UroPharma

#WellnessWednesday: Don't miss our Live Webinar: Misconceptions, Mysteries and Mistakes in Cystitis Management, presented by: Prof. Scott Glickman! 📣 Professor Glickman is clinically active with over 40 years’ experience as a surgically trained rehabilitation physician with extensive experience in the NHS and private sectors, mostly in neurorehabilitation (spinal cord injury, multiple sclerosis, traumatic brain injury, stroke etc.) with a specialist interest in neuro-urology. He is also the Chief Executive of UroPharma Ltd. Find out more > https://ow.ly/mZTe50Tk266 #Healthcare #Urology #Cystitis #NeuroUrology #SpinalCordInjury #SCI #MultipleSclerosis #BrainInjury #Stroke #FreeWebinar

Aiming at the right urological targets Last week, Professor of #urology, Chris Chapple had a review published in  Continence, titled “The sensory system is a target for pharmaceutical therapy of #overactive #bladder.” https://lnkd.in/gjBgdShm   In it he states, “Traditionally, it has been assumed that the target for treating the storage symptoms of #OAB is the #detrusor muscle.“ and also “There is now increasing evidence that there is the release of neuroeffector agents, such as acetylcholine, nitric oxide and ATP, from the mucosa (in particular, the #urothelium), especially when put under mechanical stress. The urothelium is therefore able to respond to a wide variety of mechanical stresses during bladder filling and emptying. It has been reported that the magnitude of neurotransmitter release, such as acetylcholine and ATP, is increased and may play an important role in patients with lower #urinary tract dysfunction, such as OAB” and then, “It seems likely that anticholinergic therapy is likely to additionally exert a direct effect on afferent neurotransmission. This is not a surprising conclusion, as the pivotal symptom of OAB is #urgency. This raises the question of whether the widely held view that the main target of all therapy must be the detrusor muscle and its cholinergic innervation is entirely correct.”   His conclusion includes, “The evidence provided here would support the hypothesis that the detrusor muscle is not the primary target for the effective clinical therapy of OAB. An important mode of action for effective therapy is likely to be via modulation of the sensory traffic to the brain, affecting the perceived sensory symptom of urgency and, hence, OAB.”   With classical British understatement, he indicates that, for decades, we’ve been directing pharmacotherapy for urinary urgency (OAB and NLUTS) at the wrong targets (detrusor) when we should have been aiming squarely and directly at urothelial afferents.

Anachronistic #Bladder Treatments  During much of my medical career, my understanding of the human bladder was that it was a reservoir for the body’s metabolic waste and that it simply stores #urine until it signals a sense of fullness to motivate volitional voiding. As filling increases tissue distension, intensity of desire to void increases accordingly. Throughout most of the day, the bladder just passively fills. How reassuringly simple!   I also understood that bladders, and mostly of females, are very vulnerable to infections, but that they are readily treatable by swallowed #antibiotics. For decades I prescribed them to be taken accordingly. How convenient!   Unfortunately, #standard #bladder #treatments, which I used extensively and remain consistent with today’s accepted clinical standards are “what you see is all there is” naïve.   Emergent evidence informs us, that level of understanding is dangerous, accounting, through #urge #incontinence treatment, for an incalculable number of people unnecessarily diagnosed with #dementia and transferred into nursing home care at immense personal and societal costs and through #cystitis treatments, for recurrent and ascending #infections, #urosepsis, treatment failures, #gut #microbiome #damage, overstretched and blocked hospital services and #antimicrobial #resistance that progressively is undermining #healthcare as we know it today, Pray tell, what is the point of seeking new knowledge if it doesn’t encourage us to change our behaviour for the better?

Drugs and dementia Colleagues: While I applaud last week’s publication of the Lancet Commission report on Dementia 2024 that provided updated information on #dementia risk factors and prevention, I am disappointed that drug-induced dementia has not been included. It seems the Commission approached the term exclusively as a primary brain disease rather than also as an avoidable or potentially reversible impairment of cognition.    Drugs that predispose to confusion and #cognitive impairments as side effects are ubiquitous in healthcare, most notably those that interfere with the brain’s #cholinergic receptors, the most common in the organ. People with impaired blood-brain barrier competence due to e.g. age-associated degeneration or neuropathic diseases, most notably the #elderly and people with multiple sclerosis (#MS), respectively, appear especially susceptible to cognitive impairments induced by drugs with anticholinergic effects that enter their circulatory system and travel around their bodies, so get delivered into to their brain parenchyma .   The elderly and in people with #MS commonly are treated with oral anticholinergic drugs for e.g. #urinaryurgency (as overactive bladder syndrome and neurogenic urgency) and depression. Heaven only knows how many such people consequently, have been and will be transferred into institutional care having been diagnosed with dementia that actually was due to urinary urgency and/or depression treatment. Such drug use should be considered in dementia workups.   With that in mind, given the remit of the Commission to look into factors for dementia, I wish to suggest it should include iatrogenic cognitive impairments. Treatment of urinary urgency would be a good place to start. We need to do all we can to reduce the growing burden of dementia, so should consider its iatrogenic causes and raise awareness with prescribers, patients and their significant others because anyone who is aware could pick up on the clues. #continence #overactivebladder #oab #anticholinergics

#Cystitis: Yesterday, Today and Tomorrow  Historically, cystitis generally was a problem for women, who otherwise were well. They suffered in silence, drank water like fish, and, perhaps, also guzzled K+ citrate and/or cranberry juice, for what they thought they were worth. Antibiotics’ arrival brought simple and convenient “pill-popping,” treatment with most getting symptom relief, while the others continued suffering quietly, so cystitis garnered little medico-scientific interest.   Today, cystitis presents very differently. A substantial minority suffer multiple recurrences and/or disease chronicity. Although women are affected more overall, the rise of the elderly and the increased survival of neuro-disabled people (MS, CVA, TBI, SCI, etc.), with their associated bladder and immune system impairments; and the vast increase in catheter use also have been adding immensely to natural and recurrent iatrogenic cystitis (#CAUTI) incidences and their complications. Today cystitis is a scourge in communities and the most common #hospitalacquiredinfection.   Cystitis’s pathogens ascend from the #bladder causing pyelonephritis, or transcend it causing #urosepsis. As an acute co-morbidity, cystitis complicates healthcare and imposes massive resource and bed blockage burdens. Through AMR our standard treatments risk therapeutic impotence, while also undermining future healthcare. Higher cystitis incidences with greater patient risks and reduced treatment capabilities indicates our convenient pill-popping approach, progressively and increasingly intolerably, is failing patients and healthcare more generally.   An analysis of the complications of standard oral antibiotic cystitis treatments, which I presented to the UKHSA on 17th June 2024, revealed our current approach lacks the generally presumed scientific underpinnings and is fundamentally flawed. The agency’s scientists agreed my analysis was sound. We need a radically new cystitis treatment strategy a.s.a.p.   Knowing this and observing the worsening situation without challenging our current treatment approach seems grossly negligent, but does responsibility lie with government agencies or healthcare professionals; and what should be done now? #womenproblem #sufferinsilence #UTI #Urinarytractinfection #antibiotic #infection #resistance #antimicrobialresistance

#Cystitis battles and #AMR: Looking at both sides For most of my >40-years career as a doctor, the conventional wisdom was that #bacterial mutations occurred purely as random events. Nevertheless, AMR could occur, because the Law of Large Numbers indicates a multitude of rare events occur through replication in bacterial populations sufficient to cause infection. The “pure randomness” dogma was challenged in the last decade by people such as #SusanRosenberg in Texas and others whose research suggested bacteria under #antibiotic threat can actively target and accelerate their mutation capabilities. Nevertheless, today, some #microbiologists remain skeptical. Now research published in Front Microbiol. 2024;15:1373344, by Bergum et al https://lnkd.in/eFEknHa6 having studied #Ecoli responses to exposure to DNA-damaging ciprofloxacin, suggests that DNA damage provokes the bacteria into full-throttle damage repair activity, even at the expense of replication, but if that intense activity fails, they will mutate to adapt. Bacteria aren’t bowling pins passively hanging around to be smacked down. But repair and mutation still take time, although sometimes not much. Antibiotics must hit hard and fast to overwhelm the pathogens before they can adjust to the threat with biofilm secretion or AMR mutations. Protracted battles favour the bacteria. The oral route of antibiotic administration for treating cystitis seems far too slow to be reliably effective. The symptom relief produced may be mere palliation in many cases and likely accounts for the AMR that we see progressively more on our MSU test reports, because some bacteria survive the Rx assault.  AMR is rising due to great drugs being used more and more by us for the right reasons, but too inefficiently and, consequently, become ineffective. To my #antibioticsteward colleagues: if the right drug is used in the wrong way. Don’t blame “over-prescribing.” We need better treatments.

Chronic UTI: Doing the right thing My late friend, mentor and former UCL professor of medicine James Malone-Lee advised that a good clinician does the right things very well for patients, but a medical academic is charged to determine, through research, what the right things are to do. We both sought to determine the “right way” to treat bladder infections because he, as a geriatrician, and I, as a neurorehabilitation doctor treating people with CNS diseases such as #MS, saw so many routinely.   James believed standard treatment courses were predominantly effective palliatives and chose to fight battles against bladder #infection chronicity by using #antibiotics until he was highly confident the infecting pathogens were annihilated to effect cure, which typically took several months. In doing so, he also battled against conventional thinking but had many immensely grateful patients. However, oral antibiotics progressively are becoming less effective, interfere with the gut microbiome and risk AMR.   I chose to consider delivering the antimicrobial armaments to the battlefield directly rather than sending them through the system only to leave it to act in the urinary cavity. The superiority of direct drug targeting is a fundamental tenet of therapeutics. Principles matter. What you see is not all there is.   Direct targeting is used routinely for bladder cancer treatments. #Urologists today use #intravesical aminoglycosides to treat people with chronic and recurrent UTI but do so off-label, using risky Heath-Robinson approaches for which personal responsibility must be taken for any complications. Clinicians need support to do the right things very well. I hope that when UroPharma’s direct-to-bladder drug-delivery technology is approved, we clinicians, finally, will be able to do the right things very well for cystitis patients with the regulators’ blessings.

A meeting with the UK health Security Agency on #antimicrobial resistance (AMR) development from #cystitis treatments   Colleagues   Some good news: I had a meeting with the #UKHSA this week to present my root cause analysis on #AMR. I was met by insightful experts in microbiology and infectious diseases, who agreed entirely with the analysis, and understand that AMR is a risk with every single #cystitis treatment using oral antibiotics notwithstanding best antimicrobial stewardship. This is a critical prerequisite for engineering and promoting clinical management changes rather than allowing the status quo of pushing #antibiotic pills for cystitis that could drive us further into the depths of despair about AMR. They recognize that cystitis is a unique clinical entity and that change is essential. I believe the associated essential issue is whether the 3 agencies, notably the MHRA, NICE and #UKHSA can sensibly collaborate to engineer the necessary changes and enable scale up within the NHS. Crisis management should focus their minds about collaboration. As the UK has elected to take a lead globally on AMR, I would like to believe the next government will push that agenda hard. Time is pressing.   I also learned of the initiatives being undertaken by the Agency and firmly recommend to you looking up the its website to see all the various projects and publications on the subject such as the ESPAUR Report, the 2024-2029 National Action Plan on tackling #AMR and the AMRiC (AMR in the Community) study.   All of us must cooperate to bring about the necessary changes, but after my meeting with the UKHSA, I feel we should be able to bring them about. Wishing us all good fortune with our efforts.

Colleagues, I am pleased to inform you that UroPharma has successfully completed another major step on the road to bringing our innovative #bladder drug-device #deliverysystem to market. From the perspective of #regulatory approval, we are now in the final stretch with, only one more hurdle to jump before we submit our intermittent drug-delivery device for the UKCA mark in order to launch in the UK market.   With the UKCA mark, the dtb-instilla will allow clinicians to provide intravesical (direct-to-bladder) drug delivery treatments to patients through a licensed device, providing better treatments whilst avoiding the major problems associated with the oral delivery of #antibiotics and other drugs for #bladdermanagement.   Human factors (HF) studies of the dtb-instilla intermittent device, both formative and summative, now have been completed in the UK. The latter one also validated that our instructions for use (IFU) document is suitable for incorporation with the product. Positive results on both of these aspects are compliance requirements for the device to enter the market. The conclusion from the latest study was that: “When considered as a whole, the test outcomes provide evidence that the dtb-instilla intermittent device can be safely and effectively used for intravesical administration of medication for bladder management”.   Our current intention is to launch the dtb-instilla onto the UK market in the first quarter of 2025 with only #biocompatibility studies ahead of us before we can submit for the UCKA mark we continue to seek #investment, so if you would like further information, especially given that we now have these positive results from the human factors studies, then please contact me.    The sooner we can get to market the sooner we can start helping patients who are suffering from the often life changing effects of bladder conditions and diseases and the sooner we can contribute to the overall campaign against #antimicrobialresistance that threatens the future of our #healthcare.

I have #invented and, through R&D teamwork, produced #practicalsolutions to enable #directtarget drug delivery of therapeutics that avoid some of the flaws of oral #cystitistreatments, including gut microbiome exposure to them, and hope to bring safer and better antibiotic-based therapeutics and non-antibiotic alternatives with known antimicrobial mechanisms to patients, hoping to contribute significantly to the global fight at both levels. With like-minded people, we set up #UroPharma. I suggest other similarly concerned people might wish to follow its progress. https://lnkd.in/ekBdtWWn