Xa Factor inhibition), Heptest, Stachrom D.S.. Furthermore, a kinetic analysis was performed on the activity curves calculated on the Heptest and Stachrom data. Plasma peak values and half lives of the parameters checked showed a clear dose-effect relationship. aPTT and TT showed very short-lasting variations and the inhibition of Factor Xa was moderate, but significant. The most evident and specific effects of Desmin were those on Heptest and Stachrom D.S.: both tests were influenced in a clear-cut and dose-dependent way, mainly as a consequence of the action of Desmin on HCII, with partially different kinetic patterns. A series of in vitro experiments proved an anti Xa effect of Desmin, mediated by antithrombin III, well above the possible interference of the small (< 1%) heparin contaminants in Desmin. An even more marked anti Xa activity was seen in the in vivo study, an observation so far unrecognized for this type of drug: some possible interpretations of this fact are discussed.

THE TREATMENT OF DEEP VEIN THROMBOSIS WITH CONTINUOUS INTRAVENOUS LOW-MOLECULAR-WEIGHT DERMATAN SULPHATE (DESMIN). A PILOT STUDY

Eight patients with femoro-popliteal or sural DVT, confirmed by phlebography, were treated with intravenous Desmin (LMW-dermatan sulphate): on the first day, after an initial i.v. injection of 400 mg, all patients received an infusion of 800 mg in 500 ml of saline, during 24 hours; this infusion was repeated in each of the subsequent 9 days (global treatment period: 10 days). To monitor efficacy of the antithrombotic treatment a phlebography, with calculation of Marder score, was repeated at the end of treatment. Laboratory tests monitoring blood coagulation were carried out: aPTT, TT, PT. Factor Xa inhibition (by chronometric and chromogenic method), Stachrom DS, fibrinogen, prothrombin fragments F1 + 2 and TAT. Seven patients completed the ten-day treatment: 6 patients evidenced good improvement of the phlebographic patterns, 1 remained stationary and 1 patient was withdrawn due to adverse events. During the ten days treatment we did not observe any variation of blood coagulation tests. Desmin tolerability was good and no haemorrhagic episodes were registered. The collected results point to a good antithrombotic activity of the new LMW-dermatan sulphate, that deserves to be further evaluated with controlled investigations on larger number of patients.

Tolerability and Clinical Efficacy of Desmin in the Treatment of Superficial Thrombovaricophlebitis

Fifty-six patients with superficial thrombovaricophlebitis of the lower limbs were enrolled in an open and multicenter (4 centers) trial for a period of thirty days. Patients were randomly allocated to three treatment groups to receive a new low-molecular-weight dermatan sulfate (Desmin) at the dose, respectively, of 100 mg once daily by subcuta neous (SC) route, 100 mg twice a day SC, and 200 mg once daily by intramuscular (IM) route. The general and local tolerability and the clinical efficacy of the drug were evaluated by means of clinical, instrumental, and laboratory parameters. Desmin proved capable of effectively improving the symptoms of patients affected by thrombovari cophlebitis, inducing rapid regression by the tenth day of treatment. The daily dose of 200 mg (either SC or IM) was more effective than the 100 mg dose. The systemic toler ability of the drug, administered for the first time for one month, was extremely good, without significant variations in the relevant laboratory tests. Local tolerance (at the site of injection) of the drug was also good.

Pharmacodynamics of a new low-molecular-weight dermatan sulfate after a single subcutaneous injection in elderly patients with chronic venous disorders: A phase I trial

Abstract Fourteen patients, aged older than 65 years, with chronic venous disorders, underwent a Phase I pharmacodynamic study of the single subcutaneous (SC) administration of a new low-molecular-weight dermatan sulfate. Immediately before and 1, 2, 4, 6, 8, 12, and 24 hours after the SC injection of 100 mg of the drug, the following coagulation and fibrinolysis variables were checked: activated partial thromboplastin time, thrombin time, activated factor X (Xa) inhibition, global anticoagulant activity, as measured by Heptest, selected anti-IIa activity, as measured by Stachrom DS, functional and antigenic plasminogen-activator inhibitor, and functional tissue plasminogen activator. Routine laboratory blood and urine tests to monitor systemic tolerability of the drug were performed. The local tolerability and the occurrence of adverse events were also monitored. Results show anti-Xa and anti-IIa activity, as measured by Heptest and Stachrom DS, increased significantly after administration of the drug, thus suggesting an antithrombotic action. Functional and antigenic PAI concentrations were unchanged. Both systemic and local tolerability of a single SC dose of low-molecular-weight dermatan sulfate were very good.