Spatio-Temporal Distribution of Mycobacterium tuberculosis Complex Strains in Ghana.

BACKGROUND: There is a perception that genomic differences in the species/lineages of the nine species making the Mycobacterium tuberculosis complex (MTBC) may affect the efficacy of distinct control tools in certain geographical areas. We therefore analyzed the prevalence and spatial distribution of MTBC species and lineages among isolates from pulmonary TB cases over an 8-year period, 2007-2014. METHODOLOGY: Mycobacterial species isolated by culture from consecutively recruited pulmonary tuberculosis patients presenting at selected district/sub-district health facilities were confirmed as MTBC by IS6110 and rpoß PCR and further assigned lineages and sub lineages by spoligotyping and large sequence polymorphism PCR (RDs 4, 9, 12, 702, 711) assays. Patient characteristics, residency, and risks were obtained with a structured questionnaire. We used SaTScan and ArcMap analyses to identify significantly clustered MTBC lineages within selected districts and spatial display, respectively. RESULTS: Among 2,551 isolates, 2,019 (79.1%), 516 (20.2%) and 16 (0.6%) were identified as M. tuberculosis sensu stricto (MTBss), M. africanum (Maf), 15 M. bovis and 1 M. caprae, respectively. The proportions of MTBss and Maf were fairly constant within the study period. Maf spoligotypes were dominated by Spoligotype International Type (SIT) 331 (25.42%), SIT 326 (15.25%) and SIT 181 (14.12%). We found M. bovis to be significantly higher in Northern Ghana (1.9% of 212) than Southern Ghana (0.5% of 2339) (p = 0.020). Using the purely spatial and space-time analysis, seven significant MTBC lineage clusters (p< 0.05) were identified. Notable among the clusters were Ghana and Cameroon sub-lineages found to be associated with north and south, respectively. CONCLUSION: This study demonstrated that overall, 79.1% of TB in Ghana is caused by MTBss and 20% by M. africanum. Unlike some West African Countries, we did not observe a decline of Maf prevalence in Ghana.

A multicenter, double-blind, randomized, placebo-controlled comparison of nocturnal roxatidine in the treatment of active duodenal ulcer disease. Multicenter Roxatidine Cooperative Study Group.

This multicenter randomized, double-blind, 4-wk study compared the new H2-receptor antagonistic roxatidine (R) to placebo (P) for treatment of endoscopically diagnosed active duodenal ulcer disease. Subjects were evaluated after 2 and 4 wk of treatment. Those whose ulcer was unhealed at 2 wk received 2 more weeks of treatment before final evaluation. Ulcer healing (endoscopically determined) with roxatidine was more effective than placebo at both wk 0-2 (R = 33.9%, P = 21.9%, p = 0.018) and wk 2-4 (R = 68.2%, P = 29.7%, p less than 0.001), with an overall 4-wk effectiveness of 78.9% compared to 44.8% (p less than 0.001). At the end of treatment, average maximum ulcer diameter diminished 83% in R and 50% in P (p less than 0.001). Roxatidine was also more effective than placebo in decreasing abdominal pain (p less than 0.001), decreasing the number of antacid tablets taken for pain relief (p less than 0.001), improving dyspeptic symptoms (p less than 0.001), and permitting return to a normal routine for subjects with previous illness-imposed restrictions on work and/or other daily activities. The profile of laboratory values and adverse experiences demonstrated roxatidine to be safe and well-tolerated. The efficacy of roxatidine as evaluated by the healing rate of duodenal ulcer and reduction in abdominal pain emphasize its value as an addition to the family of H2-receptor antagonists.

Prostaglandins, H2-receptor antagonists and peptic ulcer disease.

Peptic ulcer develops when offensive factors overwhelm defensive processes in the gastroduodenal mucosa. Offensive factors include NSAIDs, hydrochloric acid-peptic activity, bile reflux, and some products of the lipoxygenase pathway such as leukotriene B4; whereas defensive processes are largely mediated by prostaglandins through poorly understood mechanisms uniformly termed cytoprotection. Cytoprotection, a physiological process working through the products of arachidonic acid metabolism, may result from the net effect of the protective actions of prostaglandins versus the damaging actions of leukotrienes. Some prostaglandins also have antisecretory effects. Therefore the peptic ulcer healing effects of prostaglandin analogues, all of which have significant antisecretory activity, may be more due to their antisecretory effects than primarily to their effects on mucosal defences. Certain drug-induced gastroduodenal lesions, e.g. NSAID-induced ulcers, which are often unresponsive to H2-receptor antagonists, have been healed and their recurrence prevented by the use of PGE1 and PGE2 analogues. All the prostaglandin analogues investigated to date in humans have the potential for inducing abortion, an important side effect which may limit their worldwide use. The optimal prostaglandin analogue for ulcer healing should not induce abortion and should be potently cytoprotective. The predominant damaging agent in the development of peptic ulcer disease is gastric hydrochloric acid. Thus, the worldwide established efficacy and safety of H2-receptor antagonists such as cimetidine, ranitidine, famotidine and most recently of roxatidine acetate suggest that these agents have become the standard by which other forms of anti-ulcer therapy should be judged.

Treatment of duodenal ulcer with enprostil, a prostaglandin E2 analogue.

Enprostil is a synthetic prostaglandin E2 analogue with gastric anti-secretory, cytoprotective, and gastrin lowering properties. The current multi-center, double-blind, placebo-controlled study was undertaken to evaluate the efficacy and safety of enprostil (35 micrograms twice daily) for the treatment of duodenal ulcers. The study enrolled 87 patients between the ages of 18 and 85 with an endoscopically proved duodenal ulcer between 0.5 and 3.0 cm in its longest dimension and with no other serious medical conditions or abnormal laboratory tests results. Treatment groups were comparable in age, sex, smoking status, ulcer history, and baseline ulcer size. The results indicated that the healing rate for enprostil at two weeks was 38 percent, compared with a placebo rate of 23 percent (p = 0.151). At four weeks, 70 percent of the enprostil-treated patients had healed ulcers, compared with 49 percent of the placebo-treated patients, a statistically significant difference (p = 0.048). Although within the enprostil group the healing rate was higher in nonsmokers (86 percent) than in smokers (58 percent), this difference did not reach statistical significance. Side effects included diarrhea (14 percent) and headache (7 percent). These results indicate that 35 micrograms of enprostil twice daily provides effective and safe therapy for patients with duodenal ulcer.

A multicenter study of ranitidine treatment of duodenal ulcers in the United States.

Treatment of duodenal ulcer with the histamine H2-receptor antagonist, ranitidine, was assessed in a double-blind, randomized, multicenter trial in which patients were treated for two consecutive 4-week periods with ranitidine 150 mg b.i.d. or a placebo. All patients were allowed to take antacids as necessary for symptoms. Three hundred eighty-two patients were entered and 355 completed the first 4-week trial period. Ranitidine significantly improved healing at 2 weeks (37 versus 19%, p less than 0.01) and at 4 weeks (73 versus 45%, p less than 0.01), with better relief of pain and lower use of antacids. In the second 4-week trial period, 124 unhealed patients from the first 4 weeks were re-randomized. Ranitidine treatment resulted in a greater healing rate regardless of previous treatment (p less than 0.05). In this trial, side effects were uncommon and not different between placebo and the tested drug. One case of hepatitis in the ranitidine treated group was presumed on the evidence to be non-A non-B. Ranitidine is effective and appears to be safe in the treatment of duodenal ulcer and its symptoms.

Treatment of benign chronic gastric ulcer with ranitidine. A randomized, double-blind, and placebo-controlled six week trial.

A randomized, multicenter, double-blind, placebo-controlled study was conducted to determine whether ranitidine 150 mg b.i.d. for 6 weeks would expedite endoscopic healing or relief of symptoms in patients with benign gastric ulcer. Of 203 patients enrolled, 101 received ranitidine and 102 received placebo. Endoscopic evaluations were conducted at baseline and at 2 and 6 weeks. At 6 weeks 68% of the patients treated with ranitidine had healed compared with 53% in the placebo group (p = 0.02). In those patients who had not healed by 6 weeks, ranitidine provided greater relief from pain than placebo. More patients in the placebo group dropped out of the study because of worsening symptoms (13 versus 4, p = 0.04). No differences in laboratory abnormalities or incidence of adverse events were detected between the two study groups. These results indicate that ranitidine 150 mg b.i.d. is superior to placebo in the treatment of benign gastric ulcer.

Efficacy of misoprostol (twice daily dosage) in acute healing of duodenal ulcer. A multicenter double-blind controlled trial.

This study was undertaken to evaluate the efficacy of misoprostol taken twice daily for the healing of duodenal ulcer. Three hundred thirty patients with endoscopically proven duodenal ulcer participated in a multicenter, double-blind, controlled trial comparing placebo with misoprostol 200 micrograms and 400 micrograms twice daily for up to four weeks. Patient characteristics were similar in all three treatment groups. Ulcers were between 0.3 cm and 2.0 cm in length. Healing was determined by endoscopy at two weeks; if ulcers were not healed, endoscopy was repeated at four weeks. All patients were given Al(OH)3 antacid (up to 54 meq a day) to be used as needed for pain. Healing rates at four weeks for a total of 280 evaluable patients in the three treatment groups were as follows: misoprostol 400 micrograms bid, 65.4%; misoprostol 200 micrograms bid, 52.9%; and placebo, 42.2%. Misoprostol 400 micrograms bid was superior to placebo (P = 0.002) in healing ulcers. However, the healing rate for misoprostol 200 micrograms bid did not differ significantly from placebo. The percentage of nonsmokers who healed at four weeks was higher than that of smokers in both misoprostol-treatment groups, although the difference was not analyzed for statistical significance. There were no differences in antacid consumption or pain relief among the three experimental groups during the study. Diarrhea was the most common side effect but was mild and self-limiting, occurring in 8.9%, 5.9%, and 1.8% of the misoprostol 400 micrograms, 200 micrograms, and placebo groups, respectively. These results indicate that misoprostol 400 micrograms taken twice daily for four weeks is effective and safe for the treatment of duodenal ulcers.

Prostaglandins and chemotherapy-induced ulcers in dogs.

About 50% of patients receiving intrahepatic infusion of 5-fluorouracil deoxyriboside (5-FUDR) for colorectal cancer with hepatic metastasis develop significant gastroduodenal lesions. This paper reviews two studies on the effect of 16,16 dimethyl prostaglandin E2 (DMPGE2) on 5-fluorouracil-induced mucosal lesions in dogs. DMPGE2 at high doses (2 micrograms X kg-1 X h-1), which reduced histamine-stimulated gastric acid secretion by 65%, reduced gastric mucosal injury. Interestingly, DMPGE2 at much lower doses (0.02 micrograms X kg-1 X h-1), which had no effect on histamine-stimulated gastric acid secretion, was also effective in lowering gastric mucosal injury. These animal studies, if supported by the results of a larger patient study, would provide a rational basis for the use of prostaglandins in the prophylaxis and treatment of chemotherapy-induced ulcers.

16-16 dimethyl prostaglandin E2 reduces 5-fluorouracil-induced and mitomycin C-induced gastric mucosal injury in the dog.

Gastric complications occur in 5% to 20% of patients treated with hepatic artery infusion of chemotherapeutic agents for hepatic metastatic lesions. Often these complications are due to catheter dislodgement from the common hepatic artery into the left gastric artery. These studies were designed to answer the following questions: (1) Will chronic infusion of 5-fluorouracil into the left gastric artery produce mucosal injury in dogs; and (2) if so, will 16-16 dimethyl prostaglandin E2 afford protection against such injury? Mongrel dogs, 20 kg, were prepared with a polyethylene catheter in the left gastric artery and a Thomas cannula in the antrum 5 days prior to the study. Daily intraarterial infusions of either 5-fluorouracil, 6.7 mgM-2 X h-1, (N = 5) or 5-fluorouracil + 16-16 dimethyl prostaglandin E2, 2 micrograms X kg-1 X h-1, (N = 5) were given 12 hours a day for 5 days. In 2 dogs, 0.15 M NaCl was infused for 12 hours a day for 5 days as controls. Daily endoscopic evaluation of the gastric mucosa was made through the Thomas cannula by an unbiased observer and scored 0 to +5 based on degree of erythema, edema, friability, exudate, and gross ulceration. Results of these studies demonstrated that this dose of 5-fluorouracil had no effect on histamine-stimulated acid output. This dose of 16-16 dimethyl prostaglandin E2 inhibited histamine-stimulated maximal acid output 65%. From the observations made it was concluded that infusion of this chemotherapeutic regimen into the left gastric artery produced significant mucosal injury, simultaneous intraarterial infusion of 16-16 dimethyl prostaglandin E2 provided significant protection against this damage, and, since 16-16 dimethyl prostaglandin E2, at this dose, inhibits stimulated gastric acid secretion, it cannot be determined whether this observed mucosal protection is due to its antisecretory effect or some other mechanism.

Prostaglandins, gastroduodenal ulcer and hemorrhagic gastritis.

Today, we have effective and potent drugs such as H2-receptor antagonists for the treatment of peptic ulcers. Cimetidine and ranitidine are antisecretory drugs which heal 67-90% of duodenal ulcers in 4 weeks. Certain prostaglandins (PGs) which also heal gastroduodenal ulcers and hemorrhagic gastritis not only diminish gastric acid secretion but also confer unique protective properties on the gastroduodenal mucosa. This phenomenon of 'cytoprotection' is supported by the experimental finding that PGs prevent gastroduodenal mucosal injury caused by absolute ethanol, HCl, NaOH and other irritating agents. Other PGs which do not reduce gastric acid secretion also heal human gastroduodenal ulcers. These special properties of PGs make them potentially beneficial for the treatment of gastric ulcer, and gastroduodenal ulcers accompanying use of nonsteroidal anti-inflammatory drugs as well as hemorrhagic gastritis which is particularly refractory to other therapeutic modalities.