“Opening”. Imagine waking up exhausted, struggling to breathe at night, and disrupting your partner’s sleep. For millions with Obstructive Sleep Apnea (OSA), this is reality. AD109, a once-daily oral therapy that combines the selective norepinephrine reuptake inhibitor atomoxetine with the antimuscarinic agent aroxybutynin, is being developed by Apnimed and has now delivered compelling Phase III results (also see recent commentary). With many patients struggling to tolerate CPAP masks, an effective oral pill could offer a welcome and transformational alternative.

How AD109 Compares to Emerging OSA Treatments:

● Zepbound (tirzepatide): Approved for OSA in obese patients, effective with CPAP but reliant on weight loss, limiting its use for non-obese individuals.

● Sunosi (solriamfetol): Targets daytime sleepiness in OSA but doesn’t address airway obstruction.

● Orexin Antagonists (e.g., lemborexant): In early development for insomnia, with unproven efficacy in OSA

Unlike these, AD109 directly targets the neuromuscular cause of OSA, offering a non-invasive, weight-independent solution.

Closing Thought. As a potential first-in-class therapy, AD109 could redefine OSA care with a convenient oral solution. If approved, it may offer a broadly accessible alternative to CPAP or weight-dependent drugs.

🧪 Exploring how natural product chemistry can trigger unexpected occupational skin reactions

As someone passionate about natural products and workplace safety, I’ve always been mindful of autoxidation—and I recently discovered it’s responsible for turpentine dermatitis. This skin reaction results from exposure to turpentine, a solvent derived from pine resin commonly used in paints, varnishes, and cleaning products.

❓ What is Turpentine Dermatitis?

This condition typically presents as irritant contact dermatitis (redness, itching, scaling) or, in some cases, allergic contact dermatitis (blistering, swelling), following direct contact with turpentine or its vapours. While it’s less common today due to safer alternatives, it remains a risk for painters, artists, and industrial workers. Prevention involves protective gear, proper ventilation, and immediate washing of skin after exposure.

🔬 What is Autoxidation and The Role of Monoterpene Hydroperoxides?

A key culprit in allergic reactions is monoterpene hydroperoxides (ref. 1), formed when components of turpentine (such as Δ-3-carene, Figure 1) oxidise upon exposure to air or light—a process known as autoxidation (ref. 2). In natural products research, we often isolate the corresponding reduced alcohols. These hydroperoxides are potent skin sensitisers, triggering immune responses that cause severe itching and inflammation. They may also act as irritants, worsening skin damage. To minimise oxidation, turpentine should always be stored in airtight, dark containers.

💡 Why It Matters…

● Although turpentine use has declined, monoterpene hydroperoxides remain relevant in essential oils and pine-derived products, posing ongoing risks for sensitisation.

● Whenever natural products with allylic alcohols or peroxides are isolated, consider the possibility that they are autoxidation products. Also be mindful of autoxidation during storage—store potential candidates under argon and in the dark where possible.

References

1. One hundred years of allergic contact dermatitis due to oxidized terpenes📘Contact Dermatitis, 2021, 85: 627–636 🔗 https://doi.org/10.1111/cod.13962

2. Autoxidation vs. antioxidants – the fight for forever 📘Chemical Society Reviews, 2021, 50: 7343–7358 🔗 https://doi.org/10.1039/D1CS00265A

🦠 Since the introduction of penicillins in the 1940s, β-lactam antibiotics have been a cornerstone of modern medicine. However, bacteria quickly fought back by producing β-lactamase enzymes that degrade these antibiotics before they can exert their effect. To overcome this, β-lactamase inhibitors (BLIs) were developed to be co-administered with β-lactam antibiotics, protecting them by irreversibly binding and inactivating β-lactamase enzymes — thereby restoring the antibiotics’ ability to target penicillin-binding proteins (PBPs) and kill the bacteria.

⚙️The discovery of the first BLI, clavulanic acid from Streptomyces clavuligerus, was a key breakthrough. Most people have been prescribed Augmentin^®, the combination of amoxicillin and clavulanic acid that has been in use since 1981. This was followed by synthetic inhibitors like sulbactam and tazobactam, introduced in the mid-1980s and early 1990s respectively. More recently, two new classes of non-β-lactam inhibitors, diazabicyclooctanes (DBOs) and boronates, have been developed.

💡Fast forward to the approval in February 2024 of a new BLI/β-lactam combination: enmetazobactam + cefepime (marketed as Exblifep^®) has now been approved in the USA, Europe, and India for the treatment of complicated urinary tract infections (cUTIs). The enmetazobactam story began in India, where researchers at Orchid Research Laboratories identified that adding a methyl group to the triazole ring of tazobactam created a zwitterionic BLI. This small chemical change dramatically improved bacterial penetration and pharmacokinetic properties. Allecra Therapeutics (headquartered in Germany with operations in France) led the clinical development.

🌟 Enmetazobactam is a great example of how thoughtful chemical modifications, combined with an understanding of resistance mechanisms, can deliver clinical impact.

#AMR #IndiaInnovation #Antibiotics #DrugDevelopment #InfectiousDiseases #Innovation

Continuing on my blog posts on natural products, antibiotics and other topics…

💠 During World War II, both Allied and Axis forces used stimulants like amphetamine and methamphetamine to maintain alertness in combat. But another related compound—fenethylline, better known as Captagon—has taken a darker path in recent decades. Amphetamine ties back to natural products through the exploration of chemistry around ephedrine, originally isolated from Ephedra sinica in the 1880s. I will expand upon this link in a later blog.

💠 Developed in the early 1960s, fenethylline is a co-drug of amphetamine and theophylline, joined by an ethane bridge. It was originally prescribed for hyperkinesis (now ADHD), narcolepsy, and depression, often preferred over amphetamines for its more tolerable profile. Its clinical use was short-lived, however—it was banned in most countries by 1986 following WHO’s inclusion under the Convention on Psychotropic Substances.

💠 Pharmacologically, fenethylline is more lipophilic, enabling rapid absorption into the CNS. It metabolises into amphetamine (24.5%) and theophylline (13.7%, caffeine related compound), working synergistically: amphetamine boosts dopamine signalling as a potent stimulant, while theophylline provides weaker stimulation and bronchodilation.

💠 Though long out of medical use, fenethylline re-emerged on the black market, produced in clandestine labs across the Middle East and Southern Europe. It has since been linked to recreational and combat use—highlighting drug misuse in modern conflict zones.

🧪 This is a potent example of how drugs can be redirected far from their original therapeutic intent.

#MedicinalChemistry #Neuropharmacology #ControlledSubstances #DrugMisuse #HistoryOfMedicine #ConflictZones #ScienceCommunication

What is Nafithromycin?

• Nafithromycin (development code WCK 4873) is an orally bioavailable ketolide developed by Wockhardt Limited with broad spectrum antibacterial activity against respiratory pathogens: Gram-positive bacteria such as S. pneumoniae and S. aureus and Gram-negatives such as Haemophilus influenzae, Moraxella catarrhalis, Legionella pneumophila, Mycoplasma pneumoniae and Chlamydophila pneumoniae.
• Nafithromycin (brand name Miqnaf^®) was approved by India’s CDSCO on January 2, 2025, for the treatment of community-acquired bacterial pneumonia (CABP).
• Nafithromycin is the second ketolide ever approved globally, the first was telithromycin (approved in 2001), which is no longer in use.

Table: Differences between 14-membered macrolides such as erythromycin and clarithromycin and the ketolides nafithromycin and telithromycin – see structures in the figure below.

Why It Matters

• Nafithromycin targets drug-resistant CABP, a major killer with over 3 million deaths globally yearly with India bearing ~25% of this burden.
• Nafithromycin is India’s first ‘home grown’ antibiotic to be granted approved.
• For over 25 years, Wockhardt has focused its drug discovery efforts on the discovery and development of new antibiotics to treat MDR infections.
• The company previously introduced levonadifloxacin (IV) and alalevonadifloxacin (oral) in 2019 and continues to build an impressive antibiotic pipeline.
• This is a proud milestone for Indian drug discovery and a timely addition in the fight against antimicrobial resistance. It will be fascinating to watch how the launch unfolds in India, and whether this innovation finds its way to global markets.

Linezolid, an oxazolidinone-class protein synthesis inhibitor, has been approved since 2000 and is used to treat Gram-positive infections like MRSA. But now, it’s stepping into an entirely new arena: chronic lower back pain.

Why antibiotics?
Emerging research suggests that bacterial infections in herniated disc tissue—think Cutibacterium acnes or coagulase-negative Staphylococcus—is an underlying driver of pain for some patients. The problem? Discs are poorly vascularized, making it difficult for systemic antibiotics to reach therapeutic levels. Past studies with oral amoxicillin alone and in combination with clavulanic acid showed modest pain relief, but directly delivering antibiotics to the infected disc could be a game-changer.

Enter PP353 from Persica Pharmaceuticals
This injectable formulation of linezolid, iohexol (for imaging), and a thermosensitive gel is designed to target degenerate lumbar discs. Once injected, it provides prolonged, high-concentration linezolid exposure at the infection site. Persica’s recent Phase 1b trial results in patients with Modic Type 1 changes (a marker of disc inflammation) are promising—hinting at a future where we treat the root cause of bacterially mediated pain, not just the symptoms. If successful, this approach could also reduce reliance on long-term opioid use.

See Persica’s publications here.

Could this approach transform how we treat chronic back pain worsened by infection?