Abstract

Brain Stroke and its Effective Treatment-A stroke happens when a vein in the mind cracks and drains, or when there's a blockage in the blood supply to the cerebrum. The burst or blockage keeps blood and oxygen from arriving at the mind's tissues. Without oxygen, synapses and tissue become harmed and start to pass on in practically no time. The indications of a stroke fluctuate contingent on the zone of the mind influenced by an absence of oxygen. All strokes include manifestations that identify with impedance of nerve work. The indications ordinarily emerge abruptly and most generally happen on one side of the body. Symptoms and signs of stroke can include weakness, vision loss or changes, Confusion, changes in the level of consciousness, trouble speaking, trouble understanding speech, Headache vomiting sometimes accompany a stroke, particularly when the stroke involves bleeding inside the brain. Recently, Trofinetide was approved by the USFDA on 10 March 2023 as the first RTT treatment. This article underlines the pharmaceutical advancement, patent literature, and prospects of Trofinetide. The data for this study were gathered from the PubMed database, authentic websites (Acadia Pharmaceuticals, Neuren Pharmaceuticals, and USFDA), and free patent databases. Trofinetide was first disclosed by Neuren Pharmaceuticals in 2000 as a methyl group containing analog of the naturally occurring neuroprotective tripeptide called glycine-proline-glutamate (GPE). The joint efforts of Acadia Pharmaceuticals and Neuren Pharmaceuticals have developed Trofinetide. The mechanism of action of Trofinetide is not yet well established. However, it is supposed to improve neuronal morphology and synaptic functioning. The patent literature revealed a handful of inventions related to Trofinetide, providing excellent and unexplored broad research possibilities with Trofinetide. The development of innovative Trofinetide-based molecules, combinations of Trofinetide, patient-compliant drug formulations, and precise MECP2-mutation-related personalized medicines are foreseeable

Keywords

Brain Stroke, oxygen, synapses and tissue, cerebrum.

Introduction

       
           
       
 Fig :no. 1:  Causes of heart & brain stroke.

• Third most common cause of death after cancer and   ischeamic heart disease

       
           
       
    Fig no.:2 classification of  brain stroke.

? Ischemic strokes

       
           
       
Fig.no: 3 blood clot by brain stroke in different segments of brain.

? Ischemic stroke is the most common form of stroke, accounting for around 85% of strokes.

       
           
       
    Fig .no:4 causes of brain stroke

? Speech difficulty: if the person tries to repeat a simple phrase is their speech slurred or strange?

       
           
       
    Fig.no:5 ischemic stroke & ICH trails

• Some old drugs used to treat brain stroke include aspirin, rapamycin, and noradrenergic drugs:

Aspirin: A well-known antiplatelet drug that reduces the risk of stroke recurrence and severity. It's often given to patients immediately after an ischemic stroke.

Rifampacin: An old drug that may improve neurovascular function by inhibiting mTOR.

 Noradrenergic drugs: A lass of drugs that may promote stroke recovery by amplifying neuronal activity and increasing excitability.

Other drugs used to treat stroke include:

Clopidogrel: An antiplatelet drug that may be used after aspirin

Dipyridamole: An antiplatelet drug that may be used after aspirin

Ticagrelor: An antiplatelet drug

Cilostazol: An antiplatelet drug

Ticlopidine: An antiplatelet drug

Lorazepam (Ativan): A short-acting benzodiazepine used to treat active seizures  Diazepam (Valium): A drug that produces a calming effect and is used to control active seizures active.

9. Recently The New Drug Approved By Fda For Brain Stroke “Daybue”:

• Generic Name: trofinetide oral solution
• Brand Name: Daybue
• Drug Class: Insulinlike Growth Factors

Drug Summary

5. What Is Daybue?

Daybue (trofinetide) is indicated for the treatment of Rett syndrome in adults and pediatric patients 2 years of age and older.

• What Are Side Effects of Daybue?

Daybue may cause serious side effects including:

5. hives,
5. difficulty breathing,
5. swelling of your face, lips, tongue, or throat,
5. fever,
5. seizure,
5. anxiety,
5. loss of appetite,
5. fatigue, and
5. cold symptoms (runny nose, sneezing, and coughing)

• Side effects of Daybue include:

• diarrhoea,
• vomiting,
• weight loss,
• fever,
• seizures,
• anxiety,
• decreased appetite,
• fatigue, and
• runny or stuffy nose.

Seek medical care or call 911 at once if you have the following serious side effects:

Serious eye symptoms such as sudden vision loss, blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights; Serious heart symptoms such as fast, irregular, or pounding heartbeats; fluttering in your chest; shortness of breath; and sudden dizziness, lightheadedness, or passing out; Severe headache, confusion, slurred speech, arm or leg weakness, trouble walking, loss of coordination, feeling unsteady, very stiff muscles, high fever, profuse sweating, or tremors.

This document does not contain all possible side effects and others may occur. Check with your physician for additional information about side effects.

5. Dosage for Daybue

The recommended dosage of Daybue is twice daily, morning and evening, according to the patient’s weight. Daybue can be taken with or without food.

10. Daybue in Children:

The safety and effectiveness of Daybue for the treatment of Rett syndrome have been established in pediatric patients aged 2 years and older.  The safety and effectiveness of Daybue in pediatric patients less than 2 years of age have not been established. What Drugs, Substances, or Supplements Interact with Daybue?   Daybue may interact with other medicines such as: CYP3A4 substrates and OATP1B1 and OATP1B3 substrates. Tell your doctor all medications and supplements you use. Daybue During Pregnancy and Breastfeeding

Tell your doctor if you are pregnant or plan to become pregnant before using Daybue; it is unknown if it would affect a fetus. It is unknown if Daybue passes into breast milk. Consult your doctor before breastfeeding.

Additional Information

Our Daybue (trofinetide) Oral Solution Side Effects Drug Center provides a comprehensive view of available drug information on the potential side effects when taking this medication.

5. Side Effects for Daybue

The following clinically significant adverse reactions are described elsewhere in labeling:

Diarrhea [See Warnings And Precautions]

Weight Loss [See Warnings And Precautions]

11. Clinical Trials Experience:

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In controlled and uncontrolled trials in patients with Rett syndrome, 260 patients ages 2 to 40 years were treated with DAYBUE, including 109 patients treated for more than 6 months, 69 patients treated for more than 1 year, and 4 patients treated for more than 2 years. Adult And Pediatric Patients With Rett Syndrome 5 Years Of Age And Older The safety of DAYBUE was evaluated in a randomized, double-blind, placebo-controlled, 12-week study of patients with Rett syndrome (Study 1) [see Clinical Studies]. In Study 1, 93 patients received DAYBUE and 94 patients received placebo. All patients were female, 92% were White, and the mean age was 11 years (range 5 to 20 years). Adverse Reactions Leading to Discontinuation of Treatment Eighteen patients (19%) receiving DAYBUE had adverse reactions that led to withdrawal from the study. The most common adverse reaction leading to discontinuation of treatment with DAYBUE was diarrhoea (15%).

5. Effect of DAYBUE on other drugs:

Trofinetide is a weak CYP3A4 inhibitor; therefore, plasma concentrations of CYP3A4 substrates may be increased if given concomitantly with DAYBUE [see CLINICAL PHARMACOLOGY]. Closely monitor when DAYBUE is used in combination with orally administered CYP3A4 sensitive substrates for which a small change in substrate plasma concentration may lead to serious toxicities.

Plasma concentrations of OATP1B1 and OATP1B3 substrates may be increased if given concomitantly with DAYBUE [see CLINICAL PHARMACOLOGY]. Avoid the concomitant use of DAYBUE with OATP1B1 and OATP1B3 substrates for which a small change in substrate plasma concentration may lead to serious toxicities.

5. Warnings for Daybue:

Included as part of the "PRECAUTIONS" Section

5. Precautions for Daybue:

• Diarrhoea

In Study 1 [see Clinical Studies] and in long-term studies, 85% of patients treated with DAYBUE experienced diarrhoea. In those treated with DAYBUE, 49% either had persistent diarrhoea or recurrence after resolution despite dose interruptions, reductions, or concomitant antidiarrheal therapy. Diarrhoea severity was of mild or moderate severity in 96% of cases. In Study 1, antidiarrheal medication was used in 51% of patients treated with DAYBUE. Advise patients to stop laxatives before starting DAYBUE. If diarrhoea occurs, patients should notify their healthcare provider, consider starting antidiarrheal treatment, and monitor hydration status and increase oral fluids, if needed. Interrupt, reduce dose, or discontinue DAYBUE if severe diarrhoea occurs or if dehydration is suspected [see DOSAGE AND ADMINISTRATION].

• Weight Loss:

In Study 1, 12% of patients treated with DAYBUE experienced weight loss of greater than 7% from baseline, compared to 4% of patients who received placebo. In long-term studies, 2.2% of patients discontinued treatment with DAYBUE due to weight loss. Monitor weight and interrupt, reduce dose, or discontinue DAYBUE if significant weight loss occurs.

• Patient Counselling Information

Advise the caregiver or patient to read the FDA-approved patient labelling (PATIENT INFORMATION).

12. Daybue Administration:

Advise the caregiver or patient that DAYBUE may be given orally or via gastrostomy (G) tube; doses administered via gastrojejunal (GJ) tubes must be administered through the G-port. DAYBUE may be taken with or without food [see DOSAGE AND ADMINISTRATION]. Instruct the caregiver or patient to obtain a calibrated measuring device, such as an oral syringe or oral dosing cup, from the pharmacy to measure and deliver the prescribed dose accurately. A household measuring cup is not an adequate measuring device.

Instruct the caregiver or patient to discard any unused DAYBUE after 14 days of first opening the bottle.

5. Diarrhoea:

Advise the caregiver or patient that DAYBUE can cause Diarrhoea. Instruct the patient to stop taking laxatives before starting DAYBUE. If diarrhoea occurs, patients should notify their healthcare provider, consider starting antidiarrheal treatment, and monitor hydration status and increase oral fluids, if needed [see WARNINGS AND PRECAUTIONS].

5. Weight Loss:

Inform the caregiver or patient that DAYBUE may cause weight loss and to notify their healthcare provider if weight loss occurs [see WARNINGS AND PRECAUTIONS].

5. Vomiting:

Advise the caregiver or patient that DAYBUE can cause vomiting and if vomiting occurs after DAYBUE administration, do not take an additional dose, but continue with the next scheduled dose.

13. Storage:

Keep bottles of DAYBUE oral solution upright and refrigerated before and after opening. Do not freeze [see HOW SUPPLIED].

• Nonclinical Toxicology:

Carcinogenesis, Mutagenesis, Impairment Of Fertility

• Carcinogenesis:

Studies to evaluate the carcinogenic potential of trofinetide have not been conducted.

• Mutagenesis:

Trofinetide was negative in in vitro (bacterial reverse mutation, chromosomal aberration in Chinese hamster ovary cells) and in vivo (mouse micronucleus) assays.

14. Pediatric Use:

The safety and effectiveness of DAYBUE for the treatment of Rett syndrome have been established in pediatric patients aged 2 years and older. The safety and effectiveness of DAYBUE for the treatment of Rett syndrome in pediatric patients 5 years of age and older was established in a randomized, double-blind, placebo-controlled, 12-week study (Study 1), which included 108 pediatric patients age 5 to less than 12 years of age and 47 pediatric patients age 12 to less than 17 years of age [see ADVERSE REACTIONS and Clinical Studies]. Use of DAYBUE in patients 2 to 4 years of age is supported by evidence from Study 1 and pharmacokinetic and safety data in 13 pediatric patients 2 to 4 years of age treated with DAYBUE for 12 weeks [see DOSAGE AND ADMINISTRATION, ADVERSE REACTIONS, CLINICAL PHARMACOLOGY , and Clinical Studies]. Safety and effectiveness in pediatric patients less than 2 years of age have not been established.

5. Mechanism Of Action:

The mechanism by which trofinetide exerts therapeutic effects in patients with Rett syndrome is unknown.

5. Pharmacodynamics

Cardiac Electrophysiology

At the maximum recommended dose in healthy adult subjects, DAYBUE does not prolong the QT interval to any clinically relevant extent.

5. Pharmacokinetics:

Trofinetide exhibits linear kinetics with no time- or dose-dependent effect on pharmacokinetic parameters. Systemic exposure to trofinetide was dose-proportional across the studied dose range. Minimal to no accumulation was observed following multiple-dose administration.

5. Absorption:

The time to maximum drug concentration (Tmax) is about 2 to 3 hours after administration. Based on the mass balance study, at least 84% of the administered dose was absorbed following oral administration of 12,000 mg trofinetide.

5. Effect of Food:

Coadministration of DAYBUE with a high-fat meal had no impact on the total exposure (AUC0-inf) of trofinetide and reduced the peak plasma concentration (Cmax) by approximately 20% [see DOSAGE AND ADMINISTRATION].

5. Distribution:

Following oral administration, the apparent volume of distribution of trofinetide in adult healthy subjects was approximately 80 L. Trofinetide protein binding in human plasma is less than 6%.

5. Elimination:

The effective elimination half-life of orally administered trofinetide in healthy subjects is about 1.5 hours.

5. Metabolism:

Trofinetide is not significantly metabolized by CYP450 enzymes. Hepatic metabolism is not a significant route of trofinetide elimination.

5. Excretion:

Trofinetide is primarily excreted unchanged (approximately 80% of the dose) in urine, with minor excretion in feces.

• Specific Populations:

The drug exposure of trofinetide in pediatric patients ages 2 to 4 years of age is similar to children older than 4 years and adults when following the recommend dosage [see DOSAGE AND ADMINISTRATION]. The pharmacokinetics in patients with renal impairment have not been studied [see Use In Specific Populations]. The pharmacokinetics in patients with hepatic impairment have not been studied. However, hepatic impairment is not expected to impact the exposure of trofinetide because hepatic metabolism is not a significant route of trofinetide elimination.

15. Drug Interaction Studies:

• In Vitro:

Trofinetide is not a substrate of CYP450 enzymes, uridine diphosphate glucuronosyltransferase (UGT), or major drug transporters. Therefore, coadministration of drugs that are inducers or inhibitors of CYP450, UGT, or major drug transporters will not significantly affect the systemic exposure of trofinetide.

Trofinetide is a weak CYP3A4 inhibitor. Using physiologically based pharmacokinetic modeling, coadministration of trofinetide with orally administered midazolam, a sensitive CYP3A4 substrate, was predicted to increase the AUC of midazolam by approximately 1.33-fold [see DRUG INTERACTIONS]. No inhibition on CYP450 enzymes, CYP1A2, 2C8, 2C9, 2C19, and 2D6, is expected at therapeutic systemic concentrations based on the in vitro assays and the static mechanistic models. Time-dependent inhibition on CYP2B6 was inconclusive based on in vitro data. DAYBUE inhibits UGT enzymes, UGT1A9, 2B7, and 2B15, in vitro. No inhibition was observed at therapeutic systemic concentrations on P-gp, BCRP, BSEP, OAT1, OAT3, OCT2, MATE1, and MATE2-K, based on the in vitro assays. Trofinetide inhibits OATP1B1 and OATP1B3 in vitro [see Drug Interactions].

• In Vivo:

There have been no in vivo assessments of drug interactions with trofinetide.

• Clinical Studies:

The efficacy of DAYBUE for the treatment of Rett syndrome was established in a 12-week randomized, double-blind, placebo-controlled study in patients with Rett syndrome 5 to 20 years of age (Study 1; NCT04181723). Patients (N=187) had a diagnosis of typical Rett syndrome according to the Rett Syndrome Diagnostic Criteria with a documented disease-causing mutation in the MECP2 gene. Patients were randomized to receive DAYBUE (N=93) or matching placebo (N=94) for 12 weeks. The DAYBUE dosage was based on patient weight to achieve similar exposure in all patients [see DOSAGE AND ADMINISTRATION]. The co-primary efficacy measures were change from baseline after 12 weeks of treatment in the total score of the Rett Syndrome Behaviour Questionnaire (RSBQ) and the Clinical Global Impression-Improvement (CGI-I) score. The RSBQ is a 45-item rating scale completed by the caregiver that assesses a range of symptoms of Rett syndrome (breathing, hand movements or stereotypies, repetitive behaviors, night-time behaviors, vocalizations, facial expressions, eye gaze, and mood). Each item is scored as 0 (not true), 1 (somewhat or sometimes true), or 2 (very true or often true), with a maximum possible score of 90 points. Lower scores reflect lesser severity in signs and symptoms of Rett syndrome. The CGI-I is rated by clinicians to assess whether a patient has improved or worsened on a 7-point scale (1=very much improved to 7=very much worse) in which a decrease in score indicates improvement.

 

CONCLUSION:

Acute therapy for ischaemic stroke is now a reality with advances in treatment progressing rapidly. New information about several neuroprotective agents will soon be available, and it is highly likely that the use of these agents will be integrated into many areas of vascular neurology. Acute stroke is more than ever a medical emergency that requires a rapid response by emergency medical services teams and neurologists. Nihilistic attitudes about stroke treatment are now archaic because the future holds much promise for stroke patients. Trofinetide’s recent USFDA approval marks a significant step forward in treating RTT. Patients and their families affected by RTT would benefit greatly from this approval since they have had few alternatives for alleviating the wide range of symptoms that this condition can bring. The approval of Trofinetide will also speed up the development of new treatments and inventions for RTT and related disorders (FXS, ASD, brain injury, and stroke). Innovative Trofinetide-based molecules, patient-compliant formulations, precise MECP2-mutation-related personalized medicines, and new combinations of Trofinetide with existing RTT-based treatments, CNS-acting drugs, NSAIDs, and immunomodulators (antioxidants) are all likely shortly

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