Medication

Antihypertensive Medication After Intracerebral Hemorrhage

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Antihypertensive Medication After Intracerebral Hemorrhage

Latest PubMed Articles

🧠 1. Acute Phase Management (First Hours to Days)

🎯 Goal: Reduce hematoma expansion and improve outcomes

Target Blood Pressure (BP):

  • SBP 150–220 mmHg → Lower to <140 mmHg is generally safe and may improve outcomes (AHA/ASA 2022)
  • SBP >220 mmHg → Consider aggressive reduction with ICU-level monitoring

IV Antihypertensives:

Drug Class Notes
Labetalol α/β-blocker Often first-line; good for rapid BP control
Nicardipine Calcium channel blocker Preferred for titratable infusion
Clevidipine Calcium channel blocker Short half-life, easily adjustable
Esmolol β1-selective blocker Useful for short-term, fast-acting control
Hydralazine Direct vasodilator Less predictable; not first-line

Avoid: Overly rapid BP drops, especially with elevated intracranial pressure (ICP)

🔁 2. Secondary Prevention (Long-Term Management)

🎯 Goal: Prevent recurrent ICH and vascular events

BP Target:

  • Long-term: SBP <130 mmHg
  • Avoid SBP <110 mmHg (risk of hypoperfusion)

Preferred Antihypertensive Classes:

Class Example Notes
ACE inhibitors Enalapril, Ramipril Good stroke prevention evidence
ARBs Losartan, Candesartan Well tolerated alternative to ACEi
Thiazide diuretics Hydrochlorothiazide Often used in combo therapy
Calcium channel blockers Amlodipine Useful as monotherapy or in combinations

Key Trials:

📌 Clinical Pearls

  • Titrate IV to oral meds with continuous monitoring
  • Consider Spontaneous Intracerebral Hemorrhage Etiology (hypertensive vs amyloid-related) for long-term goals
  • Tailor treatment to age, comorbidities, renal function, and prior drug response

TRICH Score

In a prospective cohort study with external validation study components, the authors used data from a longitudinal ICH registry (2011–2022) for score development and validated the model prospectively in three independent hospitals (2020–2022) 1)

The study aims to develop and validate a clinical score (the TRICH score) to predict the need for ≥3 antihypertensive medications three months after intracerebral hemorrhage (ICH), to guide early and individualized blood pressure management.

Clinically Relevant Tool: The TRICH score addresses a clear clinical need: stratifying patients by future antihypertensive needs post-ICH.

– Well-Defined Cohorts: The development and validation cohorts are clearly defined and separate, lending credibility to the generalizability within the studied population.

– Statistical Rigor: The use of multivariate logistic regression, β-coefficients for score construction, and AUC for model performance are standard and appropriate.

– Good Discrimination: The TRICH score achieved a c-statistic of 0.79 in the development and 0.76 in the validation cohort, indicating good predictive performance.

– Subgroup Analyses: The study explores performance in subgroups (e.g., uncontrolled hypertension vs controlled, CAA vs non-CAA), which is useful for clinical interpretation.

Limitations

– Ethnic Homogeneity: All participants were from Hong Kong hospitals, likely representing predominantly Han Chinese patients. This limits external validity, especially in multiethnic or Western populations.

– Short Follow-up: The score is tailored to predict medication needs at 3 months. It remains unclear whether it has predictive power for long-term hypertension control or cardiovascular outcomes.

– Exclusion Criteria Bias: Patients who died before 90 days or lacked follow-up were excluded. These patients might represent a higher-risk group, potentially introducing survivorship bias.

– Simplification Risks: While score simplification (e.g., dichotomizing age or BP ranges) improves usability, it may reduce nuance in individual patient profiles.

The TRICH score has the potential to assist clinicians in initiating early intensive antihypertensive therapy in appropriate post-ICH patients, especially those with a high risk of needing triple therapy. However, caution is warranted to avoid overtreatment in those with transient BP elevation due to acute stress or underlying cerebral amyloid angiopathy.

The model performed better in patients with previously uncontrolled or untreated hypertension, reinforcing its value in guiding care where hypertension is known but uncontrolled. Lack of differentiation in patients with or without CAA suggests that further refinements or adjunct markers may be needed for this subgroup.

Future Directions

– External validation in diverse populations, including Caucasian, African descent, and South Asian cohorts.

– Integration of biomarkers or imaging (e.g., MRI markers of CAA) to refine predictions.

– Evaluation of the TRICH score’s impact on clinical outcome when used in routine care.

Conclusion

This well-conducted cohort study introduces a practical clinical tool—the TRICH score—for anticipating antihypertensive requirements after ICH. Despite its promise, broader validation and studies on downstream outcomes are essential before widespread implementation.

1)

So CH, Yeung C, Ho RW, Hou QH, Sum CHF, Leung W, Wong YK, Liu KCR, Kwan HH, Fok J, Yip EK, Sheng B, Yap DY, Leung GKK, Chan KH, Lau GKK, Teo KC. Triple Antihypertensive Medication Prediction Score After Intracerebral Hemorrhage (the TRICH Score). Neurology. 2025 May 13;104(9):e213560. doi: 10.1212/WNL.0000000000213560. Epub 2025 Apr 4. PMID: 40184593.

Exploring conservative avenues in subacute subdural hematoma: the potential role of atorvastatin and dexamethasone as lifesaving allies

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Title: Exploring conservative avenues in subacute subdural hematoma: the potential role of atorvastatin and dexamethasone as lifesaving allies Authors: Tao Liu et al. DOI: 10.1186/s41016-025-00393-8 PMID: 40176171

Type of Study

This is a retrospective case series involving five patients with subacute subdural hematoma (sASDH), who were managed conservatively using atorvastatin and low-dose dexamethasone without surgical intervention. It also includes a non-systematic narrative review of existing literature, lacking formal meta-analytic methodology.

Critical Appraisal

Strengths

  • The article raises an important question: can we optimize conservative treatment for sASDH in inoperable patients?
  • A novel hypothesis is proposed, leveraging two commonly available pharmacologic agents.

Fatal Flaws

1. Sample Size and Selection Bias

The study is limited to five hand-picked cases, all of whom refused surgery. There is no control group, no randomization, and no standardization in patient selection. This introduces massive selection bias and confounding, rendering the findings anecdotal at best.

2. Lack of Statistical Power

With only five patients, the study is grossly underpowered to draw any conclusions on safety or efficacy. Even if all patients improved, the positive predictive value is negligible.

3. Absence of Mechanistic Evidence

The article alludes vaguely to the “possible mechanisms” of action of atorvastatin and dexamethasone but fails to elaborate with any molecular, imaging, or biomarker-based support. The hypothesized synergy is speculative and not experimentally validated.

4. Cherry-Picking Literature

The review portion pulls from only six studies without PRISMA methodology, inclusion/exclusion criteria, or risk-of-bias assessments. This is not a systematic review but rather a collection of cherry-picked studies to support a preconceived narrative.

5. Logical Fallacy: Post Hoc Ergo Propter Hoc

The authors infer that improvement after administration of atorvastatin and dexamethasone implies causality. This is a classic post hoc fallacy. No causation can be inferred from such a weak observational structure.

6. Ethical and Practical Concerns

Presenting this treatment strategy without rigorous evidence could mislead clinicians, delay necessary surgery, or foster false confidence in a pharmacological approach for a condition where deterioration can be catastrophic.

Bottom Line

The article is a speculative and weakly documented case series attempting to repurpose two drugs in the treatment of sASDH. While the intention is noble, the scientific execution is fundamentally flawed. No clinical decisions should be influenced by this paper. What is needed is a properly designed randomized controlled trial, not a narrative built on five anecdotal successes.

See also: subdural_hematoma, conservative_management, evidence_based_medicine

Monocarboxylate transporter

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Monocarboxylate transporter

Monocarboxylate transporters (MCTs) are a family of membrane proteins that mediate the transport of monocarboxylates such as lactate, pyruvate, and ketone bodies across the plasma membrane, often coupled with H⁺ ions. These transporters are essential for maintaining intracellular and extracellular pH homeostasis and supporting metabolic adaptation, particularly under hypoxic and glycolytic conditions common in malignant tumors.

🔍 MCTs in Glioma Pathobiology

🧬 Key Isoforms: MCT1 (SLC16A1): High affinity for lactate, expressed in both oxidative and glycolytic cells.

MCT4 (SLC16A3): Low affinity but high capacity, induced by hypoxia-inducible factor 1 (HIF-1α) and upregulated in highly glycolytic, hypoxic tumors.

MCT2 (SLC16A7): Highest affinity for lactate, recently recognized for its nuanced regulation in astrocytes and glioma cells in response to pH, hypoxia, glucose, and lactate, as shown by Caruso et al. 1).

🧪 Molecular Functions in GBM: Glioblastoma (GBM), the most aggressive primary brain tumor, exhibits a hallmark aerobic glycolytic phenotype (Warburg effect), leading to excessive lactate production. MCT1 and MCT4 mediate lactate efflux to prevent “self-poisoning,” facilitating:

Tumor cell survival under metabolic stress

Invasion of surrounding tissue

Immune evasion via acidic microenvironment

🏥 Relevance in Neurosurgical Practice 1. Tumor Aggressiveness & Surgical Planning High MCT1/4 expression correlates with aggressive tumor biology in GBM 2)

Their presence may mark invasive margins or hypoxic cores, which are difficult to resect and more likely to recur. Future intraoperative imaging (e.g., hyperpolarized MRI or pH-sensitive probes) may enable visualization of metabolically active MCT-rich zones to optimize resection margins.

2. Pathological Diagnosis and Immunohistochemistry MCT1/4 immunoreactivity can aid in distinguishing IDH-wildtype GBM from lower-grade gliomas when molecular data is incomplete. Pathologists and neurosurgeons may use MCT staining to infer tumor grade, prognosis, and potential therapeutic vulnerability.

3. Adjunctive Therapies Post-Resection Targeting MCTs offers a metabolism-based adjuvant approach.

Syrosingopine, a dual MCT1/4 inhibitor with CNS penetration, demonstrates apoptotic and anti-invasive effects in glioma cell lines and is a candidate for clinical repurposing.

Combined therapies (e.g., with metformin) may synergize to exhaust tumor metabolic plasticity.

4. Neurosurgical Research and Innovation MCTs are a valuable focus in translational neuro-oncology:

Biopsy targeting, tumor banking, and delivery of MCT inhibitors (e.g., via convection-enhanced delivery) are emerging research avenues.

Understanding the pH-lactate-hypoxia interplay via MCT regulation (as described by Caruso et al.) may lead to new molecular imaging markers or pH-responsive delivery systems.

⚠️ Current Limitations

No MCT-targeting therapy is yet approved for clinical neurosurgical use.

Expression heterogeneity within tumors and across patients complicates therapeutic targeting.

Isoform-specific inhibitors with safe CNS profiles are needed.

Non-invasive radiological detection of MCT activity is still under development.

🧩 Clinical Takeaway for Neurosurgeons

Monocarboxylate transporters—particularly MCT1 and MCT4—are more than molecular curiosities; they are critical markers and mediators of glioma aggressiveness. Their expression informs diagnosis, surgical planning, and offers a metabolic Achilles’ heel that could be exploited through adjuvant therapy. As glioma therapy moves toward precision medicine, MCTs represent a bridge between metabolic biology and neurosurgical practice.

References

1)

Caruso JP et al. pH, Lactate, and Hypoxia: Reciprocity in Regulating High-Affinity Monocarboxylate Transporter Expression in Glioblastoma. Neoplasia. 2017;19(2):121-134. doi: 10.1016/j.neo.2016.12.011.
2)

Behera MM et al. The Monocarboxylate Transporters MCT1 and MCT4 Are Highly Expressed in Glioblastoma and Crucially Implicated in the Pathobiology. Neuropathology. 2025 Mar 27. doi: 10.1111/neup.70006. PMID: 40145253.

Peginterferon alfa-2a for cystic craniopharyngioma treatment

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Peginterferon alfa-2a for cystic craniopharyngioma treatment

J.Sales-Llopis

Neurosurgery Department, General University Hospital Alicante, Spain

Craniopharyngiomas, especially their cystic forms, pose unique management challenges due to their proximity to critical neurovascular structures. Intracystic therapies offer a minimally invasive alternative to repeated surgical interventions. Over the past decade, interferon-alfa-2a/2b emerged as a viable intracystic treatment due to its anti-proliferative and immune-modulating properties, coupled with low toxicity. However, discontinuation of commercial availability prompted the search for alternatives.

Hedrich et al. describes a retrospective case series, including five patients with intracystic peginterferon alfa-2a for cystic craniopharyngioma treatment according to an innovative care protocol. After initial CP cyst aspiration, peginterferon alfa-2a was injected once per week via an Ommaya reservoir for 6 weeks followed by response assessment with MRI.

Patients’ age ranged from 4 to 54 years (four patients <12 years, one adult patient). Intracystic therapy with peginterferon alfa-2a was tolerated well by all five individuals without any major toxicities and resulted in cyst shrinkage in all of the five patients. The importance of a permeability study prior to commencing intracystic therapy became apparent in one patient who suffered from cyst leakage.

Intracystic treatment with peginterferon alfa-2a was found to be a tolerable and efficacious treatment modality in patients with cystic craniopharyngioma. This experience warrants further research with a larger number of patients with measurement of long-term efficacy and safety outcomes 1).

The authors propose peginterferon alfa-2a, a pegylated form with extended half-life and established safety profile in other indications, as a substitute, presenting a retrospective case series evaluating its feasibility and safety.

Study Design and Methodology

– Design: Retrospective case series

– Sample: 5 patients (age 4–54; 4 children, 1 adult)

– Protocol: After initial cyst aspiration, peginterferon alfa-2a was administered weekly for 6 weeks via an Ommaya reservoir.

– Follow-up: MRI for response assessment

– Pre-treatment: Permeability study was highlighted as essential following one adverse case of leakage.

🔎 Strengths:

– Innovative use of peginterferon alfa-2a to fill a therapeutic gap.

– Uniform protocol across cases.

– Clear documentation of safety and early efficacy.

– Broad age range increases generalizability.

⚠️ Limitations:

– Very small sample size (n=5) limits statistical validity.

– Retrospective nature introduces potential bias and lacks standardized outcome metrics.

– Short-term follow-up; no data on recurrence, endocrine impact, or long-term survival.

– No comparator group (e.g., standard interferon alfa-2a or surgery-only) limits interpretation of relative efficacy.

Results

– Safety: No major toxicities reported in any patient.

– Efficacy: Cyst shrinkage achieved in all five patients.

– Complication: One patient experienced leakage, underscoring the need for a permeability test.

The data supports the hypothesis that peginterferon alfa-2a is a safe and potentially effective intracystic agent in this context.

Discussion and Clinical Relevance

This study provides preliminary real-world evidence that peginterferon alfa-2a can serve as an effective intracystic treatment option for cystic craniopharyngiomas, particularly important in the wake of discontinued access to interferon alfa-2a. The lack of significant toxicity is encouraging, especially in pediatric patients.

However, due to the small number of cases and lack of long-term outcome data, the findings should be interpreted as hypothesis-generating rather than practice-changing. Further research in prospective, multi-institutional trials with larger cohorts is warranted.

Conclusion Hedrich et al. offer a promising alternative approach for managing cystic craniopharyngiomas using peginterferon alfa-2a. The treatment appears feasible, safe, and effective in the short term. Yet, the study’s limitations — particularly its size and retrospective design — mean that broader validation is essential before widespread clinical adoption.

Comparative Analysis of Intracystic Treatments

Peginterferon alfa-2a vs Bleomycin vs Radioisotopes

Feature/Agent Peginterferon alfa-2a Bleomycin Radioisotopes (e.g., P-32, Y-90)
Mechanism of Action Immunomodulatory and antiproliferative Cytotoxic antibiotic causing DNA strand breaks Beta radiation causing localized cyst wall necrosis
Dosing Protocol Weekly x6 via Ommaya Multiple instillations (e.g., 4–6 doses over weeks) Single or repeated instillation; dosimetry-based
Age Use Pediatric and adult Caution in young children due to neurotoxicity Generally avoided in children <5–6 years old
Safety Profile Excellent short-term tolerability in small series Risk of chemical meningitis, neurotoxicity Risk of CSF leak, radiation necrosis, hypothalamic damage
Key Risks Cyst leakage (1 case in 5); minimal toxicity Seizures, necrosis if drug leaks to parenchyma Radiation exposure to critical adjacent structures
Regulatory Access Off-label, emerging use Widely available Often restricted, requires radiopharmacy services
Onset of Response Gradual shrinkage over weeks Moderate to rapid Rapid but with potential delayed adverse effects
Imaging Follow-up MRI after 6 weeks MRI at regular intervals Imaging + dosimetry (CT/SPECT) required
Long-Term Data Limited (new approach, case series only) Moderate, decades of use Available, esp. from Europe, but often in outdated protocols
Procedure Requirements Ommaya reservoir; permeability test recommended Ommaya reservoir or catheter Ommaya + radiation safety protocols

Summary Recommendations

Agent Advantages Disadvantages
Peginterferon alfa-2a Favorable safety, non-cytotoxic, off-label alternative to IFN-α2a Limited experience, unclear long-term outcomes
Bleomycin Effective and accessible; longer track record Neurotoxicity risk if leakage occurs; more systemic side effects
Radioisotopes Potent and often effective with fewer instillations Technically demanding; radiation risks; contraindicated in very young children

When to Consider Each Treatment?

* Peginterferon alfa-2a → Ideal for younger children or when minimal toxicity is essential. Requires close monitoring and permeability testing. * Bleomycin → Suitable where experience exists with its use. Effective but requires caution regarding leakage and systemic toxicity. * Radioisotopes → Best reserved for specialized centers with radiation safety protocols and older pediatric or adult patients with refractory cysts.

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🧠 Flowchart Logic

Is the patient under 5 years old?

→ Yes → ❌ Avoid radioisotopes

→ No → ✅ Radioisotopes may be considered

Is radiation facility & radiopharmacy available?

→ Yes → Consider radioisotopes

→ No → Proceed to next

Is cyst accessible with Ommaya and permeability confirmed?

→ No → ❌ Intracystic therapy not recommended

→ Yes → Proceed to next

Is neurotoxicity a major concern (e.g., very young child, hypothalamic proximity)?

→ Yes → ✅ Prefer Peginterferon alfa-2a

→ No → Proceed to next

Institutional experience with bleomycin?

→ Yes → Consider bleomycin

→ No → Consider peginterferon alfa-2a

1)

Hedrich C, Patel P, Haider L, Taylor T, Lau E, Hook R, Dorfer C, Roessler K, Stepien N, Lippolis MA, Schned H, Koeller C, Mayr L, Azizi AA, Peyrl A, Lopez BR, Lassaletta A, Bennett J, Gojo J, Bartels U. Feasibility, tolerability, and first experience of intracystic treatment with peginterferon alfa-2a in patients with cystic craniopharyngioma. Front Oncol. 2024 Jul 10;14:1401761. doi: 10.3389/fonc.2024.1401761. PMID: 39050573; PMCID: PMC11266088.

Salovum for severe traumatic brain injury

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Salovum for severe traumatic brain injury

J.Sales-Llopis

Neurosurgery Department, General University Hospital Alicante, Spain

Antisecretory Factor and Salovum® in Severe Traumatic Brain Injury: A New Frontier in Neurocritical Care

Severe traumatic brain injury (TBI) remains a leading cause of disability and mortality worldwide despite continuous advancements in neuroimaging, neurocritical care, and surgical techniques. Elevated intracranial pressure (ICP) is a major contributor to secondary brain injury, often determining patient prognosis. Current treatments, including hyperosmolar therapy, decompressive craniectomy, and sedation, provide variable efficacy with significant risks.

A promising new approach involves the use of antisecretory factor (AF), a naturally occurring protein with anti-inflammatory and fluid-regulating properties, commercially available as Salovum®. Recent studies suggest that AF may play a crucial role in reducing ICP and improving clinical outcomes in severe TBI.

Clinical Evidence Supporting Antisecretory Factor in Severe TBI

The AFISTBI and SASAT Trials

Two exploratory randomized, placebo-controlled clinical trials are currently evaluating the role of AF in severe TBI. The AFISTBI trial (ClinicalTrials.gov NCT04117672) is a single-center phase 2 study conducted at Skane University Hospital, Sweden. This trial examines the impact of Salovum® supplementation for five days in adults with severe TBI (GCS < 9) requiring ICP monitoring and microdialysis catheter insertion. The primary endpoint is ICP reduction, while secondary endpoints include inflammatory mediator levels in plasma and cerebrospinal fluid.

Similarly, the SASAT trial (ClinicalTrials.gov NCT03339505) is a phase 2, double-blind, randomized trial conducted at Tygerberg University Hospital, South Africa. It evaluates 30-day mortality, treatment intensity level (TIL), and ICP control in 100 patients randomized to receive either Salovum® or placebo.

Pilot Studies and Case Series

Several preliminary studies have demonstrated the potential of AF in reducing ICP. A pilot study by Gatzinsky et al. investigated four patients with severe TBI and refractory intracranial hypertension treated with Salovum®. The study found that when administered rectally, AF significantly reduced ICP without adverse events, offering a novel delivery route for neurocritical care patients with impaired gastric emptying.

Additionally, a case series by Cederberg et al. evaluated five patients with severe TBI who received Salovum® via nasogastric tube for five days. Three patients exhibited successful ICP control without the need for barbiturates, while four had favorable long-term outcomes. Importantly, no toxicity or adverse effects were observed, underscoring the safety of AF therapy in this population.

Mechanism of Action and Potential Therapeutic Implications

AF exerts its effects by modulating fluid balance and inflammatory responses in the brain. Preclinical models suggest that AF can suppress excessive cerebrospinal fluid production, reduce blood-brain barrier permeability, and attenuate neuroinflammation, all critical mechanisms in controlling ICP and secondary brain injury.

The ability of AF to reduce ICP through non-invasive means could have profound implications for the management of TBI. In resource-limited settings where advanced neurosurgical interventions may not be readily available, Salovum® presents a cost-effective adjunct to standard neurocritical care.

Challenges and Future Directions

While preliminary data are promising, larger, multicenter randomized controlled trials (RCTs) are needed to validate these findings. Understanding the optimal dosing, administration route, and long-term effects of AF therapy remains crucial. Additionally, integrating AF into current TBI treatment protocols will require further evaluation of its interactions with existing therapies.

Conclusion

Antisecretory factor, as delivered via Salovum®, represents an exciting new frontier in TBI management. With ongoing trials exploring its efficacy, AF has the potential to become a groundbreaking adjunctive therapy for reducing ICP and improving outcomes in severe TBI patients. If confirmed in larger studies, the use of Salovum® could redefine the standard of care in neurocritical care settings, providing a safer and more accessible treatment alternative for ICP control.

Despite recent advances in neuroimaging and neurocritical care, severe traumatic brain injury (TBI) is still a major cause of severe disability and mortality, with increasing incidence worldwide. Antisecretory factor (AF), commercially available as Salovum®, has been shown to lower intracranial pressure (ICP) in experimental models of, e.g., TBI and herpes encephalitis. A study by Réen et al. aims to assess the effect of antisecretory factors in adult patients with severe TBI on ICP and inflammatory mediators in extracellular fluid and plasma.

In a single-center, randomized, placebo-controlled clinical phase 2 trial, investigating the clinical superiority of Salovum® given as a food supplement for 5 days to adults with severe TBI (Glasgow Coma Scale (GCS) < 9), admitted to the neurocritical intensive care unit (NICU) at Skane university hospital. All patients with GCS < 9 and clinical indication for insertion of ICP-monitor and microdialysis catheter will be screened for inclusion and assigned to either the treatment group (n = 10) or placebo group (n = 10). In both groups, the primary outcome will be ICP (mean values and change from baseline during intervention), registered from high-frequency data monitoring for 5 days. During trial treatment, secondary outcomes will be inflammatory mediators in plasma and intracerebral microdialysis perfusate days 1, 3, and 5.

Trial registration: ClinicalTrials.gov NCT04117672. Registered on September 17, 2017. Protocol version 6 from October 24, 2023 1).

A study aims to assess the effect as measured by 30-day mortality, treatment intensity level (TIL), and intracranial pressure (ICP).

This single-center, double-blind, randomized, placebo-controlled clinical phase 2 trial, investigating the clinical superiority of Salovum® given as a food supplement to adults with severe TBI (GCS < 9), presenting to the trauma unit at Tygerberg University Hospital, Cape Town, South Africa, that are planned for invasive ICP monitoring and neurointensive care, will be screened for eligibility, and assigned to either treatment group (n = 50) or placebo group (n = 50). In both groups, the primary outcome will be 30-day mortality, recorded via hospital charts, follow-up phone calls, and the population registry. Secondary outcomes will be treatment intensity level (TIL), scored from hospital charts, and ICP registered from hospital data monitoring.

Trial registration: ClinicalTrials.gov NCT03339505 . Registered on September 17, 2017. Protocol version 3.0 from November 13, 2020 2)

Four patients with severe TBI (Glasgow Coma Scale < 9) that required neurointensive care with ICP monitoring due to signs of refractory intracranial hypertension were investigated. One hundred milliliters of Salovum®, a commercially available egg yolk powder with high contents of AF peptides, was administrated either via nasogastric (patients 1 and 2) or rectal tube (patients 2, 3, and 4) every 8 h for 2 to 3 days as a supplement to the conventional neurointensive care. ICP was registered continuously. Plasma levels of AF were measured by enzyme-linked immunosorbent assay (ELISA) to confirm that Salovum® was absorbed appropriately into the bloodstream.

Results: In the first two patients, we observed that when delivered by the nasogastric route, there was an accumulation of the Salovum® solution in the stomach with difficulties to control ICP due to impaired gastric emptying. Therefore, we tested to administer Salovum® rectally. In the third and fourth patients, who both showed radiological signs of extensive brain edema, ICP could be controlled during the course of rectal administration of Salovum®. The ICP reduction was statistically significant and was accompanied by an increase in blood levels of AF. No adverse events that could be attributed to AF treatment or the rectal approach for Salovum® administration were observed.

Conclusions: The outcomes suggest that AF can act as a suppressor of high ICP induced by traumatic brain edema. Use of AF may offer a new therapeutic option for targeting cerebral edema in clinical practice 3).

A case series of five adult patients with severe TBI, treated with Salovum. The objective of the intervention was to evaluate safety and, if possible, its effect on intracranial pressure and outcome. Patients received 1 g Salovum per kilo of body weight divided into six doses per 24 h. Each dose was administered through the nasogastric tube. Patients were scheduled for 5 days of treatment with Salovum. Intracranial pressure was controlled in all patients. In three of five patients, intracranial pressure could be controlled with Salovum and deep sedation (no barbiturates), except during periods of gastroparesis. Five of five patients had a favorable short-term outcome, and four of five patients had a favorable long-term outcome. No toxicity was observed. We conclude that at least three of the five treated patients experienced an effect of Salovum with signs of reduction of intracranial pressure and signs of clinical benefit. To validate the potential of antisecretory factors in TBI, a prospective, randomized, double-blind, placebo-controlled trial with Salovum has been initiated. The primary outcome for the trial is 30-day mortality; secondary outcomes are treatment intensity level, intracranial pressure, and number of days at the neurointensive care unit 4).

References

1)

Réen L, Cederberg D, Marklund N, Visse E, Siesjö P. Antisecretory factor in severe traumatic brain injury (AFISTBI): protocol for an exploratory randomized placebo-controlled trial. Trials. 2025 Feb 7;26(1):43. doi: 10.1186/s13063-025-08760-7. PMID: 39920739.
2)

Cederberg D, Harrington BM, Vlok AJ, Siesjö P. Effect of antisecretory factor, given as a food supplement to adult patients with severe traumatic brain injury (SASAT): protocol for an exploratory randomized double blind placebo-controlled trial. Trials. 2022 Apr 23;23(1):340. doi: 10.1186/s13063-022-06275-z. PMID: 35461285; PMCID: PMC9034076.
3)

Gatzinsky K, Johansson E, Jennische E, Oshalim M, Lange S. Elevated intracranial pressure after head trauma can be suppressed by antisecretory factor-a pilot study. Acta Neurochir (Wien). 2020 Jul;162(7):1629-1637. doi: 10.1007/s00701-020-04407-5. Epub 2020 May 22. PMID: 32445122; PMCID: PMC7295841.
4)

Cederberg D, Hansson HA, Visse E, Siesjö P. Antisecretory Factor May Reduce ICP in Severe TBI-A Case Series. Front Neurol. 2020 Mar 6;11:95. doi: 10.3389/fneur.2020.00095. PMID: 32210902; PMCID: PMC7067821.

Regorafenib for glioblastoma

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Regorafenib for glioblastoma

J.Sales-Llopis

Neurosurgery Department, General University Hospital Alicante, Spain

Regorafenib, a multi-kinase inhibitor, has emerged as a potential therapeutic option for glioblastoma, particularly in cases where standard treatments such as surgery, radiation, and temozolomide chemotherapy have failed.

Mechanism of Action

Regorafenib targets multiple receptor tyrosine kinases involved in tumor proliferation, angiogenesis, and the tumor microenvironment, including:

VEGFR (Vascular Endothelial Growth Factor Receptors)

PDGFR (Platelet-Derived Growth Factor Receptors)

FGFR (Fibroblast Growth Factor Receptors)

KIT, RET, and BRAF These pathways are often dysregulated in glioblastoma, promoting tumor growth and resistance to standard therapies.

Clinical Evidence

REGOMA Trial (2019): A phase II clinical trial evaluated regorafenib in patients with recurrent glioblastoma:

Results: The study showed an improvement in overall survival (OS) compared to lomustine, a standard second-line therapy. Median OS for regorafenib was 7.4 months versus 5.6 months for lomustine. Implications: This result demonstrated the potential of regorafenib as a viable treatment option in recurrent settings. Ongoing Studies:

Further trials (e.g., phase III) are assessing its safety, efficacy, and potential biomarkers for predicting response. Studies are exploring combination therapies, such as regorafenib with immunotherapy, to overcome resistance mechanisms.

Potential Benefits

Angiogenesis Inhibition: Glioblastoma’s hallmark feature is its high vascularity, making anti-angiogenic therapy a promising strategy. Tumor Microenvironment Modulation: Regorafenib can alter the tumor’s supportive environment, potentially enhancing the efficacy of other treatments. Side Effects Regorafenib is associated with several adverse effects that require careful management, including:

Hypertension Hand-foot skin reactions Fatigue Diarrhea Hepatotoxicity Future Directions Biomarker Development: Identifying patients who would benefit most from regorafenib based on genetic and molecular tumor profiles. Combination Therapies: Combining regorafenib with checkpoint inhibitors, radiotherapy, or other targeted agents. Optimization of Dosing: Balancing efficacy with tolerability, particularly in patients with fragile health due to glioblastoma.

Meta-analysis of randomized controlled clinical trials

A meta-analysis, based on searches in PubMed and Web Of Science, evaluated 12 randomized controlled trials (RCTs) examining PKIs in patients with newly diagnosed or recurrent GBM. Pooled analysis of shared clinical outcomes – progression-free survival (PFS) and overall survival (OS) – revealed a lack of significant improvements with the use of PKIs. In newly diagnosed GBM, no significant differences were observed in median [-1.02 months, 95% confidence interval (CI), -2.37-0.32, p=0.14] and pooled [hazard ratio (HR)=1.13, 95% CI, 0.95-1.35, p=0.17) OS, or in median (0.34 months, 95% CI, -0.9-1.58, p=0.60) and pooled (HR=0.98, 95% CI, 0.76-1.27, p=0.89) PFS, when comparing PKI addition to standard chemo-radiotherapy versus chemo-radiotherapy alone. In recurrent GBM, three different analyses were conducted: PKI versus other treatments, PKI combined with other treatments versus those treatments alone, PKI versus PKI combined with other treatments. Also, across these analyses, no significant clinical benefits were found. For instance, when comparing PKI treatment with other treatments, median OS and PFS showed no significant difference (-0.78 months, 95% CI, -2.12-0.55, p=0.25; -0.23 months, 95% CI, -0.79-0.34, p=0.43, respectively), and similar non-significant results were observed in the pooled analyses (OS: HR=0.89, 95% CI, 0.59-1.32, p=0.55; PFS: HR=0.83, 95% CI, 0.63-1.11, p=0.21). Despite these overall negative findings, some data indicate improved clinical outcomes in a subset of GBM patients treated with certain PKIs (i.e., regorafenib) and encourage further research to identify PKIs with better blood-brain barrier penetration and lower risk for resistance development 1)

This meta-analysis underscores the limited efficacy of current PKIs in GBM, despite rigorous methodological approaches. While the findings are largely negative, the identification of potential benefits in specific patient subsets offers a pathway for refining PKI therapy. Future research should prioritize biomarker-driven trials, focus on agents with enhanced BBB penetration, and explore novel combination strategies. The ultimate challenge lies in overcoming the heterogeneity and treatment resistance characteristic of GBM, which remain formidable barriers to improving patient outcomes.

Systematic Reviews

Schettini et al. conducted a systematic review and Bayesian trial-level network metaanalysis (NMA) to identify the regimens associated with the best outcomes. The primary endpoint was overall survival (OS). Secondary endpoints were progression-free survival (PFS) and overall response rates (ORR). They estimated separate treatment rankings based on the surface under the cumulative ranking curve values. Only phase II/III prospective comparative trials were included.

Twenty-four studies (3733 patients and 27 different therapies) were ultimately included. Twenty-three different regimens were compared for OS, 21 for PFS, and 26 for ORR. When taking lomustine as a common comparator, only regorafenib was likely to be significantly superior in terms of OS (hazard ratio: 0.50, 95% credible interval: 0.33-0.75). Regorafenib was significantly superior to other 16 (69.6%) regimens, including NovoTTF-100A, bevacizumab monotherapy, and several bevacizumab-based combinations. Regarding PFS and ORR, no treatment was clearly superior to the others.

This NMA supports regorafenib as one of the best available options for relapsing/refractory glioblastoma. Lomustine, NovoTTF-100A, and bevacizumab emerge as other viable alternative regimens. However, evidence on regorafenib is controversial at best. Moreover, most studies were underpowered, with varying inclusion criteria and primary endpoints, and no longer adapted to the most recent glioblastoma classification. A paradigmatic change in clinical trials’ design for relapsing/refractory glioblastoma and more effective treatments are urgently required 2)

Schettini et al.’s systematic review and Bayesian NMA make an important contribution to understanding the relative efficacy of available therapies for relapsing/refractory GBM, particularly by highlighting regorafenib as a potentially effective option. However, the study is hindered by limitations inherent to the included trials and the analytical framework, including the heterogeneity of studies, underpowered designs, and outdated glioblastoma classifications.

The findings underscore the pressing need for a paradigm shift in GBM clinical trials. Future research should prioritize large, well-powered, multicenter trials incorporating molecularly stratified patient cohorts and harmonized endpoints. Additionally, the exploration of novel therapeutic strategies is critical to advancing the treatment landscape for this devastating disease. While regorafenib appears promising, its clinical utility must be validated in robust, contemporary trials to establish its place in the therapeutic arsenal for GBM.

Retrospective Studies

In a retrospective study, Kebir et al. investigated the efficacy and radiographic tumor growth patterns of regorafenib in recurrent high-grade astrocytoma.

They screened for patients with a high-grade astrocytoma in whom regorafenib was administered for at least 4 weeks. We assessed treatment efficacy in terms of progression-free survival (PFS), overall survival, and adverse events defined by Common Toxicity Criteria (CTC). In addition, radiographic tumor growth patterns were determined at baseline and recurrence.

A total of 6 patients met the eligibility criteria. The number of recurrences prior to regorafenib varied between 2 and 6. Patients were on regorafenib treatment for at least 4 weeks and maximally 14 weeks. Median PFS was 3.5 months and ranged from 2.0 to 4.0 months. Radiographic response was progressive disease in all patients with an objective response rate of 0%. CTC°3 adverse events were observed in all but one patient. The most common radiographic growth pattern was local with no change in growth pattern at recurrence. An infiltrative tumor growth was not induced in any patient.

This retrospective study indicates the very poor performance of regorafenib in recurrent high-grade astrocytoma with a fairly high number of CTC°3 adverse events. In addition, regorafenib does not seem to bear a potential for infiltrative tumor growth promotion 3).

1)

Pinto-Fraga J, García-Chico C, Lista S, Lacal PM, Carpenzano G, Salvati M, Santos-Lozano A, Graziani G, Ceci C. protein kinase inhibitors as Targeted therapy for glioblastoma: A meta-analysis of randomized controlled clinical trials. Pharmacol Res. 2024 Dec 3:107528. doi: 10.1016/j.phrs.2024.107528. Epub ahead of print. PMID: 39637954.
2)

Schettini F, Pineda E, Rocca A, Buché V, Donofrio CA, Mazariegos M, Ferrari B, Tancredi R, Panni S, Cominetti M, Di Somma A, González J, Fioravanti A, Venturini S, Generali D. Identifying the best treatment choice for relapsing/refractory glioblastoma: a systematic review with multiple Bayesian network meta-analyses. Oncologist. 2024 Dec 14:oyae338. doi: 10.1093/oncolo/oyae338. Epub ahead of print. PMID: 39674575.
3)

Kebir S, Rauschenbach L, Radbruch A, Lazaridis L, Schmidt T, Stoppek AK, Pierscianek D, Stuschke M, Forsting M, Sure U, Keyvani K, Kleinschnitz C, Scheffler B, Glas M. Regorafenib in patients with recurrent high-grade astrocytoma. J Cancer Res Clin Oncol. 2019 Apr;145(4):1037-1042. doi: 10.1007/s00432-019-02868-5. Epub 2019 Feb 28. PubMed PMID: 30820715.

Effects of paroxetine, a P2X4 inhibitor, on cerebral aneurysm growth and recanalization after coil embolization: the NHO Drug for Aneurysm Study

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A study, published in the Journal of Neurosurgery, investigates the effect of paroxetine, a P2X4 inhibitor, on the growth and recurrence (recanalization) of cerebral aneurysms following coil embolization. Despite being primarily used as an antidepressant, paroxetine’s inhibition of the P2X4 purinoceptor appears to influence vascular responses, which the authors propose could be protective against aneurysm progression and recurrence 1)

Study Objectives and Rationale The authors address a critical gap in the management of cerebral aneurysms, which, despite increased coil embolization procedures, face a high risk of recurrence compared to surgical clipping. Given that hemodynamic stress on the aneurysm wall is a known factor in aneurysm progression, and P2X4 purinoceptor inhibition appears to counteract these stress responses, this study is scientifically grounded in exploring the secondary effects of paroxetine. Prior animal studies that supported reduced aneurysm induction and growth through P2X4 inhibition provide a basis for this human observational study.

Methodology The study utilized Japan’s J-ASPECT Stroke Registry to analyze data retrospectively, identifying patients who were prescribed paroxetine and who had either unruptured cerebral aneurysms or had undergone coiling. A rigorous approach was taken, comparing these patients against matched controls over a decade, with multivariate and propensity score-matched analyses strengthening the study’s internal validity by reducing confounding variables.

Key Metrics: Growth incidence and growth rate for unruptured aneurysms. Odds ratio (OR) for aneurysm recanalization within one year of coiling. Results The results suggest that paroxetine was significantly associated with reduced aneurysm growth and recanalization:

Aneurysm growth incidence and rate showed reductions, with incidence rate ratios (IRR) substantially favoring paroxetine use (IRR for growth incidence: 0.24; for growth rate: 0.57). Paroxetine lowered the odds of recanalization one year post-coiling (OR: 0.21). Propensity score matching yielded even more striking results, supporting the robustness of the findings (growth incidence IRR: 0.02, and recanalization OR: 0.18). Strengths Large Dataset: Using the extensive J-ASPECT registry allows for a broad patient sample and enhances the study’s statistical power. Robust Statistical Controls: Multivariate analysis and propensity score matching help address potential biases, lending credibility to the associations found. Clinical Applicability: The study opens up a pathway for potential pharmaceutical intervention, especially given paroxetine’s established use and safety profile. Limitations Retrospective Design: Observational studies inherently have limitations in establishing causation, which might limit the clinical applicability of findings without further prospective trials. Selection Bias and Confounders: Despite statistical adjustments, unmeasured confounders related to patient health status, comorbidities, or the precise dosage and adherence to paroxetine may still influence results. Generalizability: This study is based on a Japanese cohort, and cultural or healthcare system differences might impact the generalizability to other populations. Clinical Implications If confirmed through prospective studies, the use of paroxetine or other P2X4 inhibitors could offer a novel approach to managing aneurysm growth and preventing recurrence after coiling, potentially improving patient outcomes. However, the potential side effects and the drug’s primary use as an antidepressant might limit its broad applicability without further targeted research into P2X4 inhibition.

Conclusion This study contributes promising preliminary evidence that paroxetine, as a P2X4 inhibitor, could have a significant role in aneurysm management. Nevertheless, more robust, prospective clinical trials are necessary to confirm these findings and fully establish the drug’s efficacy and safety for this indication.

1)

Fukuda S, Niwa Y, Ren N, Yonemoto N, Kasahara M, Yasaka M, Ezura M, Asai T, Miyazono M, Korai M, Tsutsumi K, Shigeta K, Oi Y, Nishimura A, Fukuda H, Goto M, Yoshida T, Fukuda M, Yasoda A, Iihara K. Effects of paroxetine, a P2X4 inhibitor, on cerebral aneurysm growth and recanalization after coil embolization: the NHO Drug for Aneurysm Study. J Neurosurg. 2024 Oct 25:1-8. doi: 10.3171/2024.6.JNS24714. Epub ahead of print. PMID: 39454214.

Anti-Inflammatory Thrombolytic JX10 (TMS-007) in Late Presentation of Acute Ischemic Stroke

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The investigational drug TMS-007 (now branded JX10), developed as a novel thrombolytic agent for acute ischemic stroke, has been heralded for its potential to expand the therapeutic window for treatment. However, despite the initial enthusiasm surrounding its clinical development, there are numerous critical flaws in both the study design and the interpretation of the findings that undermine its promise as a groundbreaking stroke therapy.

First, the methodology of the Phase 2a study raises substantial concerns. While the randomized, double-blind, placebo-controlled design is theoretically robust, the small sample size (90 patients) severely limits the generalizability of the findings. With such a small cohort, the study lacks statistical power to make definitive conclusions about the true efficacy and safety of JX10. Moreover, the stratification of patients by dose (1, 3, or 6 mg/kg) and gender (with a skewed distribution of females across doses) introduces an additional layer of complexity and potential bias that goes unaddressed in the analysis. This lack of statistical rigor leaves the results open to question.

The primary endpoint, the incidence of symptomatic intracranial hemorrhage (sICH), demonstrated no significant difference between JX10 and placebo (0% vs. 2.6%, respectively). The authors highlight this as a favorable outcome, but the fact that such a small incidence of sICH was observed in both groups calls into question the clinical relevance of this outcome. With so few patients experiencing a clinically meaningful event, the observed lack of difference between groups is not as compelling as it may initially appear. This failure to show a significant reduction in sICH, an important safety endpoint, undermines the argument that JX10 is substantially safer than existing thrombolytics.

Furthermore, while vessel patency at 24 hours was reportedly improved in patients receiving JX10, the difference between the groups (58.3% vs. 26.7%) was modest at best. The odds ratio of 4.23, while statistically significant, is misleading without further context. The actual clinical significance of such a finding remains uncertain, as vessel reopening does not necessarily equate to improved functional outcomes. The secondary endpoint of modified Rankin Scale scores also demonstrates a modest benefit for JX10, with 40.4% of patients achieving a score of 0-1 versus 18.4% for placebo. While statistically significant, the clinical impact of this difference is questionable given the early nature of stroke treatment, the small sample size, and the inherent variability in patient recovery.

One of the more concerning aspects of the study is the lack of long-term follow-up. Stroke patients who receive thrombolytic treatment face a range of risks, and it is essential to understand the longer-term outcomes of therapies like JX10, including mortality, disability, and quality of life. The absence of these critical data points further weakens the study’s conclusions, as it provides a limited snapshot of the therapy’s true impact.

Finally, the novel mechanism of action for JX10, which involves modulating plasminogen conformation and inhibiting soluble epoxide hydrolase, remains speculative. The proposed benefits of enhanced endogenous fibrinolysis and anti-inflammatory properties are interesting, but there is insufficient evidence to support their clinical relevance in the context of acute ischemic stroke. The mechanism may sound promising in theory, but without more robust data from larger studies, these claims remain unsubstantiated.

In conclusion, while JX10 has shown some potential in expanding the therapeutic window for acute ischemic stroke treatment, the current clinical evidence does not justify the enthusiasm surrounding its future. The small sample size, the lack of meaningful safety and efficacy differences, and the absence of long-term data all point to the need for much more rigorous studies before this drug can be considered a viable treatment option. As it stands, JX10 remains an unproven, underdeveloped therapy with far too many unanswered questions to be hailed as the next generation of stroke treatment.