INTRODUCTION:

Narcolepsy is a sleep disorder that makes a person very drowsy during the day. Person with narcolepsy find it hard to stay awake for long periods of time. Person may fall asleep suddenly. This may cause serious problems in their daily routine. Sometime narcolepsy causes a sudden loss of muscle tone K/a Cataplexy (KAT- uh – plek-see). This can be triggered by strong emotion, especially laughter¹.

There are two types of narcolepsies 1. Narcolepsy with cataplexy – Type 1

2. Narcolepsy without cataplexy – Type 2

In a normal sleep cycle, a person enters rapid eye movement (REM) sleep after about 1 or 1.5 hr.

Dreams occur during REM sleep and musclehobble during sleep stage, which prevents a person from acting out their dreams. The person with narcolepsy frequently enter with REM sleep rapidly and falling asleep within 15 minutes with muscle weakness or dream activity of REM sleep can occur during wakefulness or be absent during sleep².

The most common symptoms of narcolepsy both day time and night time includes:

1. Excessive day time sleeping (EDS)– Its urge to sleep, its irresistible and monotonous situation.

2. Automatic behaviors – Behave while a person is unaware, for example, a student in class may continue writing but are actually just scrawling lines or gibberish over the page.

3. Disrupted night time sleep – Its common person may awaken multiple times during the night. Other problem like excessive physical movement and sleep apnea are also common with narcoleptics.

4. Sleep Paralysis – Narcoleptics have higher rate of feeling of being unable to more that occurs. While falling asleep or waking up.

5. Sleep – related hallucinations – Realistic image can occur while falling asleep or when waking up. This may followed by sleep paralysis.

6. Cataplexy – Cataplexy is a sudden loss of muscle control^3,4.

Narcolepsy Symptoms in Children:

There is considerable overlapping between symptoms in children and adults but some differences are also there. Children may sleep longer and have more active body movement during sleep. Cataplexy is more complex in children (80%). It commonly involves the face rather than body and may be perceived as facial tics^3,4.

What causes Narcolepsy:

Researches are going on but the exact causes and risk factors for each condition are not fully understood.

Narcolepsy Type 1 – Due to loss of neurons (90%) in brain that are responsible for making hypocretin, also known as orexin, a chemical substance that helps to regulate wakefulness and sleep. It may be due to brain injury or infection, genetically, autoimmune fashion due to environmental trigger and in some evidences influenza virus infection increase the NT1.

Narcolepsy Type 2 –Person with NT2 have similar symptoms as people with NT1, but do not show low level of hypocretin or do not have cataplexy. If cataplexy or low hypocretin levels develop than diagnosis can be reclassified as NT1. This change in diagnosis occurs only in 10% cases.

Other variety of causes are there – An acquired heredity issue, psychological pressure, flu virus immunization, a disease like swineflu or streptococcal infection, hormonal changes and a sudden change in sleep patterns ^5,6.

How Narcolepsy effects:

1. Accidents may occur due to sleep attacks and cataplexy can be life threatening when driving or environment there is no safety. Four to five times narcoleptics are more likely to be involved in Car accidents.

2. It also interferes with school and work without proper support, this may contribute to mental Health disorders (may affect negatively).

3. These patients are also associated with obesity, cardiovascular problems like high B.P. and psychiatric issues like depression, anxiety, attention deficit etc^5,6.

How common is narcolepsy:

Various researches showed that it affects 25 to 50 people out of every 1,000 worldwide. However, actual numbers is difficult to estimate due to delayed diagnosis.

Stages of narcolepsy:

Human sleep cycle involves following stages

Stage 1 – Light sleep (5% of total sleep)

Stage 2 – Deeper sleep (45% to 50% of all the time you spend for sleep and number goes with age)

Stage 3 – Slow wave sleeps (25% of the time you spend on sleeping, this number goes down with stage. It’s very hard to wake someone up in this stage and walking up directly from it usually causes “sleep inertia” a state where sleep walking or sleep talking typically happens.

RE sleep – “Rapid eye movement” it’s a stage when you dream, at this time your eyes moving beneath their eyelids.

In normal cases, a person enters stage 1, 2 and 3 then start dreaming. After REM cycle, you start a new cycle and go back into same stages. One cycle takes 90 mints before another begin and normal people go through 4 to 5 cycles per night. If you have narcolepsy, no matter how well you sleep at night, you’ll feel extremely sleepy during the daytime, impossible to resist, but this sleep periods are also short (about 15 to 30 mints) during the day. Once you wake up, you will feel rested and ready resume whatever you were doing before. However, this happens several times the day which is why narcolepsy is so disruptive^5,6.

Diagnosis of Narcolepsy:

Test may be conducted to evaluate EDS and sleep-

1. EP worth sleepiness scale (ESS) - It’s based on the patient’s subjective sense of their symptoms.

2. Polysomnography (PSG) - A detailed test in which sensors monitor brain and body activity, may be necessary. This study is done overnight in a specialized clinic.

3. Multiple Sleep Latency Test – Objective of test to assess sleepiness. In this study, the patient is instructed to try to fall asleep at five different intervals while remaining connected to sensors used in the PSG. Narcolepsy patient fall asleep quickly and to rapidly begin REM sleep during the MSLT.

4. Cerebrospinal Fluid (CSF) - Removed of CSF and to assess its level of hypocretin. This is done with procedure called a spinal tap or lumbar puncture. Low levels of hypocretin are indicative of narcolepsyType 1 and helps in distinguished it from narcolepsy Type 2^5,6,7.

How narcolepsy is treated and is there a cure?

Medication is the main method for treating narcolepsy. Most medications work a daytime sleep but also target other symptoms.

1. Wakefulness medications - It’s a first line treatment. These medications stimulate nervous system which reduces severity or frequency of the daytime sleep examples Modafinil or Armodafinil.

2. Amphetamines and amphetamines like stimulant drugs which increases dopamine and serotonin levels in the synaptic cleft through a variety of mechanisms. Examples Ritalin or Adderall.

3. Antidepressants – Medications like serotonin, norepinephrin reuptake inhibitors such as Venlafaxine, Fluxoxatine or Tricyclic antidepressants like Clomipramine.

4. Sodium oxybate – This drug activates the GABA_B receptor and suppresses dopaminergic neuronal activity, leading to an increase in slow wave sleep and a decrease in awakenings at night. Improved sleep efficiency is the end results.

5. Histamine affecting drugs – This are histamine receptor agonist increase the level of histamine and enhance activity of histaminergic neurons thereby promotes wakefulness example Pitolisant.

We can choose multiple options but for children options are limited pediatrician or specialist advice will be best in narcolepsy cases^5,6,7.

Complications or side effects related to narcolepsy treatment:

Many medicines are used to treat narcolepsy more likely to interact with other drugs or alcohol and can show significant side effects. Researchers are studying other potential treatments for narcolepsy. Medicines and its dosage form being studied include those that target hypocretin chemical system. Researchers also are studying novel drug delivery system to overcome the side effects related to therapy. Further researches are needed to make treatment more efficacious.

Novel Drug Delivery System:

First we should know what is drug delivery system? It can be understood as a method or process of administering or delivering a pharmaceutical active compound in systemic circulation to get desired therapeutic response in humans or animals. Types of drug delivery systems are –

1. Conventional or traditional drug delivery system.

2. Novel drug delivery system

Conventional drug delivery systems are the classic methods for the delivery of drugs into the body. Generally non-invasive routes are there peroral routes (through the mouth), the topical route (through the skin), the transmucosal route (through nasal, ocular, vaginal, sublingual, rectal) and inhalation routes. Conventional drug delivery system also have some limitations frequent dosing so chances of missing dose and fluctuation in plasma peak and valley effect. Due to fluctuation in plasma concentration we are in need of a Novel Drug Delivery System which maintains the concentration of drug within the therapeutic window in order to minimize undesired effects and maximize therapeutic benefits. Many other drugs are not taken by conventional drug delivery system like proteins, peptides, antibiotic, vaccines and gene based drugs undergoes enzymatic degradation or drugs shows poor bioavailability or poor penetration through intestinal mucosa. In order to overcome aforementioned problems, a novel drug delivery system has been introduced.

Novel drug delivery systems are nonconventional, nontraditional, newer way of drug delivery other than conventional drug delivery. A novel drug delivery system can be defined as a new approach or methodology that combines innovative development, new technologies and novel methodologies for delivering pharmaceutical active moiety in the body as needed to safely achieve its desired therapeutic and pharmacologic effects. It may include site specific targeting within body, improves drug potency, control drug release with prolong therapeutic effect. It involves the development of novel and safer drug delivery system with increased biological half life and large therapeutic indices.

Drug targeting to brain:

The blood brain barrier (BBB) is a great hurdle for delivery of drugs to the brain. This barrier is a diffusion barrier essential for protecting normal brain function by restricting entry of most compounds from blood to the brain; only small molecules can cross BBB. In certain pathological conditions BBB gets disturbed. This review could inspire readers to discover possible approaches to deliver drugs to the brain in Narcolepsy and to develop new drug delivery system to reduce drug related side effects.

Problems encountered in brain targeted drug delivery:

1. Small amount of drug passes the BBB.

2. Protein binding of the drug in other parts of body rendering drug ineffective.

3. Presence of enzymes in brain that could render the drug inactive.

Strategies for brain targeted drug delivery:

Numerous drug delivery systems have been developed to overcome the multitude of barriers restricting CNS drug delivery of potential therapeutic agents. These strategies divided into following categories-

A. Invasive

· Intracerebroventricular (ICV) infusion

· Convection-enhanced delivery (CED)

· Intra-cerebral injection or implants

· Disruption of the BBB.

B. Non-invasive

· Chemical techniques

a. Prodrug

· Colloidal Techniques

a. Nanoparticles

b. Liposomes.

C. Miscellaneous techniques a. Intranasal delivery

Recent Advances in brain targeting⁸

1. Dendrimer

2. Scaffolds

3. Lipoplexes and polyplexes

4. Polyanhydrides

5. Modified Nanoparticles

· Multifunctional Nanoparticles

· Magnetic Nanoparticles

6. Receptor – mediated transport

· Monoclonal antibody molecular Trojen horses

· Trojen horse liposomes for CNS gene therapy

· In vivo brain imaging of gene

7. Transporter – independent mechanisms to circumvent the BBB

· Convection enhanced drug delivery system

· Ultrasound mediated BBB opening

· Bradykinin receptor mediated BBB opening

CONCLUSION:

Novel drug delivery like targeted or site specific delivery of the drug with optimum doses decreased the toxicity as well as side effects of the drug and it will become beneficial to patients with improved comfort and standard of living. On NDDS researches has begun since long back, however it’s popular since most recent couple of years. In last few decade microparticles, nanoparticles, liposomes, niosomes, trasdermal drug delivery, microencapsulation and recent techniques were developed as various types of NDDS with the motive to deliver drugs to targeted tissue in control manner to cure certain diseases. Noteworthy contribution of NDDS is successful treatment of cancer by targeting the affected cells. NDDS opened up numerous research exposures in nanotechnology and its derivative for delivery of drugs to brain. Considering depth and breadth of the ongoing research in NDDS it’s highly anticipated that the patient with narcolepsy will be benefitted during their therapy from this novel technology.

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Received on 25.07.2023 Modified on 14.08.2023

Research J. Pharm. and Tech 2023; 16(11):5502-5505.

DOI: 10.52711/0974-360X.2023.00890