Aneuploidy: Abnormal Chromosome Numbers

Aneuploidy refers to the presence of an abnormal number of chromosomes, which can result from errors during meiosis. Typically, human cells have 23 pairs of chromosomes, but aneuploidy can lead to extra of missing chromosomes. Trisomies, which involve the presence of an additional chromosome, are the most common aneuploidies in humans. However, most trisomies are not compatible with life, and only trisomy 21 (Down’s syndrome), trisomy 18 (Edwards syndrome), and trisomy 13 (Patau syndrome) survive to birth. Aneuploidy can result in imbalances in gene expression, which can lead to a range of symptoms and developmental issues.

Compared to autosomal trisomies, humans are more able to tolerate extra sex chromosomes. Klinefelter’s syndrome, which involves the presence of an extra X chromosome, is the most common sex chromosome aneuploidy. Individuals with Klinefelter’s and XYY often remain undiagnosed, but they may experience reduced sexual development and fertility. Monosomies, which involve the loss of a chromosome, are rare in humans. The only viable human monosomy involves the X chromosome and results in Turner’s syndrome. Turner’s females display a wide range of symptoms, including infertility and impaired sexual development.

The frequency and severity of aneuploidies vary widely. Down’s syndrome is the most common viable autosomal trisomy, affecting 1 in 800 births. Klinefelter’s syndrome affects 1-2 in 1000 male births, while XYY syndrome affects 1 in 1000 male births and Triple X syndrome affects 1 in 1000 births. Turner syndrome is less common, affecting 1 in 5000 female births. Edwards syndrome and Patau syndrome are rare, affecting 1 in 6000 and 1 in 10,000 births, respectively. Understanding the genetic basis and consequences of aneuploidy is important for diagnosis, treatment, and genetic counseling.

The term PrPSc originated from scrapie, a prion disease that affects sheep. In humans, the normal isoform of prion protein is PrPC, while the abnormal form is known as PrPres (protease-resistant) of PrPSc. Scrapie has been observed in sheep for over 300 years, while BSE in cattle was only identified in the 1980s. Feline spongiform encephalopathy (FSE) is a prion disease that affects cats, and Chronic wasting disease (CWD) is a similar condition that affects deer.

Confidence intervals become wider as the level of variance increases. Typically, researchers report confidence intervals at the 95% level. The level of confidence is predetermined by the researcher and reflects a significance level of 0.05. The range within which the true value of a parameter is likely to fall given repeated sampling is described by the confidence intervals.

Brain Blood Supply and Consequences of Occlusion

The brain receives blood supply from the internal carotid and vertebral arteries, which form the circle of Willis. The circle of Willis acts as a shunt system in case of vessel damage. The three main vessels arising from the circle are the anterior cerebral artery (ACA), middle cerebral artery (MCA), and posterior cerebral artery (PCA). Occlusion of these vessels can result in various neurological deficits. ACA occlusion may cause hemiparesis of the contralateral foot and leg, sensory loss, and frontal signs. MCA occlusion is the most common and can lead to hemiparesis, dysphasia/aphasia, neglect, and visual field defects. PCA occlusion may cause alexia, loss of sensation, hemianopia, prosopagnosia, and cranial nerve defects. It is important to recognize these consequences to provide appropriate treatment.

Hyponatremia is commonly linked to the use of SSRIs (antidepressants) and typical antipsychotics.

Hyponatremia in Psychiatric Patients

Hyponatremia, of low serum sodium, can occur in psychiatric patients due to the disorder itself, its treatment, of other medical conditions. Symptoms include nausea, confusion, seizures, and muscular cramps. Drug-induced hyponatremia is known as the syndrome of inappropriate antidiuretic hormone hypersecretion (SIADH), which results from excessive secretion of ADH and fluid overload. Diagnosis is based on clinically euvolemic state with low serum sodium and osmolality, raised urine sodium and osmolality. SSRIs, SNRIs, and tricyclics are the most common drugs that can cause SIADH. Risk factors for SIADH include starting a new drug, and treatment usually involves fluid restriction and sometimes demeclocycline.

Rett syndrome is caused by mutations in the MeCP2 gene.

Tuberous Sclerosis: A Neurocutaneous Syndrome with Psychiatric Comorbidity

Tuberous sclerosis is a genetic disorder that affects multiple organs, including the brain, and is associated with significant psychiatric comorbidity. This neurocutaneous syndrome is inherited in an autosomal dominant pattern with a high penetrance rate of 95%, but its expression can vary widely. The hallmark of this disorder is the growth of multiple non-cancerous tumors in vital organs, including the brain. These tumors result from mutations in one of two tumor suppressor genes, TSC1 and TSC2. The psychiatric comorbidities associated with tuberous sclerosis include autism, ADHD, depression, anxiety, and even psychosis.

Pregabalin: Pharmacokinetics and Mechanism of Action

Pregabalin is a medication that acts on the alpha-2-delta subunit of voltage-gated calcium channels in the central nervous system. It is known for its anticonvulsant, analgesic, and anxiolytic properties. By decreasing presynaptic calcium currents, it reduces the release of excitatory neurotransmitters that contribute to anxiety. Despite being a GABA analogue, it does not affect GABA receptors of metabolism.

Pregabalin has predictable and linear pharmacokinetics, making it easy to use in clinical practice. It is rapidly absorbed and proportional to dose, with a time to maximal plasma concentration of approximately 1 hour. Steady state is achieved within 24-48 hours, and efficacy can be observed as early as day two in clinical trials. It has a high bioavailability and a mean elimination half-life of 6.3 hours.

Unlike many medications, pregabalin is not subject to hepatic metabolism and does not induce of inhibit liver enzymes such as the cytochrome P450 system. It is excreted unchanged by the kidneys and does not bind to plasma proteins. This means that it is unlikely to cause of be affected by pharmacokinetic drug-drug interactions.

While there is some potential for abuse of pregabalin, the euphoric effects disappear with prolonged use. Overall, pregabalin is a safe and effective medication for the treatment of various conditions, including anxiety and neuropathic pain.

Understanding Emotional Lability

Emotional lability is a condition characterized by an excessive and brief emotional response to a minor stimulus. It is a common symptom of various neurological and psychiatric disorders, including traumatic brain injury, multiple sclerosis, Parkinson’s disease, bipolar disorder, and borderline personality disorder. People with emotional lability may experience sudden and intense mood swings, such as crying, laughing, anger, of irritability, that are out of proportion to the situation.

One of the most challenging aspects of emotional lability is the lack of control over one’s emotions. Pathological crying of laughing is a common manifestation of emotional lability, where a person may burst into tears of laughter without any apparent reason of context. This can be embarrassing, distressing, and socially isolating, as it may be perceived as a sign of weakness, instability, of immaturity.

Treatment for emotional lability depends on the underlying cause and severity of the symptoms. In some cases, medication, such as antidepressants, antipsychotics, of mood stabilizers, may be prescribed to regulate the mood and reduce the frequency and intensity of emotional outbursts. Psychotherapy, such as cognitive-behavioral therapy of dialectical behavior therapy, can also help individuals with emotional lability to develop coping skills, emotional regulation strategies, and interpersonal communication skills.

It is important to note that emotional lability is not a character flaw of a personal weakness, but a medical condition that requires proper diagnosis and treatment. Seeking professional help from a qualified healthcare provider can help individuals with emotional lability to improve their quality of life, enhance their relationships, and regain their emotional stability and resilience.

While ventricular enlargement is often observed in individuals with schizophrenia, it is not a definitive indicator of the condition as it can also be present in other disorders.

Schizophrenia is a pathology that is characterized by a number of structural and functional brain alterations. Structural alterations include enlargement of the ventricles, reductions in total brain and gray matter volume, and regional reductions in the amygdala, parahippocampal gyrus, and temporal lobes. Antipsychotic treatment may be associated with gray matter loss over time, and even drug-naïve patients show volume reductions. Cerebral asymmetry is also reduced in affected individuals and healthy relatives. Functional alterations include diminished activation of frontal regions during cognitive tasks and increased activation of temporal regions during hallucinations. These findings suggest that schizophrenia is associated with both macroscopic and functional changes in the brain.

, coma, respiratory depression (rare)

The first two stages of moral development, punishment and obedience orientation and individuation and exchange, are collectively referred to as preconventional morality. At this stage, children understand right and wrong based on the consequences of their actions, with punishment being a deterrent in the first stage and risk avoidance in the second stage.

The ascent of the National Socialist Party during the 1930s had a negative effect on psychiatry in Germany, which was previously a leading force in European psychiatry. As a result of the Second World War, numerous skilled scientists and psychiatrists fled Germany and sought refuge in the United States. Their contributions were instrumental in establishing the US as the dominant force in both academic and clinical psychiatry.

Promethazine is utilized for its sedative properties in cases of agitation due to the fact that first generation H1 antihistamines easily penetrate the BBB and induce drowsiness.

Antihistamines: Types and Uses

Antihistamines are drugs that block the effects of histamine, a neurotransmitter that regulates physiological function in the gut and potentiates the inflammatory and immune responses of the body. There are two types of antihistamines: H1 receptor blockers and H2 receptor blockers. H1 blockers are mainly used for allergic conditions and sedation, while H2 blockers are used for excess stomach acid.

There are also first and second generation antihistamines. First generation antihistamines, such as diphenhydramine and promethazine, have uses in psychiatry due to their ability to cross the blood brain barrier and their anticholinergic properties. They tend to be sedating and are useful for managing extrapyramidal side effects. Second generation antihistamines, such as loratadine and cetirizine, show limited penetration of the blood brain barrier and are less sedating.

It is important to note that there are contraindications to first-generation antihistamines, including benign prostatic hyperplasia, angle-closure glaucoma, and pyloric stenosis in infants. These do not apply to second-generation antihistamines.

Electroencephalography

Electroencephalography (EEG) is a clinical test that records the brain’s spontaneous electrical activity over a short period of time using multiple electrodes placed on the scalp. It is mainly used to rule out organic conditions and can help differentiate dementia from other disorders such as metabolic encephalopathies, CJD, herpes encephalitis, and non-convulsive status epilepticus. EEG can also distinguish possible psychotic episodes and acute confusional states from non-convulsive status epilepticus.

Not all abnormal EEGs represent an underlying condition, and psychotropic medications can affect EEG findings. EEG abnormalities can also be triggered purposely by activation procedures such as hyperventilation, photic stimulation, certain drugs, and sleep deprivation.

Specific waveforms are seen in an EEG, including delta, theta, alpha, sigma, beta, and gamma waves. Delta waves are found frontally in adults and posteriorly in children during slow wave sleep, and excessive amounts when awake may indicate pathology. Theta waves are generally seen in young children, drowsy and sleeping adults, and during meditation. Alpha waves are seen posteriorly when relaxed and when the eyes are closed, and are also seen in meditation. Sigma waves are bursts of oscillatory activity that occur in stage 2 sleep. Beta waves are seen frontally when busy of concentrating, and gamma waves are seen in advanced/very experienced meditators.

Certain conditions are associated with specific EEG changes, such as nonspecific slowing in early CJD, low voltage EEG in Huntington’s, diffuse slowing in encephalopathy, and reduced alpha and beta with increased delta and theta in Alzheimer’s.

Common epileptiform patterns include spikes, spike/sharp waves, and spike-waves. Medications can have important effects on EEG findings, with clozapine decreasing alpha and increasing delta and theta, lithium increasing all waveforms, lamotrigine decreasing all waveforms, and valproate having inconclusive effects on delta and theta and increasing beta.

Overall, EEG is a useful tool in clinical contexts for ruling out organic conditions and differentiating between various disorders.

The combination of the patient’s symptoms and medical history strongly suggests the presence of neuromuscular malignant syndrome. To confirm the diagnosis, a serum creatine kinase test would be the most beneficial investigation to conduct. Although creatine kinase is a highly sensitive marker for muscle tissue damage, it is not specific to this condition and may also be elevated in other conditions such as acute alcohol intoxication of acute psychosis.

Serotonin Syndrome and Neuroleptic Malignant Syndrome are two conditions that can be difficult to differentiate. Serotonin Syndrome is caused by excess serotonergic activity in the CNS and is characterized by neuromuscular abnormalities, altered mental state, and autonomic dysfunction. On the other hand, Neuroleptic Malignant Syndrome is a rare acute disorder of thermoregulation and neuromotor control that is almost exclusively caused by antipsychotics. The symptoms of both syndromes can overlap, but there are some distinguishing clinical features. Hyper-reflexia, ocular clonus, and tremors are more prominent in Serotonin Syndrome, while Neuroleptic Malignant Syndrome is characterized by uniform ‘lead-pipe’ rigidity and hyporeflexia. Symptoms of Serotonin Syndrome usually resolve within a few days of stopping the medication, while Neuroleptic Malignant Syndrome can take up to 14 days to remit with appropriate treatment. The following table provides a useful guide to the main differentials of Serotonin Syndrome and Neuroleptic Malignant Syndrome.

The Paddington Alcohol Test (PAT) is a quick and efficient tool designed to identify alcohol-related problems in emergency department settings. Unlike other questionnaires, such as AUDIT, the PAT features a table of commonly consumed beverages coded in British units, which allows for a more accurate estimation of alcohol consumption. The PAT also takes into account the relative strengths of different products, providing a better indication of total units consumed. Overall, the PAT is a valuable tool for identifying hazardous drinking patterns in the UK. (Reference: Patton R, Alcohol and Alcoholism, 2004)

Alcohol screening tools are available to assist in the diagnosis of alcohol problems. One such tool is the AUDIT (Alcohol Use Disorders Identification Test), which consists of 10 questions and covers harmful use, hazardous use, and dependence. Another tool is the FAST (Fast Alcohol Screening Test), which has just 4 questions and was developed for use in a busy medical setting. The CAGE is a well-known 4 question screening tool, but recent research has questioned its value. Other tools include SASQ (Single alcohol screening questionnaire), PAT (Paddington Alcohol Test), MAST (Michigan Alcoholism Screening Test), and RAPS4 (Rapid Alcohol Problem Screen 4). These tools can help identify hazardous of harmful alcohol consumption and alcohol dependence.

When using methadone and haloperidol together, it is important to closely monitor the QTc interval due to their significant effect on it. EEG and electrolyte screening are not necessary. While liver function tests may be useful to perform periodically, they are not the primary concern with this combination. It is important to be cautious of respiratory depression when using high doses of methadone in combination with other sedative medications, but respiratory function tests are unlikely to provide helpful information.

The two main ethical approaches in philosophy are teleological ethics, which focuses on the end result, and deontological ethics, which focuses on an individual’s actions being morally right regardless of the end result. In medicine, deontology is patient-centered, while utilitarianism is society-centered. Deontological ethics judges the moral status of actions according to rules of principles, such as the duty not to harm the patient versus the duty to help them. Kantian ethics is a strict form of deontological ethics that emphasizes behaving as though one’s behavior is creating a universal ethical rule. Utilitarianism is a teleological approach that prioritizes the action that leads to the greatest happiness of the greatest number, regardless of how it is brought about. In medicine, autonomy is one of four ethical principles, along with beneficence, non-maleficence, and justice, that enable patients to choose their own treatment and ensure fairness and equality.

All the other choices are components of the WAIS (Wechsler Adult Intelligence Scale).

Thurstone’s Theory of Intelligence

Louis Leon Thurstone believed that intelligence could not be reduced to a single factor. Instead, he proposed that intelligence is composed of seven distinct abilities, which he called the primary abilities. These abilities include word fluency, verbal comprehension, spatial visualization, number facility, associative memory, reasoning, and perceptual speed. According to Thurstone, each of these abilities is independent of the others and contributes to an individual’s overall intelligence. This theory challenged the prevailing view of intelligence at the time, which held that intelligence could be measured by a single factor known as the g factor. Thurstone’s theory has had a lasting impact on the field of psychology and has influenced the development of modern intelligence tests.

Knowing the half life of a drug is important in determining the steady state concentration, which occurs when absorption and elimination reach an equilibrium after repeated doses. This equilibrium depends on factors such as dose, time between doses, and the drug’s elimination half life. Typically, steady state is achieved after four to five half lives. The following are the half lives of some atypical antipsychotics: Aripiprazole – 90 hours, Clozapine – 16 hours, Olanzapine – 30 hours, Risperidone – 15 hours, and Quetiapine – 6 hours.

The Role of the Ventral Tegmental Area in Reward and Pleasure

The midbrain contains a cluster of dopaminergic cells known as the ventral tegmental area (VTA), which plays a crucial role in the experience of reward and pleasure. These cells are involved in the release of dopamine, a neurotransmitter that is associated with feelings of pleasure and motivation. The VTA is activated in response to various stimuli, such as food, sex, and drugs, and is responsible for the pleasurable sensations that accompany these experiences. Dysfunction in the VTA has been linked to addiction and other disorders related to reward processing. Understanding the role of the VTA in reward and pleasure is essential for developing effective treatments for these conditions.

Sublimation is a type of psychodynamic defence mechanism that involves directing unacceptable emotions into more acceptable outlets. In this case, going for a run is a positive way for the patient to cope with the emotions brought about by thinking about their abuser. The other answer options are also types of psychodynamic defence mechanisms described by Sigmund and Anna Freud, but they are considered less healthy ways of coping.

NMS is a potential side effect of antipsychotics.

Serotonin Syndrome and Neuroleptic Malignant Syndrome are two conditions that can be difficult to differentiate. Serotonin Syndrome is caused by excess serotonergic activity in the CNS and is characterized by neuromuscular abnormalities, altered mental state, and autonomic dysfunction. On the other hand, Neuroleptic Malignant Syndrome is a rare acute disorder of thermoregulation and neuromotor control that is almost exclusively caused by antipsychotics. The symptoms of both syndromes can overlap, but there are some distinguishing clinical features. Hyperreflexia, ocular clonus, and tremors are more prominent in Serotonin Syndrome, while Neuroleptic Malignant Syndrome is characterized by uniform ‘lead-pipe’ rigidity and hyporeflexia. Symptoms of Serotonin Syndrome usually resolve within a few days of stopping the medication, while Neuroleptic Malignant Syndrome can take up to 14 days to remit with appropriate treatment. The following table provides a useful guide to the main differentials of Serotonin Syndrome and Neuroleptic Malignant Syndrome.

Kleine-Levin Syndrome: A Mysterious Condition

Kleine-Levin syndrome is a peculiar disorder that typically affects adolescent boys. It is characterized by an excessive need for sleep and an insatiable appetite when awake. The condition is also associated with emotional and behavioral issues such as irritability and aggression.

The onset of symptoms is sudden and can last for several days to weeks before disappearing. This is followed by a period of normalcy, only to be followed by another episode. This pattern can continue for years, but the severity of symptoms tends to decrease over time. During the periods between episodes, those affected appear to be perfectly healthy with no signs of physical of behavioral dysfunction. The media has dubbed this condition as Sleeping Beauty syndrome.

Despite extensive research, the cause of Kleine-Levin syndrome remains unknown. However, the prognosis is generally positive, with most individuals making a full recovery.

Neurotransmitters are substances used by neurons to communicate with each other and with target tissues. They are synthesized and released from nerve endings into the synaptic cleft, where they bind to receptor proteins in the cellular membrane of the target tissue. Neurotransmitters can be classified into different types, including small molecules (such as acetylcholine, dopamine, norepinephrine, serotonin, and GABA) and large molecules (such as neuropeptides). They can also be classified as excitatory or inhibitory. Receptors can be ionotropic or metabotropic, and the effects of neurotransmitters can be fast of slow. Some important neurotransmitters include acetylcholine, dopamine, GABA, norepinephrine, and serotonin. Each neurotransmitter has a specific synthesis, breakdown, and receptor type. Understanding neurotransmitters is important for understanding the function of the nervous system and for developing treatments for neurological and psychiatric disorders.

Genetic Disorders

Phenylketonuria (PKU) is a metabolic genetic disorder that occurs when the body is unable to metabolize the amino acid phenylalanine, leading to its accumulation in the body. This can cause severe medical problems, including seizures and learning disabilities. PKU can be detected through neonatal screening and can be managed by restricting dietary phenylalanine.

Fragile X is a genetic disorder caused by a mutation on the X chromosome. While there is no specific cure for this disorder, some of the resulting problems, such as ADHD, can be treated.

Neurofibromatosis is an autosomal dominant genetic condition that currently has no cure.

Trisomy 13, also known as Patau syndrome, is a chromosomal abnormality that occurs randomly and is usually incompatible with life.

Trisomy 21, also known as Down’s syndrome, is a genetic disorder that occurs when there is an extra copy of chromosome 21. This disorder can cause a range of medical problems, including intellectual disability and heart defects.

Ethical theory and principles are important in medical ethics. There are three key ethical theories that have dominated medical ethics: utilitarianism, deontological, and virtue-based. Utilitarianism is based on the greatest good for the greatest number and is a consequentialist theory. Deontological ethics emphasize moral duties and rules, rather than consequences. Virtue ethics is based on the ethical characteristics of a person and is associated with the concept of a good, happy, flourishing life.

More recent frameworks have attempted to reconcile different theories and values. The ‘four principles’ of ‘principlism’ approach, developed in the United States, is based on four common, basic prima facie moral commitments: autonomy, beneficence, non-maleficence, and justice. Autonomy refers to a patient’s right to make their own decisions, beneficence refers to the expectation that a doctor will act in a way that will be helpful to the patient, non-maleficence refers to the fact that doctors should avoid harming their patients, and justice refers to the expectation that all people should be treated fairly and equally.

Controversial studies in psychiatry have been a popular topic in exams. One such study was the Willowbrook School Study, where healthy children with learning difficulties were inoculated with hepatitis to assess the potential of gamma globulin to treat the disorder. Beecher’s study listed over 20 cases of mainstream research where subjects were experimented on without being fully informed of the risks. The Tuskegee syphilis experiment followed impoverished African-American sharecroppers with syphilis, and a significant proportion did not receive available treatment. Stanford’s prison experiment created a simulated prison environment where participants became their assigned roles, with guards becoming harsh and cruel to prisoners. The Tearooms Study involved Humphreys pretending to be a ‘watch queen’ to study men who have sex in public toilets, raising the issue of informed consent. Milgram’s Study investigated authority and obedience, where participants administered fake shocks to a confederate, with 30 participants continuing to administer shocks until 450 volts was reached. The Rosenhan experiment involved pseudopatients presenting themselves at institutions with the same symptoms and being admitted and diagnosed with serious mental disorders, leading to deinstitutionalisation.

There is no indication of feigning symptoms for personal benefit.

The Sick Role and Illness Behavior

Mechanic and Volkart (1961) introduced the term illness behavior to describe how individuals perceive, evaluate, and respond to symptoms of physical dysfunction. Meanwhile, Talcott Parsons (1951) introduced the concept of the sick role as a temporary form of deviant behavior that is medically sanctioned.

According to Parsons, a sick person experiences conflicting desires to recover from the illness and to enjoy the secondary gains of attention and exemption from normal duties. The sick role is characterized by several rules, including the exemption of the sick person from their normal social roles, which is legitimized by society through the physician. The severity of the illness determines the strength of the exemption.

Additionally, sick persons are not held responsible for their illnesses, as they are beyond personal control. However, they have a duty to try to get well, as sickness is considered undesirable by society. Seeking competent technical help and cooperating with caregivers are also expected of sick persons.

In summary, the sick role and illness behavior are important concepts in understanding how individuals respond to physical dysfunction and how society legitimizes and responds to illness.

The exact way in which acamprosate helps maintain alcohol abstinence is not fully understood. However, it is believed that chronic alcohol exposure disrupts the balance between neuronal excitation and inhibition. Studies conducted on animals suggest that acamprosate may interact with the glutamate and GABA neurotransmitter systems in the brain, which may help restore this balance. Acamprosate is thought to inhibit glutamate receptors while activating GABA receptors, specifically GABA-A and metabotropic glutamate receptors. It should be noted that some sources suggest that acamprosate affects NMDA receptors, which are a type of ionotropic glutamate receptor. However, this is not entirely accurate and may not be reflected in exam questions.

Mechanisms of Action of Different Drugs

Understanding the mechanisms of action of different drugs is crucial for medical professionals. It is a common topic in exams and can earn easy marks if studied well. This article provides a list of drugs and their mechanisms of action in different categories such as antidepressants, anti dementia drugs, mood stabilizers, anxiolytic/hypnotic drugs, antipsychotics, drugs of abuse, and other drugs. For example, mirtazapine is a noradrenaline and serotonin specific antidepressant that works as a 5HT2 antagonist, 5HT3 antagonist, H1 antagonist, alpha 1 and alpha 2 antagonist, and moderate muscarinic antagonist. Similarly, donepezil is a reversible acetylcholinesterase inhibitor used as an anti dementia drug, while valproate is a GABA agonist and NMDA antagonist used as a mood stabilizer. The article also explains the mechanisms of action of drugs such as ketamine, phencyclidine, buprenorphine, naloxone, atomoxetine, varenicline, disulfiram, acamprosate, and sildenafil.