Tag: calcium channel blockers

New Compound Outperforms Gabapentin for Pain Relief

Photo by Louis Reed on Unsplash

A new compound reversed four types of chronic pain in animal studies, according to new research published online in the Proceedings of the National Academy of Sciences (PNAS). It outperformed gabapentin without troublesome side effects, providing a promising candidate for treating pain.

Researchers led by NYU College of Dentistry’s Pain Research Center developed this small molecule, which binds to an inner region of a calcium channel to indirectly regulate it.

Calcium channels play a central role in pain signaling, in part through the release of neurotransmitters such as glutamate and GABA – “the currency of the pain signal,” according to Rajesh Khanna, director of the NYU Pain Research Center and professor of molecular pathobiology. The Cav2.2 (or N-type) calcium channel is the target for three clinically available drugs, including gabapentin and pregabalin, which are widely used to treat nerve pain and epilepsy.

Gabapentin mitigates pain by binding to the outside of the Cav2.2 calcium channel, affecting the channel’s activity. However, like many pain medications, gabapentin use often comes with side effects.

“Developing effective pain management with minimal side effects is crucial, but creating new therapies has been challenging,” said Khanna, the senior author of the PNAS study. “Rather than directly going after known targets for pain relief, our lab is focused on indirectly targeting proteins that are involved in pain.”

Inside the channel

Khanna has long been interested in a protein called CRMP2, a key regulator of the Cav2.2 calcium channel that binds to the channel from the inside. He and his colleagues previously discovered a peptide derived from CRMP2 that could uncouple CRMP2 from the calcium channel. When this peptide – calcium channel-binding domain 3 (CBD3) – was delivered to cells, it acted as a decoy, blocking CRMP2 from binding to the inside of the calcium channel. This resulted in less calcium entering the calcium channel and less neurotransmitter release, which translated to less pain in animal studies.

Peptides are difficult to synthesise as drugs because they are short-acting and easily degrade in the stomach, so the researchers sought to create a small molecule drug based on CBD3. Starting with the 15 amino acids that make up the CBD3 peptide, they honed in on two amino acids that studies showed were responsible for inhibiting calcium influx and mitigating pain.

“At that point, we realised that these two amino acids could be the building blocks for designing a small molecule,” said Khanna.

From 27 million to one

In collaboration with colleagues at the University of Pittsburgh, the researchers ran a computer simulation that screened a library of 27 million compounds to look for a small molecule that would “match” the CBD3 amino acids.

The simulation narrowed the library down to 77 compounds, which the researchers experimentally tested to see if they lessened the amount of calcium influx. This further pared the pool down to nine compounds, which were assessed using electrophysiology to measure decreases in electrical currents through the calcium channels.

One compound, which the researchers named CBD3063, emerged as the most promising candidate for treating pain. Biochemical tests revealed that CBD3063 disrupted the interaction between the CaV2.2 calcium channel and CRMP2 protein, reduced calcium entering the channel, and lessened the release of neurotransmitters.

“Many scientists have screened the same library of compounds, but have been trying to block the calcium channel from the outside. Our target, these two amino acids from CRMP2, is on the inside of the cell, and this indirect approach may be the key to our success,” said Khanna.

Four labs, four types of pain

Khanna’s lab then tested CBD3063 with mouse models for pain related to injury. The compound was effective in alleviating pain in both male and female mice – and notably, in a head-to-head test with the drug gabapentin, the researchers needed to use far less CBD3063 (1–10mg) than gabapentin (30 mg) to reduce pain.

To explore whether CBD3063 helped with different types of chronic pain, Khanna partnered with researchers at Virginia Commonwealth University, Michigan State University, and Rutgers University. Collaborators ran similar studies administering CBD3063 to treat animal models of chemotherapy-induced neuropathy, inflammatory pain, and trigeminal nerve pain – all successfully reversing pain, similar to gabapentin.

But unlike gabapentin, the use of CBD3063 did not come with side effects, including sedation, changes to cognition such as memory and learning, or changes to heart rate and breathing.

What’s next

The researchers are continuing to study CBD3063, refining its chemical composition and running additional tests to study the compound’s safety and assess if tolerance develops.

Long-term, they hope to bring a CBD3063-derived drug to clinical trials in an effort to offer new options for safe and effective pain relief.

“Identifying this first-in-class small molecule has been the culmination of more than 15 years of research. Though our research journey continues, we aspire to present a superior successor to gabapentin for the effective management of chronic pain,” said Khanna.

Source: New York University

Antihypertensive Drugs Not Linked to Cancer Risk

A review of 33 clinical studies  showed that antihypertensive drugs did not have a consistent association with cancer risk.

Patients treated with any of five different classes of antihypertensive drugs had essentially the same cancer risk as those receiving placebo. Comparisons of each antihypertensive class against all the others showed no association with an increased risk of cancer, save for calcium channel blockers (CCBs), which had only a modestly higher risk versus the other drug classes (HR 1.06, 95% CI 1.01-1.11).

The data do not conclude the issue, since some comparisons had insufficient data to exclude the possibility of excess cancer risk, reported Kazem Rahimi, DM, of the University of Oxford in England, and colleagues in Lancet Oncology.

“Our study has addressed an ongoing controversy about the safety of blood pressure-lowering medication with respect to cancer risk, using the largest sample of individual-level randomized evidence on blood pressure-lowering treatment to date, to our knowledge,” they wrote. “The main implication of our study is that patients using antihypertensive medication should continue to take their medications because concerns about increased cancer risk seem to be unfounded.”

The author of an accompanying commentary noted that the findings could have been due to chance. The number of trials per drug class varied greatly, and small sample sizes were used in analyses by type of cancer.

“Taken together, these limitations raise a more fundamental question about how the findings of randomised controlled trials should be interpreted,” wrote Laurent Azoulay, PhD, of McGill University in Montreal.

Randomised trials are the “gold standard” for assessing drug efficacy, but are not typically designed to assess safety, he continued. This is especially important for outcomes like cancer, which have a delayed onset. Since the median follow-up was only 4.2 years , “a potential association between cancer and the long-term use of antihypertensive drugs cannot be ruled out.”

“Such analyses are necessary to understand the short-term effects of these drugs on cancer incidence,” Azoulay concluded. “However, moving forward, these studies will need to be complemented with well-designed, real-world studies in heterogeneous patient populations who are followed up for extended periods of time to fully understand their carcinogenic potential.”

Several meta-analyses have yielded conflicting evidence, Rahimi and colleagues stated. The Blood Pressure Lowering Treatment Trialists’ Collaboration (BPLTTC) is the world’s largest individual patient-level data on blood pressure-lowering trials, and data from this formed the basis for the meta-analysis.

The authors identified 33 trials for inclusion in the meta-analysis, which comprised 260 447 patients with available data on cancer outcomes. CCBs were the antihypertensive class most commonly represented in the trials (n=19), followed by ACE inhibitors (15), angiotensin-receptor blockers (ARBs, 11), thiazide diuretics (six), and beta-blockers (five). Median follow-up ranged from 4 to 5 years across the trials, grouped by drug class.

Patient age ranged between 64 and 68 by drug class, and pretreatment systolic blood pressure ranged from 147mm Hg (ACE inhibitors) to 166mm Hg (beta-blockers).

Across the five classes of antihypertensive drugs, individual comparisons for cancer risk versus the other drug classes yielded only a maximum hazard ratio of 1.06 for CCBs.

“We found no consistent evidence that antihypertensive medication use had any effect on cancer risk,” the authors stated.

Source: MedPage Today

Journal information 1: Copland E, et al “Antihypertensive treatment and risk of cancer: An individual participant data meta-analysis” Lancet Oncol 2021; DOI: 10.1016/S1470-2045(21)00033-4.

Journal information 2: Azoulay L “Elucidating the association between antihypertensive drugs and cancer: A need for real-world studies” Lancet Oncol 2021; DOI: 10.1016/S1470-2045(21)00085-1.