ABSTRACT
Background: Diffuse sclerosing osteomyelitis (DSO) affecting the mandible is an uncommon condition characterised by recurrent pain and functional disturbances. Traditional treatments involving antibiotics, steroids, and analgesics have generally yielded unsatisfactory results. Numerous articles have proposed the utilisation of bisphosphonate therapy as an alternative approach to achieve sustained symptom relief. This study aims to consolidate the available evidence on the effectiveness of bisphosphonate therapy in managing DSO. Methods: A systematic review protocol was registered with PROSPERO and reported in accordance with the Preferred Reporting for Items for Systematic Reviews and Meta-Analyses. Comprehensive electronic search strategies were devised, and studies were screened based on predefined inclusion and exclusion criteria. Results: Ten articles met the eligibility criteria, encompassing a total of 135 patients diagnosed with DSO who received bisphosphonate treatment. All included studies consistently reported a reduction in pain levels and swelling, along with a decrease in the cumulative use of analgesics. The majority of patients reported long-lasting symptom improvement with bisphosphonate therapy. Notably, four studies documented improvements in maximal mouth opening, with one study reporting a mean increase of 9.6mm. Furthermore, six studies observed improvements in panoramic radiographs and cone beam computed tomography scans, with one publication describing two patients exhibiting near-normal bone architecture. Importantly, all studies reported the absence of long-term complications. Conclusions: Bisphosphonate therapy emerges as a promising treatment modality for DSO, exhibiting efficacy in symptom alleviation and radiological enhancement while conferring lasting benefits. Nevertheless, further prospective studies are warranted to refine treatment protocols and substantiate these findings.
ABSTRACT
12-Bis-THA Cl2 [12,12'-(dodecane-1,12-diyl)-bis-(9-amino-1,2,3,4-tetrahydroacridinium) chloride] is a cationic bolalipid adapted from dequalinium chloride (DQC), a bactericidal anti-infective indicated for bacterial vaginosis (BV). Here, we used a structure-activity-relationship study to show that the factors that determine effective killing of bacterial, fungal, and mycobacterial pathogens differ, to generate new analogues with a broader spectrum of activity, and to identify synergistic relationships, most notably with aminoglycosides against Acinetobacter baumannii and Pseudomonas aeruginosa, where the bactericidal killing rate was substantially increased. Like DQC, 12-bis-THA Cl2 and its analogues accumulate within bacteria and fungi. More hydrophobic analogues with larger headgroups show reduced potential for DNA binding but increased and broader spectrum antibacterial activity. In contrast, analogues with less bulky headgroups and stronger DNA binding affinity were more active against Candida spp. Shortening the interconnecting chain, from the most lipophilic twelve-carbon chain to six, improved the selectivity index against Mycobacterium tuberculosis in vitro, but only the longer chain analogue was therapeutic in a Galleria mellonella infection model, with the shorter chain analogue exacerbating the infection. In vivo therapy of Escherichia coli ATCC 25922 and epidemic methicillin-resistant Staphylococcus aureus 15 (EMRSA-15) infections in Galleria mellonella was also achieved with longer-chain analogues, as was therapy for an A. baumannii 17978 burn wound infection with a synergistic combination of bolaamphiphile and gentamicin. The present study shows how this class of bolalipids may be adapted further to enable a wider range of potential applications. IMPORTANCE While we face an acute threat from antibiotic resistant bacteria and a lack of new classes of antibiotic, there are many effective antimicrobials which have limited application due to concerns regarding their toxicity and which could be more useful if such risks are reduced or eliminated. We modified a bolalipid antiseptic used in throat lozenges to see if it could be made more effective against some of the highest-priority bacteria and less toxic. We found that structural modifications that rendered the lipid more toxic against human cells made it less toxic in infection models and we could effectively treat caterpillars infected with either Mycobacterium tuberculosis, methicillin resistant Staphylococcus aureus, or Acinetobacter baumannii. The study provides a rationale for further adaptation toward diversifying the range of indications in which this class of antimicrobial may be used.
