What is the development behind levosulpiride?

Development of Levosulpiride

Levosulpiride was developed as a benzamide derivative that functions as both a D2 dopamine receptor antagonist and a serotonin 5HT4 receptor agonist, giving it dual mechanism prokinetic properties for treating functional dyspepsia and gastric motility disorders. 1

Pharmacological Development and Mechanism of Action

• Levosulpiride is the levorotatory enantiomer of sulpiride, specifically designed to enhance prokinetic effects while minimizing adverse effects compared to the racemic mixture 1
• The drug exerts its prokinetic action through two primary mechanisms:
  • Antagonism of D2 dopamine receptors in the enteric nervous system 1, 2
  • Agonism of serotonin 5HT4 receptors, which confers additional cholinergic effects 1
• This dual mechanism allows levosulpiride to effectively accelerate gastric emptying and improve gastric motility in patients with functional dyspepsia 1, 3

Clinical Development and Testing

• Levosulpiride was developed and tested at a standard dosage of 25 mg three times daily for treating functional dyspepsia 1, 3
• Randomized clinical trials demonstrated that levosulpiride was at least as effective as cisapride (another prokinetic agent) in treating dysmotility-like functional dyspepsia 3
• In comparative studies, levosulpiride showed similar or superior efficacy to other dopamine antagonists used for treating dyspepsia 1
• A multicenter trial showed that levosulpiride significantly reduced individual dyspeptic symptoms and improved global symptom scores by approximately 80% 3

Formulation Advancements

• Initial formulations were immediate-release tablets taken three times daily 1, 3
• Later pharmaceutical development included sustained-release formulations incorporating bioresorbable cellulose derivatives to address the short half-life and frequent dosing requirements 4
• Sustained-release formulations were developed using various cellulose derivatives such as CMC sodium, HPC, and HPMC in different polymer-to-drug weight ratios 4

Therapeutic Applications

• Levosulpiride was primarily developed for treating dysmotility-like functional dyspepsia 1, 3, 5
• The British Society of Gastroenterology recognizes levosulpiride (25 mg three times daily) as a potential second-line treatment for functional dyspepsia 6
• It has also shown efficacy in treating non-erosive reflux disease when administered at 75 mg/day or 50 mg/day 5

Safety Profile and Side Effects

• The development process identified a generally favorable safety profile with manageable side effects 1, 5
• Common adverse events identified during development included:
  • Hyperprolactinemia leading to galactorrhea (26.7% of adverse events) due to central D2 receptor blockade 5, 2
  • Somnolence (17.8% of adverse events) 5
  • Fatigue (11.1% of adverse events) 5
  • Headache (11.5% of adverse events) 5
• A significant finding during development was that levosulpiride can cause substantial elevation of serum prolactin levels, sometimes exceeding 200 ng/mL, which can manifest as menstrual abnormalities in females 2

Current Clinical Positioning

• Levosulpiride is now positioned as a second-line treatment option for functional dyspepsia, particularly when first-line treatments (such as PPIs, H2 receptor antagonists, or H. pylori eradication) have failed 6
• It is specifically recommended for patients with dysmotility-like symptoms including fullness, bloating, and early satiety 1, 5
• The British Society of Gastroenterology guidelines recommend careful explanation of the rationale for its use and counseling about potential side effects 6

The development of levosulpiride represents an important advancement in the treatment of functional dyspepsia, particularly for patients with predominant dysmotility-like symptoms who have not responded adequately to first-line therapies.