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.

Phagocyte-specific S100 proteins are released from affected mucosa and promote immune responses during inflammatory bowel disease.

Phagocyte-derived S100 proteins are endogenous activators of innate immune responses. S100A12 binds to the receptor for advanced glycation end-products, while complexes of S100A8/S100A9 (myeloid-related proteins, MRP8/14; calprotectin) are ligands of toll-like receptor 4. These S100 proteins can be detected in stool. In the present study we analyse the release of S100A12 and MRP8/14 from intestinal tissue. Specimens from patients with Crohn's disease (CD; n = 30), ulcerative colitis (UC; n = 30), irritable bowel syndrome (IBS; n = 30) or without inflammation (n = 30) were obtained during endoscopy. After 24 h culture, S100A12 and MRP8/14 were analysed in supernatants. Endoscopic, histological, laboratory and clinical disease activity measures were documented. We found an increased spontaneous release of S100A12 from tissue in inflammatory bowel disease (IBD). The release of S100A12 into the supernatants was 28-fold enhanced in inflamed tissue when compared to non-inflamed tissue (mean 46.9 vs. 1.7 ng/ml, p < 0.0001). In active CD, release of S100A12 and MRP8/14 was strongly dependent on localization, with little release from sites of active ileal inflammation compared to colonic inflammation. This difference was more pronounced for S100A12 than for MRP8/14. S100A12 and MRP8/14 provoked up-regulation of adhesion molecules and chemokines on human intestinal microvascular endothelial cells (HIMECs) isolated from normal colonic tissue. The direct release of phagocyte-derived S100 proteins from inflamed tissues may reflect secretion from infiltrating neutrophils (S100A12) and also monocytes or epithelial cells (MRP8/14). Via activation of pattern recognition receptors, these proteins promote inflammation in intestinal tissue. The enhanced mucosal release can explain the correlation of fecal markers with disease activity in IBD.

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.

Evaluation of anti-Helicobacter pylori IgG2 antibody for the diagnosis of Helicobacter pylori infection in western and Chinese populations.

BACKGROUND: The performance of commercial Helicobacter pylori diagnostic kits developed for particular geographic regions has often been found to be of poor diagnostic value when applied to other regions, possibly because of infections being caused by different H. pylori strains in different regions. AIM: To evaluate the performance of an IgG2 anti-H. pylori enzyme-linked immunoassay test (Helirad Alert) for detection of H. pylori infection in both Australian and Hong Kong (Chinese) subjects. METHODS: Serum samples were tested for H. pylori specific IgG2 and IgG antibodies by enzyme-linked immunoassay kits using identical antigen preparation in 168 Australian and 160 Hong Kong (Chinese) subjects diagnosed with dyspepsia. RESULTS: Using a cut-off value determined by analysis of H. pylori-negative Australian samples, the sensitivity, specificity and accuracy of the IgG2 assay were 77.8, 97.4 and 91.1%, respectively, for the Australian samples and 96.3, 83.8 and 90% for Hong Kong samples. For the IgG assay, sensitivity, specificity and accuracy were 87.0, 99.1 and 95.2% for Australian samples and 97.5, 75 and 86.3% for Hong Kong samples respectively. Receiver-operating characteristic analysis showed better discrimination of H. pylori status when the IgG2 assay was applied to Hong Kong samples, while the IgG assay was better in the Australian samples. CONCLUSION: These data demonstrate that the Helirad Alert enzyme-linked immunoassay could provide a reliable method for screening H. pylori infection in both western and Chinese populations.

Efficacy and safety of single-triple capsules of bismuth biskalcitrate, metronidazole and tetracycline, given with omeprazole, for the eradication of Helicobacter pylori: an international multicentre study.

BACKGROUND: The high prevalence of Helicobacter pylori resistance to metronidazole demands treatments more effective than standard bismuth-based triple therapy against these strains. AIM: To evaluate the H. pylori eradication rate in both metronidazole-sensitive and -resistant strains following quadruple therapy using single-triple capsules of bismuth biskalcitrate, metronidazole and tetracycline, given with omeprazole. METHODS: One hundred and seventy valid patients with duodenal ulcer, gastric ulcer or non-ulcer dyspepsia were treated in eight centres located in five countries. H. pylori was confirmed at baseline using 13C-urea breath test, histology and/or culture. Patients received three single-triple capsules q.i.d. and omeprazole, 20 mg b.d., for 10 days. Each capsule contained bismuth biskalcitrate, 140 mg (as 40 mg Bi2O3 equivalent), metronidazole, 125 mg, and tetracycline, 125 mg. 13C-Urea breath test was repeated at least 4 and 8 weeks post-treatment. RESULTS: Overall eradication rates were 93% (158/170) by modified intention-to-treat analysis and 97% (142/146) by per protocol analysis. Eradication rates were 93% (40/43) and 95% (38/40) for strains resistant to metronidazole and 95% (82/86) and 99% (75/76) for strains sensitive to metronidazole by modified intention-to-treat and per protocol analysis, respectively. CONCLUSION: This omeprazole-bismuth biskalcitrate-metronidazole-tetracycline 10-day regimen is a very effective and well-tolerated treatment, which overcomes metronidazole resistance.

Nizatidine in combination with amoxycillin and clarithromycin in the treatment of Helicobacter pylori infection.

BACKGROUND: The efficacy of H2-antagonists in combination with antibiotics in curing Helicobacter pylori infection remains controversial, and it is uncertain whether double dose H2-antagonist therapy is superior to standard dose. AIM: To determine the efficacy of two doses of nizatidine in combination with two antibiotics in the treatment of H. pylori. METHODS: A randomized controlled trial was conducted in 160 patients comparing nizatidine 150 mg with 300 mg b.d. (standard vs. double dose), in combination with clarithromycin (500 mg) and amoxycillin (1000 mg) b.d. for 14 days, in Australia and Taiwan. Compliance was based on a clinical assessment and pill count. H. pylori status was determined by histology (antrum and corpus) and CLO-test. RESULTS: Baseline clinical and endoscopic findings were similar in both arms of the study. Based on an intention-to-treat analysis, cure of H. pylori was achieved in 78% (95% CI: 70.4-85.4%) in the standard nizatidine dose arm and 70% (95% CI: 61.6-78.2%) in the double dose arm (P=0.2). Similar cure rates were observed in ulcer and non-ulcer patient groups. Compliance was excellent in the single and double dose arms (85 and 91%, respectively). CONCLUSIONS: The combination of nizatidine in standard or double dose with clarithromycin and amoxycillin is similarly efficacious in curing H. pylori infection.

Cholecystokinin and gallbladder contraction: effect of CCK infusion.

Cholecystokinin octapeptide (CCK-8) was infused intravenously in five normal subjects. Plasma levels of CCK-8 and infusion concentrations were measured by a specific radioimmunoassay and gallbladder volumes wee monitored using ultrasound. Calculated CCK-8 infusion rates were 16.4, 32.8, and 65.6 pmol.kg(-1) hr(-1). During infusion of the lowest dose plasma concentrations rose from 8 +/- S.E. 5 to 18 +/- 4 pmol.1(-1) equivalent to normal postprandial concentrations of CCK and were accompanied by a 76 +/- 7% reduction in gallbladder volume. Infusion at the two higher rates resulted in 87 +/- 3% and 88 +/- 3% reduction of initial gallbladder volumes returned to 73 +/- 26% of initial volumes within 30 minutes. These studies are consistent with the hypothesis that CCK is the main postprandial stimulus for gall-bladder contraction.

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.

Radioimmunoassay of cholecystokinin in human plasma.

A sensitive radioimmunoassay for cholecystokinin (CCK) has been developed. Porcine CCK-33 was labelled by conjugation with 125I-hydroxyphenyl-propionic acid succinimide ester. Antibodies were raised against porcine CCK-33 covalently coupled to egg albumin. Plasma samples were extracted with 96% ethanol prior to assay. Free and bound hormone were separated by dextran-coated charcoal. The antibodies bound CCK-8 and CCK-33 with equimolar potency. The assay detection limit was 1 pmol/l plasma. Within and between assay coefficients of variation were +/- 12.7 and 13.0% at mean plasma CCK concentrations of 13.2 and 13.6 pmol/l. The concentration of CCK in 47 normal fasting subjects ranged from undetectable to 22 pmol/l. Ingestion of a mixed meal in 9 normal subjects increased the plasma concentration from 8.3 +/- 2.5 S.E. to 24.4 +/- 6.5 pmol/l.

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.

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.

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.

Myasthenia gravis in Melanesians in the Solomon islands.

Myasthenia gravis is a rare neuromuscular disease believed to be due to an autoimmune reaction affecting the neuromuscular junction. Two cases occurring in Melanesians of the Solomon Islands are described. Standard treatment includes anticholinesterase medication, and corticosteroids may be required for severe disease. Thymectomy, and plasmapharesis together with immunosuppressive therapy are other measures that may be considered in severe, refractory or generalised disease. Treatment is unlikely to be satisfactory in this Melanesian society where patients are irregular in taking medication and in attending hospital.

The use of serology to diagnose active Campylobacter pylori infection.

A serological test that predicts accurately active Campylobacter pylori infection in the human stomach has been developed and validated by means of serum from 189 patients who were undergoing endoscopy in Sydney. Our enzyme-linked immunosorbent assay (ELISA) has a sensitivity of 100% and a specificity of 94%. An important part of the test is the inclusion of a simple absorption step with C. jejuni for those sera whose results are close to the cut-off point for positivity. This has been shown to be particularly relevant in epidemiological studies on populations that are likely to be exposed to C. jejuni continually. For example, by means of the ELISA test without an absorption step, the infection rate in Papua New Guineans was shown to be 56%, whereas use of the validated test showed the infection rate to be 25%. Compared with an age-matched normal control group of Australians, this still is higher. These studies suggest a need for the reappraisal of some of the reported epidemiological data. The development of a validated diagnostic test that is a highly-accurate predictor of active C. pylori infection will be useful for epidemiological studies, particularly for comparative studies among populations that are known to differ significantly in the incidence of stomach disease. However, routine use of this test in diagnosis in general practice awaits the definition of more precise markers of C. pylori-associated symptomatology and the development of improved regimens for the treatment of C. pylori infections.

In vitro dissolution of cholesterol gallstones. A study of factors influencing rate and a comparison of solvents.

Models of the common bile duct and gallbladder were constructed to study conditions that affect the rate of cholesterol gallstone dissolution by monooctanoin and other potential solvents. In the bile duct model, the rate of monooctanoin infusion was not an important factor in accelerating dissolution time. In contrast, the exclusion of bile from interfering with solvent-stone contact or the enhancement of solvent-stone contact by stirring significantly accelerated stone dissolution. The combination of both bile exclusion and stirring increased the dissolution rate of gallstones by monooctanoin 15-fold. When compared with two other ethers and with monooctanoin, methyl tert-butyl ether was found to be the most potent gallstone solvent. Methyl tert-butyl ether completely dissolved 219-mg cholesterol stones within 60 min. In the gallbladder model, in the absence of stirring both methyl tert-butyl ether and monooctanoin floated on bile, whereas the gallstones sank resulting in minimal stone-solvent contact. To increase the stone-solvent contact, we used a pump to create sufficient turbulence to mix the solvent with bile. Pump stirring of monooctanoin in the presence of bile achieved rates of stone dissolution approaching that of stirred monooctanoin without bile. Stirring of methyl tert-butyl ether and bile, however, did not achieve sufficient solvent-stone contact to appreciably accelerate dissolution in the presence of 50% bile. Stone-solvent contact was a critical factor in determining the rate of gallstone dissolution in both gallbladder and common bile duct models. Efforts to enhance contact include bile exclusion and intraluminal stirring--both of which are clinically applicable. Methyl tert-butyl ether is a potent new cholesterol gallstone solvent with excellent potential for use in humans. Even with this potent agent, however, rapid gallstone dissolution is likely to require removal of most of the bile from the dissolution medium.

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.