Drugs acting in CNS were among the first to be discovered by primitive humans and are still the most widely used group of pharmacologic agents. In addition to their use in therapy, many drugs acting on the CNS are used without prescription to increase one’s sense of well being.
The mechanism by which various drugs act in the CNS have not been clearly understood. In last three decades, however, dramatic advances have been made in the methodology of CNS pharmacology. It is now possible to study the action of a drug on individual cells and even single ion channels with synapses. The information obtained from such studies is on the basis for several major developments in studies of the CNS. These are the classification of CNS acting drugs.
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In addition to many medical uses, drugs acting on the cns are using worldwide i.e. alcohol, nicotine, caffeine with various degrees of societal controls due to production of addiction or dysfunctional behaviours. We know that CNS acting agents mainly exert their effects by modulation of synaptic transmission of information between neurons. These actions alter the electrical exciteability of nerve cells by changing the movement of chemical ions across nerve and neuron cell membrane. In general, these drugs ct on a receptor to directly or indirectly open or close ion channels in the cell membrane and thus make the nerve cell more exciteable with regard to its ability to send information.
The membrane of nerve cells contain two types of channels defined on the basis of the mechanism controlling their gating: voltage-gated and ligand-gated channels.Voltage gated channels see Table-1 are respond to changes in the membrane potential of the cell.In nerve cells, these channels are concentrated on the initial segment and the axon and are responsible for the fast action potential,which transmitthe signal from cell body to nerve terminal. There are many types of voltage-sensitive calcium and potassium channels on the cell body, dendrites and initial segment, which act on a much slower time scale and modulate the rate at which the neuron discharge.
MODE OF TOXIN ACTION: Tetrodotoxin
VOLTAGE-GATED: Blocks channel from outside
MODE OF TOXIN ACTION: Betrachotoxin
VOLTAGE-GATED: Slows inactivation
MODE OF TOXIN ACTION: Apamin
VOLTAGE-GATED: Blocks small Ca-activated K-channels
MODE OF TOXIN ACTION: Agatoxin
VOLTAGE-GATED: Blocks p-type channels
MODE OF TOXIN ACTION: Omega-conotoxin
VOLTAGE-GATED: Blocks n-type channels
MODE OF TOXIN ACTION: Charybdotoxin
VOLTAGE-GATED: Blocks big Ca-activated K-channels
IDENTIFICATION OF CENTRAL NEUROTRANSMITTER:
Because drug selectivity is based on the fact that different pathways use different transmitters, a primary goal of neuropharmacologists is to identify the transmitter in CNS pathways. Establishing that a chemical substance is a transmitter has been far more difficult for central synapses than for peripheral synapses. The following criteria have been established for transmitter identification:
Approaches prove that a suspected transmitter resides in the presynaptic terminal of the pathway uder study include biochemical analysis of regional concentrations of suspected transmitters and immunocutochemical techniques for enzymes and peptides.
To determine whether the substance is released from a particular region, local collection of the extracellular fluid can sometimes be accomplished. In addition, slices of brain tissue can be electically or chemically stimulated in vitro and the released substances measured. To determine whether release is relevant to synaptic transmission, it is important to establish that the release is calcium-dependent.
Finally, application of the suspected substance should produce a response that mimics the action of the transmitter released by nerve stimulation. Furthermore, application of the selective antagonist should block the response. The excitatory neurotransmitter released from these cells is in most instances. The information is typically phasic and bursts of action potential.
Microionophoresis, which permits highly localized drug administration, has been a valuable technique in assessing the action of suspected transmitter. Because of the complexity of the CNS, specific pharmacologic antagonism of a synaptic response provides a particular powerful technique for transmitter identification.
DRUG CONCENTRATION AND INTESITY OF ITS EFFECTS:
Intensity of pharmacological effect is given as,
Intensity of effect=
DRUGS ACTING UPON CNS:
Caffeine and the chemically related xanthenes, theophylline and theobromine
Decreases in the order given in their stimulatory action.They are over-the-counter drugs, used to block adenosine receptor as an antagonist.
The stimulation caused by excessive release of norepinephrine from storage sites in the peripheral nervous system. It is not known whether the same action occurs in the CNS. Two other theories regarding for their action are that they are degraded slower than epinephrine or that they could act on serotonin receptor sites.
Narcotic agents are potent and effective for the relief of severe pain. Analgesics are selective cns drug to reduce pain.Long term administration produces tolerance, pstchic and physical dependence.
CENTRAL NERVOUS SYSTEM DEPRESSANTS AND STIMULANTS:
CNS depressants slows down normal brain functions. In higher doses, some CNS depressants can become general anesthetics. Tranquilizers and sedatives are example of CNS depressants. CNS depressants are based on two groups such as:
Stimulants increase alertness, attention and energy which are accompanied by increases in blood pressure rate and respiration. Stimulants were used to treat asthma and other respiratory problems, obesity, neurological disorder and a variety of other ailments. As their potential for abuse and addiction became apparent to wane. Now, stimulants are prescribed for treating only a few health conditions, include attention deficit hyperactivity disorder and depression that has not responded to other treatment. It is also used for short-term treatment of obesity and for patients of asthma.
INTODUCTION TO SEDATIVE-HYPNOTIC:
Interms of drugs, sedative refers to a substance that moderates the activity and excitement while inducing a calming effect, while hypnotic effect refers to a substance that causes drowsiness and facilitates the onset and maintenance of natural sleep. The term anxiolytic is sometimes applied to a sedative-hypnotic; however, be aware that many drugs especially the selective serotonin secretion reuptake inhibitors are useful as a chronic anxiolytic dug demonstrated by their efficacy in certain psychiatric disordres like generalized anxiety disorder.
THERAPEUTIC EFFECTS OF SEDATIVE-HYPNOTICS:
All drugs in this class produce sedation,, with relief of anxiety. Benzodiazepenes also exert anterograde amnesic effects (i.e the inhability to remember events occuring during the drug action ) at sedative doses. The amnesic action is a primary reason some benzodiazepenes ( i.e., midozam ) are commonly used for short duration invasive procedures. They donot provide pain relief however, and must be used in conjunction with analgesics.
Sedative-hypnotics promote sleep onset and increase the duration of sleep. All of the sedative-hypnotics will induce sleep if given in high enough dose. Rapid eye movement ( REM ) sleep stages are usually decreased at high doses. REM rebound can be detected following termination of sedative-hypnotics.
At high doses, sedative- hypnotic produce a loss of consciousness with amnesia at high level and a suppression of reflexes. Anesthsia can be produced by most barbiturates and some benzodiazepene, which is generally used frequently as a induction agent for general anesthesia. Only three, diazepam, midazolam and lorazepam are formulated I.V.
Most barbiturates and some benzodiazepene suppress seizures activity at high dose. However, often this occur along with marked sedation. Selective have anti-convulsant activity and can decrease the spread of epileptiform activity without CNS depression. Some are administered intravenously to treat status epilacticus.
Most sedative-hypnotics causes muscle relaxation at high doses. Diazepam is effective at sedative doses and is useful for treating specific spasticity state including cerebral palsy.
TOLERANCE AND DEPENDENCE:
Decreased responsiveness to a drug following repeated exposure commonly occurs with the continuous use of sedative-hypnotics. The mechanism of action of sedative-hypnotics are not well known.
Psychologicaaly dependence usually occurs wit h most of the sedative-hypnotics with leads to the compulsive use of these agents to reduce anxiety.
Physical dependence is the development of withdrawal syndrome occurs when the drugs are discontinued. Withdrawal syndrome includes, tremors, hyper reflexia, and seizures. These symptoms occur most commonly with shorter acting drugs.
EFECTS ON CNS WITH INCREASING DOSAGE:
- Calmness or drowsiness (sedation)
- Sleep (pharmacological hypnosis)
- Surgical anesthesia
- Fatal respiratory/ cardiac depression
INTRODUCTION TO ANALGESICS:
An analgesic also known as a painkiller is any member of the group of drugs used to relieve pain. Analgesic drugs act in various ways on the peripheral and central nervous system they include paracetamol and acetylaminophetol also known in the us as acetaaminophen, the NSAIDs such as the acetyl salicylic acid and opiods drugs such as morphine and opium. They are distinct from anesthesia who reversibly eliminate sensation.
In choosing analgesics, the severity and response to the medication determines the pain ladder is originally developed in cancer-related pain is widely applied to find suitable drugs in a step wise manner. The choice is also determined by the type of pain, for neuropathic pain, traditional analgesics are less effective and there is often benefit from classes of drugs that are normally not considred analgesics such as tricyclic anti-depressants and anti-convulsants.
WHAT IS PAIN ?
Pain is physiological process that can be classified interms of its intensity ( mold, moderate, severe) its duration (acute, convulascent, chronic) its mechaism ( neurologic, nociceptive, physiologic) and its clinical context ( post surgical, malignancy) pain detection or nocicepter requires activation of specialized transducers called nociceptor, see Table-2, which are activating following thermal, mechanical or chemical tissue injury and initiate different transmission of action potential to the dorsal horn of spinal cord.
Cause: Brief exposure to a noxious stimulus
Symptoms: Rapid, yet brief pain perception
Example: Touching a pin or hot object
Cause: Somatic or visceral tissue injury with medication impacting on intact nervous system
Symptoms: Moderate to severe pain, described as crushing, stabbing, usually worsen after the first 24 hours
Example: Surgical pain, traumatic pain, sickel cell crisis
Cause: Damage of dysfunctional of peripheral nerves or CNS
Symptoms: Severe lancinating, burning or electrical shock like pain
Example: Neuropathy, chronic regional pain syndrome, postherpetic neuralgia
Cause: Combined somatic and nervous tissue injury
Symptoms: Combination of symptoms, soft tissue pain and radicular pain
Example: Low back pain, back surgery pain
Analgesics are a class of drugs used to relief pain. The pain relief by analgesics occurs either by blocking pain signals or by interfering with the brain interpretation of the signalwithout producing anesthesia or loss of consciousness. There are basically two kinds of analgesics:
KINDS OF ANALGESICS:
It should be noted that some reference include aspirin and other non-steroidal anti inflammatory drugs (NSAIDs) in the class of analgesics because they have some analgesic properties. Aspirin and NSAIDs primarily have an anti-inflammatory affect, as opposed to being solely analgesic.
Acetaminophen is the most commonly used over-the-counter, non-narcotic analgesic. Acetaminophen is a popular pain reliver because it is both effective for mild and moderate relief of pain and relatively inexpensive. It must be emphasized though that the safety of acetoaminophen is tied to proper use of the drug (use according to specific prescribed instructions). If acetoaminophen is not used according to the directions on the label, serious side effects and possible fatal consequences can occur. For example, taking more than 4000 mg/day or using it long term can increase the risk of liver damage. The risk of liver damage also increased by ingesting alcohol. Many people donot realize that acetoaminophen is found in more than 600 OTC. It can be found in combination with other active ingredients in many cold, sinus and cough medications. The commulative effect of acetaminophen must be considered if you are taking multiple drugs which contain acetaminophen.
There are two types of narcotic analgesics:
- The opiates (found in alkaloid, opium)
- The opioids (derivatives of opiates)
Opiods are any medication which binds to opioid receptors in the CNS or gastrointestinal tract.
There are four broad classes of opioids:
- Endogenous oopioids peptides (produced in the body: endorphins, dynorphins, enkephalins)
- Opium alkaloids (morphine, codeine, theibaine)
- Semi-synthetic opiods ( heroin, oxycodone, hydrocodone, dihydrocodeine, hydromorphone, oxymorphone)
- Fully synthetic opioids (pethidine, methadone, fentanyl, propoxyphene, buprenorphine)
Opioids are used in medicine as strong analgesics, for relief of severe or chronic pain. There is no upper limit for the dosage of opioids used to achieve pain relief, but the dose must be increased gradually to allow for the development of tolerance to adverse effects ( for eg. Respiratory depression).
According to emedicine: some people with intense pain get such high doses would be fatal if taken by someone who was not suffering from pain.
PHARMACOLOGY OF SYSTEMIC ANALGESICS:
Systemic administration of analgesic drugs is still the most widely used method for providing pain relief in acute painful situations. Opioids may be selected on the basis of their physicochemical characteristics and their diffusion index to the brain. But in clinical practice, their very steep concentration-analgesic effect relationship remains a critical aspect of opioid therapy. Thus, small fluctuations in plasma concentrations of opioids may lead to profound fluctuations in analgesic effect when their plasma and effect-site concentrations are near the minimum effective analgesic concentration (MEAC). Combining drugs acting on different mechanisms of nociceptive modulation offers benefits from additive/synergistic effects and will decrease the incidence of their adverse effects. Evidence-based reviews showed that effective pain relief using non-opioid analgesics relied on paracetamol supplemented with non-steroidal anti-inflammatory drugs (NSAIDs). The role of COX-2 selective inhibitors (CSIs) in acute pain relief still requires further evaluation. NSAIDs, CSIs and paracetamol share the property of morphine sparing in situations of severe (post-operative) pain. CSIs may be beneficial in patients in whom post-operative bleeding is a major surgical risk as the effects of NSAIDs on coagulation may last for days. Finally, low-dose ketamine infusions remain a worthwhile addition to opioid therapy. Analgesic concentrations of ketamine are 1/5th to 1/10th the anaesthetic concentration and exert significant inhibition on N-methyl-d-aspartate (NMDA) receptor activation.
There have been debates over the additine potential of opioids vs. the benefits of their analgesic properties for treating non-malignant chronic pain such as chronic arthritis. Some experts believe opioiods can be taken for years without addiction or toxic side effects. The enhanced quality of life which opioids may provide the patient must considered.
Common SIDE EFFECTS and ADVERSE REACTION:
- Dry mouth
- Miosis (contraction of pupil)
- Urinary retention
- Constipation or fecal impaction
- Orthostatic hypotension
Less common SIDE EFFECTS and ADVERSE REACTION:
- Raised intracranial pressure
- Muscle rigidity
Most severe SIDE EFFECTS and ADVERSE REACTION:
- Respiratory depression
- Fatal overdose
INTRODUCTION TO ANTI-SEIZURES:
After stroke, epilepsy is the second common disorder of CNS affecting about 1% of the population worldwide. Most (80%+) cases can be well controlled with anti-seizures drugs. However, that leaves many characterized by periods of abnormal firing of CNS neurons and can be caused by many neurological conditions (i.e. tumors, injury, infection). In some cases, there is also agenetic predisposition to epilepsy.
Anti-seizures medication were originally designed to help people who have epilepsy, but the nerve-calming quality of some of these drugs can also help quiet the burning, stabbing or shooting pain often caused by nerve damage.
Nerve damage (neuropathy) can be caused by many factors, including:
High blood sugar levels, common in diabetes, can damage the nerves throughout the body, but the first symptomatically is numbnessand pain in the hands and feet.
Anyone who has had chicken pox is at risk of shingles a rash of blisters that can be painful or itchy. A condition called postherpetic neuralgia occurs if shingles pain persists after the rash disappears. Because the risk of shingles increases with age, evryone everyone everyone age 60 or older should receive the zoster vaccine which can help prevent this painful condition.
Some chemotherapy drugs can damage nerves causing pain and numbness that typically begins in the tip of toes and fingers.
Nerve damage can occur if a herniated in your spine squeezes a nerve passing through your vertebrae too tightly.
Some neuropathies are passed on genetically and affects different nerves, depending upon the type of disorder. The most common hereditary neuropathy is Charcot-Marie-Tooth disease which affects motor and sensory nerves.
MECHANISMS OF ANTI-SEIZURE DRUGS:
Exact mechanism of anti-seizues drugs are not well understood but tese medications appear to interfere with the over react transmission of pain signals sent from damaged nerves.
Some anti-seizures work particularly well for certain conditions. Carbamazepine is prescribed for trigeminal neurolgia, a condition that causes facial painn appears as electrical shocks. It is important note that FDA has issued a warning that all anti-seizures associated with a slight increased risk of suicidal thoughts or actions. Talk to your doctor if you are experiencing feeling of depression or suicidal thoughts.
Used with other epilepsy drugs to treat partial and some generalized seizures.
Few lasting side effects. During the first week of treatment, a person may experience tiredness and dizziness.
Controls partial seizures and generalized tonic-clonic seizure. Also can be given by intravenously in the hospital to rapid control active seizures.
Side effects include dizziness, fatigue, acne, slurred speech, rash, and increase hair. Over the long term the drug can cause bone thinning.
Used to treat partial, absence and generalized tonic-clonic seizures.
Common side effects include dizziness, nausea, vomiting, tremor, hair loss, reduced attention, depression in adults, irritability in children, a decrease in thinking speed. Over the long term, the drug can cause bone thinning, swelling of the ankles, liver damage, decreased platelets.
INTRODUCTION TO ANTI-PSYCHOTICS:
A person who is psychic out of touch with the reality. People with psychosis may hear ‘voices’ or have strange and illogical ideas for eg, thinking that others can hear their thought or are trying to harm them or they are president o f us or some famous person. They may get excited or angry with no apparent reason, or spend lots of time by themselves or in bed, sleeping during the day and awake at night. The person may neglect appearance, not bathing or changing clothes, hard to talk to- barely talking or saying things that make non-sense. They often are initially unaware that their condition is an illness.
These kinds of behavior are symptoms of a psychotic illness such as schizophrenia. Anti-psychotic drugs reduces these symptoms. These medications cannot cure the disease but they can take away many of the symptoms or make them mild. In some cases, they can shorten the course of episode of illness well.
There are number of anti-psychotic medications available. These medications affect the neurotransmitter that allow communication between nerve cells. One such neurotransmitter, dopamine, is thought to be relevant to schizophrenia symptoms. All thes e medications have some effect for schizophrenia. The main differences are in their potency that is the dosage prescribed to produce therapeutic effect. Some people may think that thehigher doses of medication prescribed the more serious the illness but this is not always true.
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The 1990s saw the development of several new drugs for schizophrenia called ” atypical antipsychotics” because they have fewer side effects than the older drugs, today they are often called and used as afirst line of treatment. The first atypical antipsychotic drug was introduces in 1990. In clinical trials, these medications were found to be more effective than conventional or typical Antipsychotic drugs in individuals with treatment-resistant schizophrenia, that is not responded to other drugs and the risk of tardive dyskinesia ( a movement disorder was lower). However because of the potential side effects of serious blood disorder -agranulocytosis, white blood cells loss that fight infection. Patient who are on clozapine must have a blood test on every 1 or 2 weeks. The inconvenience and cost of blood tests and the medication itself have made maintenance for adults for many people.
Several other atypical antipsychotics have been developed since clozapine was introduced.
INDICATIONS OF ANTI-PSYCHOTIC DRUGS:
Common conditions with which antipsychotics might be used include schizophrenia, bipolar disorder and delusional disorder. Antipsychotics might also be used to counter psychosis associated with a wide range of other diagnoses, such as psychotic depression. However, not all symptoms require heavy medication and hallucinations and delusions should only be treated if they distress the patient or produce dangerous behaviors.
For non-psychotic disorders:
In addition, “antipsychotics” are increasingly used to treat non-psychotic disorders. For example, they are sometimes used off-label to manage aspects of Tourette syndrome or autism spectrum disorders. They have multiple off-label uses as an augmentation agent (i.e. in addition to another medication), for example in “treatment-resistant” depression essive, anti-impulsive, anti-suicidal and hypnotic (sleep) medications.
Antipsychotics have also been increasingly used off-label in cases of dementia in older people, and for various disorders and difficulties in children and teenagers. A survey of children with pervasive developmental disorder found that 16.5% were taking an antipsychotic drug, most commonly to alleviate mood and behavioral disturbances characterized by irritability, aggression, and agitation. Recently, risperidone was approved by the US FDA for the treatment of irritability in children and adolescents with autism.
Antipsychotics are sometimes used as part of compulsory treatment via inpatient (hospital) commitment or outpatient commitment. This may involve various methods to persuade a person to take the medication, or actual physical force. Administration may rely on an injectable form of the drug rather than tablets. The injection may be of a long-lasting type known as a depot injection, usually applied at the top of the buttocks. Those that are available in injectable form are haloperidol, olanzapine, and ziprasidone while those available as depot are haloperidol, flupenthixol, clopenthixol, and risperidone.
Antipsychotics are among the biggest selling and most profitable of all drugs, generating $22 billion in global sales in 2008. By 2003 in the US, an estimated 3.21 million patients received antipsychotics, worth an estimated $2.82 billion. Over 2/3 of prescriptions were for the newer more expensive atypicals, each costing on average $164 compared to $40 for the older types. By 2008, sales in the US reached $14.6 billion, the biggest selling drugs in the US by therapeutic class. The number of prescriptions for children and adolescents doubled to 4.4 million between 2003 and 2006, in part because of increases in diagnoses of bipolar disorder.
Due to the chronic nature of the treated disorders, antipsychotic medications, once started, are seldom discontinued, and the aim of the treatment is often to gradually reduce dosage to a minimum safe maintenance dose that is enough to control the symptoms. Only when the side-effects have become too severe and/or a patient have been symptom-free for a long periods of discontinuation carefully attempted.
Antipsychotic medications can produce unwanted effects when taken with other medications therefore, doctor should be told about all the medications being taken including over -the-counter medications and vitamin, mineral, and herbal supplements and the extent of alcohol use.
Some antipsychotic interfere with anti-hypertensive drugs (taking for high blood pressure), anticonvulsants (taken for epilepsy) and medicine used for parkinson’s disease. Other anti-psychotic add to the effect of a alcohol and other CNS depressants such as anti-histamines, barbiturates, anti-depressants, some sleeping and pain medications and narcotics.
Long term treatment of schizophrenia with one of the older, or, ” conventional” antipsychotics may cause to develop tardiye dyskinesia. Tardiye dyskinesia is a condition characterized by involuntary movements, most often around the mouth. It may range from mild to severe. In some people, it cannot be reversed, while others recoverd partially or completely. Tardiye dyskinesia is sometimes in people with schizophrenia who have never been treated with an antipsychotic medications is called ” spontaneous dyskinesia” however, it is most often seen after long term treatment with older antipsychotic medications. The risk has been reduced with newer” atypical” medications. There is a higher incidence in women, and the risk increases with the age. The possible risks of long-term treatment with with an anti-psychotic medications must be weighed against the benefit in each case. The risk of TD is 5% per year with older medications. It is less with newer medications.
PSYCHOTIC DISORDER CAUSES:
Functional causes of psychosis include the following:
- Drug abuse amphetamines, cocaine, marijuana, http://en.wikipedia.org/wiki/Alcoholismalcohol among others.
- Brain damage
- Schizophrenia, schizophreniform disorder, schizoaffective disorder, brief psychotic disorder
- Bipolar disorder (manic depression)
- Severe clinical depression
- Severe psychosocial stress
- Sleep deprivation.
- Some traumatic events.
DOSAGES AND SIDE EFFECTS:
Some medications are very potent and prescribed in low doses, others are not as potent and higher doses are prescribed.
Most side effects of antipsychotic drugs are mild. Many common ones lessens or disappear after the first week of treatment. these includes drowsiness, rapid heart beat and dizziness when posture changes.
Some people may gain weight while taking medications and need to pay extra attention to diet or exercise to control their weight.
All anti-psychotic drugs tend to block D2- receptors in the dopamine pathways of the brain. This means that dopamine released in these pathways has less effect. Excess release of dopamine in the mesolimbic pathway has been linked to psychotic experiences. It is the blockade of dopamine receptors in the pathway that is thought to control psychotic experience.
Typical antipsychotic are not particularly selective and also block dopamine receptors in the mesolimbic pathway, tuberoinfundibular pathway and the nigrostriatal pathway. Blocking D2- receptor s in these pathway is thought to produce some of the unwanted effects which typical antipsychotics produce.
LITHIUM, MOOD STABILIZING DRUGS, AND OTHER TREATMENT FOR BIPOLAR DISORDER:
Bipolar disorder once known as manic-depressive illness, was conceived of as a psychotic disorder distinct from schizophrenia at the end of the 19th century. Before that both of these disorders were considered part of a continuum. It is ironic that the weight of the evidence today is that there is profound overlap in these disorders. This is not to say that there are no pathophysiology important difference or that some drugs treatment are differentially effective in these disorders. According to DSM, they are separate disease entities while research continues to define the dimensions of these illnesses and their genetic and other biological markers.
TYPES OF BIPOLAR DISORDER
There are several types of bipolar disorder. Each type is identified by the pattern of episodes of mania and depression. The treatment that is best for you may differ depending on the type of bipolar disorder you have. Your doctor will look carefully to determine where your symptoms fit.
Bipolar I Disorder (mania and depression) – Bipolar I disorder is the classic form of the illness, as well as the most severe type of bipolar disorder. It is characterized by at least one manic episode or mixed episode. The vast majority o
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