Ivermectin: a multifaceted drug of Nobel prize-honoured distinction with indicated efficacy against a new global scourge, COVID-19.

In 2015, the Nobel Committee for Physiology or Medicine, in its only award for treatments of infectious diseases since six decades prior, honoured the discovery of ivermectin (IVM), a multifaceted drug deployed against some of the world's most devastating tropical diseases. Since March 2020, when IVM was first used against a new global scourge, COVID-19, more than 20 randomized clinical trials (RCTs) have tracked such inpatient and outpatient treatments. Six of seven meta-analyses of IVM treatment RCTs reporting in 2021 found notable reductions in COVID-19 fatalities, with a mean 31% relative risk of mortality vs. controls. During mass IVM treatments in Peru, excess deaths fell by a mean of 74% over 30 days in its ten states with the most extensive treatments. Reductions in deaths correlated with the extent of IVM distributions in all 25 states with p < 0.002. Sharp reductions in morbidity using IVM were also observed in two animal models, of SARS-CoV-2 and a related betacoronavirus. The indicated biological mechanism of IVM, competitive binding with SARS-CoV-2 spike protein, is likely non-epitope specific, possibly yielding full efficacy against emerging viral mutant strains.

Anti-mycobacterial therapy in Crohn's disease heals mucosa with longitudinal scars.

BACKGROUND: A possible causative link between Crohn's disease and Mycobacterium avium ss paratuberculosis has been suggested. AIM: To report unique scarring in Crohn's disease patients treated with anti-Mycobacterium avium ss paratuberculosis therapy. PATIENTS: A retrospective review of 52 patients with severe Crohn's disease was conducted. Thirty-nine patients who had at least one follow-up colonoscopy during treatment were included. METHODS: Patients received rifabutin (up to 600 mg/day), clofazimine (up to 100 mg/day) and clarithromycin (up to 1 g/day) - anti-Mycobacterium avium ss paratuberculosis therapy - for 6 months to 9 years. Ramp-up dosing was used. Colonoscopies and histological analyses monitored progress. RESULTS: Twenty-two patients (56.4%, 22/39) healed with unusual scarring, which appeared as branched, ribbon-like, elevated lines. In 2/6 patients (33.3%) who had > 3 years of treatment after scarring occurred, scars receded, becoming imperceptible as full healing occurred. Histologically, a marked reduction in inflammation occurred in 15/39 patients (38.5%). Of these, 6/15 patients (40%) displayed restoration of normal mucosa. Longitudinal scarring occurred in 12/15 patients (80%) with improved histology. CONCLUSIONS: The presence of scarring fading to normal mucosa on anti-MAP therapy implies a more profound healing not seen with standard anti-inflammatory and immunosuppressant drugs. Longitudinal scarring and consequent healing with normal histology should become a standard treatment goal for Crohn's disease.

Efficacy and safety of rifabutin-containing 'rescue therapy' for resistant Helicobacter pylori infection.

BACKGROUND: Current 'rescue' therapies provide inadequate Helicobacter pylori eradication rates because of antibiotic resistance. AIM: To test the efficacy of a modified triple regimen combining rifabutin, pantoprazole and amoxicillin as rescue therapy for patients in whom eradication of H. pylori had failed standard clarithromycin-based triple therapy. METHODS: One hundred and thirty patients (mean age 51.7 +/- 14.8 years) who had failed one or more eradication attempts with omeprazole, clarithromycin and amoxicillin were treated for 12 days with rifabutin 150 mg daily, amoxicillin 1 g or 1.5 g t.d.s, and pantoprazole 80 mg t.d.s. RESULTS: The intention-to-treat and per-protocol eradication rates were 90.8/90.8%. Metronidazole or/and clarithromycin resistance had no significant impact on H. pylori eradication rates. A higher overall eradication rate of 96.6% (95% CI: 92.1-101%) was obtained in patients treated with a regimen containing 1.5 g amoxicillin t.d.s compared with 90.7% (95% CI: 82-98.6%) using a regimen with 1 g amoxicillin t.d.s but the difference was not significant. Side-effects reported in 40% of patients were mild. CONCLUSION: A 12-day course of low dose of rifabutin with an increased dose of amoxicillin and pantoprazole is well-tolerated and highly effective against dual-resistant H. pylori infection after failure of triple therapy.

Laparoscopic excision of a Brunner's gland hamartoma of the duodenum.

Brunner's gland hamartoma (adenoma) was first described in 1876. It is a rare hamartomatous lesion, with only 100 cases reported in the world literature. Treatment has been by endoscopic snaring. Open surgical excision was reserved for cases where snaring had failed. We report a case of a Brunner's gland hamartoma (2.4 cm) that was successfully resected by laparoscopic techniques. Postoperative hospital stay was brief (2 days), and there were no complications. This is the second reported case to be resected laparoscopically.

Treatment of severe Crohn's disease using antimycobacterial triple therapy--approaching a cure?

BACKGROUND: Mycobacterium avium subspecies paratuberculosis is probably the best candidate for a microbial cause of Crohn's disease although arguments to the contrary can be equally convincing. Growing evidence suggests that prolonged antimycobacterial combination therapy can improve Crohn's disease in some patients. AIM: To report long-term observations in patients with severe Crohn's disease treated with triple macrolide-based antimycobacterial therapy. PATIENTS: A series of 12 patients (7 male, 5 female; aged 15-42 years) with severe, obstructive or penetrating Crohn's disease were recruited. METHODS: Patients failing maximal therapy were commenced prospectively on a combination of rifabutin (450 mg/d), clarithromycin (750 mg/d) and clofazimine (2 mg/kg/d). Progress was monitored through colonoscopy, histology, clinical response and Harvey-Bradshaw activity index. RESULTS: Follow-up data were available for up to 54 months of therapy Six out of 12 patients experienced a full response to the antiMycobacterium avium subspecies paratuberculosis combination achieving complete clinical, colonoscopic and histologic remission of Crohn's disease. Four of these patients were able to cease treatment after 24-46 months, 3 of whom remained in total remission without treatment for up to 26 months and one patient relapsed after six months off treatment. A partial response to the anti-Mycobacterium avium subspecies paratuberculosis combination was seen in 2 patients showing complete clinical remission with mild histologic inflammation. Return to normal of terminal ileal strictures occurred in 5 patients. Harvey-Bradshaw activity index in patients showing a full or partial response to therapy fell from an initial 13.4 +/- 1. 91 to 0. 5 +/- 0. 47 [n = 8, p < 0. 001) after 52-54 months. CONCLUSIONS: Reversal of severe Crohn's disease has been achieved in 6/12 patients using prolonged combination anti-Mycobacterium avium subspecies paratuberculosis therapy alone. Three patients remain in long-term remission with no detectable Crohn's disease off all therapy These results support a causal role for Mycobacterium avium subspecies paratuberculosis in Crohn's disease while also suggesting that a cure may become possible.

Eradication therapies for Helicobacter pylori.

Eradication therapies for Helicobacter pylori evolved from monotherapy, through dual therapies and finally to bismuth-based triple therapies by the mid-1980s. The advent of proton pump inhibitors (PPI) and clarithromycin added a new impetus in the development of newer and often more effective regimens. Following large numbers of therapeutic trials, two broad groups of therapies stand out which consistently achieve over 90% eradication. Both are PPI-based. PPI/amoxycillin/clarithromycin twice daily therapy is the simplest but perhaps the most expensive. The 7-day quadruple (quad) therapy, consisting of a PPI and bismuth/tetracycline/metronidazole, is rapidly emerging as the "all rounder" therapy able not only to overcome metronidazole and clarithromycin resistance but to also have a consistently high eradication rate of well over 90%. Extensive clinical use of older and cut-down versions of combination therapies is resulting in a rising population of treated patients who continue to be infected with H. pylori, often resistant to further eradication attempts. Failure to recognise the need to use regimens which achieve high first-time eradication success will lead inexorably to an enlarging pool of patients with resistant strains and "difficult-to-eradicate" H. pylori.

Evaluation of whole blood antibody kit to detect active Helicobacter pylori infection.

OBJECTIVES: To evaluate the sensitivity and specificity of a whole blood antibody test (Helisal Rapid Blood test) for the detection of Helicobacter pylori using endoscopic diagnostic criteria of histology and urease tests as the "gold standard." METHODS: A prospective trial of Helisal Rapid Blood (HRB) test was carried out in patients undergoing investigations for dyspepsia that included endoscopic biopsy for rapid urease test, microbiological culture, and histology. Blood samples were obtained at the time of endoscopy and were tested for the presence of antibody to H. pylori using the HRB test. In a separate patient group, results of antibody tests in whole venous and capillary blood were compared (n = 25). RESULTS: The rapid blood test was carried out immediately after the endoscopic examination with a result available in under 10 min in all cases. In 203 patients examined, the HRB test detected 70 of 203 to be H. pylori positive as compared with 71 of 203 using urease/histology. Against combined urease/histology tests, the HRB test achieved 82% sensitivity and 91% specificity. Five patients were judged to be "false negative" on endoscopic tests for H. pylori (extensive intestinal metaplasia n = 3; recent use of antimicrobials) yet the HRB test diagnosed the presence of infection, which could be shown to resolve on treatment. The HRB achieved 89% sensitivity and 91% specificity upon correctly including these five patients in the calculations. In all 25 patients tested, venous and capillary blood results concurred giving HRB test positivity in each case. CONCLUSIONS: Whether using whole venous or capillary blood, the HRB test is a quick, convenient, and accurate test for the diagnosis of active H. pylori infection in patients previously not treated. In a subgroup of patients with low level infection due to recent antimicrobials or intestinal metaplasia negative to all endoscopic tests, the blood test can still correctly diagnose H. pylori infection. Because blood samples require no centrifugation before testing, the greatest usefulness of this test will be that of a primary office diagnostic device.

Proposal for use of a standard side effect scoring system in studies exploring Helicobacter pylori treatment regimens.

Many antibiotic regimens for treating Helicobacter pylori infection are currently used in clinical trials. The reported side-effect profiles of similar anti-Helicobacter therapies vary widely due to the use of different scoring systems. Therefore side-effect data from separate studies cannot be compared. Only randomized controlled trials will show how side-effect profiles and tolerability really differ between regimens, but few such studies are available. Therefore a choice of treatment based on side-effect profile is not possible at present. We seek standardization of side-effect registration among investigators and propose a side-effect questionnaire which, if generally accepted, would make it possible to compare data between trials.

Omeprazole enhances efficacy of triple therapy in eradicating Helicobacter pylori.

Triple therapy has been recommended as the most effective treatment for Helicobacter pylori eradication. Despite achieving a comparatively high eradication result, however, around 10% of patients still fail to be cured. Omeprazole can enhance efficacy of single and double antibiotic protocols and is particularly effective when combined with clarithromycin and a nitroimidazole. This study examined the effect of combining triple therapy with omeprazole. A prospective, randomised, unblinded, single centre trial was carried out on consecutive patients with symptoms of dyspepsia and H pylori infection confirmed by rapid urease test, microbiological culture, and histological assessment. Patients were given a five times/day, 12 day course of colloidal bismuth subcitrate chewable tablets (108 mg), tetracycline HCl (250 mg), and metronidazole (200 mg) with either 20 mg omeprazole twice daily (triple therapy+omeprazole) or 40 mg famotidine (triple therapy+famotidine) at night. Compliance and side effects were determined using a standard questionnaire form. One hundred and twenty five of 165 triple therapy+omeprazole patients and 124 of 171 triple therapy+famotidine patients returned for rebiopsy four weeks after completion of treatment. Significantly more triple therapy+omeprazole patients achieved eradication 122 of 125 (97.6%) as assessed by negative urease test, culture, and histological assessment, when compared with 110 of 124 (89%) triple therapy+famotidine patients (p = 0.006; chi 2). There were 30 triple therapy+omeprazole (24%) and 26 triple therapy+famotidine (21%) patients with de novo metronidazole resistant H pylori included in the study. Side effects were mild and infrequent and were comparable in both groups, although pain in duodenal ulcer, gastric ulcer, and oesophagitis patients seemed to subside earlier in those taking omeprazole. Compliance (>95% of drugs taken) was achieved by 98% of patients of both groups. A 12 days regimen of triple therapy with omeprazole is more effective in achieving H pylori eradication than is triple therapy plus famotidine. Use of 20 mg omeprazole twice daily rather than 40 mg famotidine with a 12 day, low dose triple therapy enhances eradication to over 97% whether the H pylori is metronidazole sensitive or resistant.

Helicobacter pylori reinfection rate, in patients with cured duodenal ulcer.

OBJECTIVE: To determine the reinfection rate of the gastric mucosa in patients previously cured of duodenal ulcers, following the eradication of Helicobacter pylori. Only those remaining H. pylori-negative beyond 12 months of follow-up were studied, to minimize the potential inclusion of patients with H. pylori recrudescence. METHODS: Patients with endoscopically proven duodenal ulcers who had been treated with triple therapy, resulting in documented eradication of H. pylori and cure of the ulcer for at least 4 years, were recalled and had their H. pylori status determined by the 14C-urea breath test. Those found positive for H. pylori underwent endoscopic confirmation of the infection. RESULTS: Of the 94 patients restudied, with a follow-up period range of 48-96 months or a total of 549.8 yr, only two (2.2%) were again H. pylori positive. This gives an effective reinfection rate of 0.36% per patient year. In the two H. pylori-positive patients, one had normal mucosa endoscopically, whereas duodenitis without active ulceration was present in the other. The former was asymptomatic, whereas the latter patient was using ranitidine daily for symptom control. CONCLUSION: In the Australian setting, following cure of duodenal ulcer disease by eradication of H. pylori, subsequent reinfection is an unusual phenomenon. We conclude that efforts aimed at eradication of H. pylori in duodenal ulcer are justified and are worthwhile.

Use of high efficacy, lower dose triple therapy to reduce side effects of eradicating Helicobacter pylori.

OBJECTIVES: To evaluate two triple-therapy (TT) regimens of colloidal bismuth subcitrate (CBS), metronidazole, and tetracycline HCl in eradicating Helicobacter pylori, with particular attention to the frequency of resulting adverse effects of the two therapies. METHODS: A prospective, randomized controlled trial was conducted in patients with symptoms of dyspepsia who were positive for H. pylori. Subjects received a 14-day course of either 4 x/day therapy of CBS (108 mg), tetracycline HCl (500 mg), and metronidazole (250 mg), or 5 x/day therapy of CBS (108 mg), tetracycline HCl (250 mg), and metronidazole (200 mg). H. pylori status was determined endoscopically by urease test, histology, and culture. Standard questionnaires were administered to determine compliance to treatment and side effects of therapy. RESULTS: H. pylori was eradicated in 196/213 (92%) patients in the 4 x/day group and 202/210 (96%) in the 5 x/day group (p = 0.07). Side effects were significantly less frequent and less severe in the 5 x/day group (p < 0.01). CONCLUSIONS: We conclude that a lower dose, 5 x/day triple therapy treatment of H. pylori is equally efficacious to the standard 4 x/day therapy, but is accompanied by fewer and milder adverse effects.