Wilbert S. Aronow, MD

• Department of Medicine
• Division of Cardiology
• New York Medical College
• Westchester Medical Center
• Valhalla, NY

F reports may sometimes present a picture of a viral or pyogenic infection and if there is a laxity in the treatment of any of the three infections due to lack of proper diagnosis rheumatoid arthritis wrist mri purchase indocin 50 mg line, it could lead to dangerous consequences arthritis of feet diagnosing buy cheap indocin 75mg line. Almost all the specialist physicians agree that the diagnosis should never be done with guesswork can arthritis in the neck cause jaw pain cheap indocin 25mg mastercard. In resistant cases arthritis of the spine buy indocin 50 mg cheap, sparfloxacin or ciprofloxacin arthritis hot indocin 50mg discount, kanamycin injection arthritis in neck lump in throat buy indocin 75 mg mastercard, ethionamide or cycloserine can also be used as secondary medicines. All these drugs have some or the other side effects and therefore along with the symptoms of the patient, laboratory tests are regularly carried out. Small tumors can be removed along with biopsy by the latest surgery called stereotaxis biopsy. Surgery is rarely required for these tumors as they start resolving with the medicines. In this case, a small tube is introduced in to ventricles of the brain through the skull, and the extra fluid is drained out through a tunnel beneath the skin up to the stomach via the tube. Symptoms range from high fever, severe unbearable headache, vomiting, pain in the posterior part of the neck and photophobia to ultimately unconsciousness, seizures and eventually death in a short time, in the absence of proper treatment. The various types of Gram-positive and Gramnegative bacteria that can rapidly cause harm to the brain are, meningococcus, staphylococcus, pneumococcus, streptococcus, listeria, H. An early diagnosis and treatment can cure the patient without any long-term disability or side effects. If there is a severe headache with high fever, there is always a doubt of an infection of the brain. These germs can be identified accurately under a microscope with the help of gram stain. This allows the doctor to decide whether the medicines, which are prescribed prior to the test, are accurate or need to be changed. Thus, it is confirmed that the patient is definitely suffering from pyogenic meningitis and appropriate drugs are given after identifying the disease causing organisms. Drugs: If necessary drugs like cephalosporin, penicillin, vancomycin, gentamycin, chloramphenicol, metronidazole etc. All these medicines are very effective and 80 to 95 % cases can be cured if these drugs are used in appropriate dose and combination at an early stage. Usually, these medicines are given for 10 to 14 days continuously and if required, changes can be made on the basis of the culture report. F examination shows that all organisms have been destroyed and no more pus formation is taking place. Even if a little infection remains in the brain, there is a possibility of a recurrence of the disease in a short time. In such cases lumbar puncture is not carried out and suitable medicines are given. If necessary, surgery is done or the pus is extracted from the abscess by an expert neurosurgeon. Increase in the swelling of the brain (raised Intracranial tension), seizure, hydrocephalus, subdural effusion or subdural empyema (abscess between the membranes of the brain) or brain abscess, hearing loss, venous thrombosis, vasculitis etc. These strong medicines at times can cause side effects and therefore they should be taken carefully. There are many types of fungus like Cryptococcus, Coccidosis, Candida, Aspergillus, Histoplasma etc. This disease starts with low grade fever, headache, weakness, anxiety and therefore, initially it is not diagnosed and the disease advances in the absence of proper treatment leading to unconsciousness and seizures etc. These medicines have severe side effects on the kidney, liver, ears etc and thus should be administered carefully. Viral Encephalitis: this is an extremely fast spreading disease in which the patient gets fever, headache, sudden behavioural changes, depression, photophobia. This disease quickly damages the cells of the brain and many times leaves residual damage in the body, like memory loss, seizures or behavioral changes. Sometimes, the virus affects only the membranes of the brain causing viral meningitis, which is not a very serious disease in comparison. If the disease is diagnosed in the initial stage, immediate treatment can save life and disabilities. Like all medicines, the doctor determines the exact dosage and the duration of the medicine. There are not many side effects of this medicine, but caution should still be exercised. Similarly, there are some other viruses affecting the brain, they are called slow virus, and they destroy the brain cells slowly, in months and years. Medicines which are available are hardly effective and in most of the cases the patient is pushed to the brink of death. Falciparum Malaria: Malarial organisms are a part of the micro-organisms, but they are completely different from the virus and bacteria and belong to protozoa group. There are basically four types of malarial parasites, but the main are vivax and falciparum. The second part of-the cycle takes place in the cells of the human liver and in the red blood cells. When the Anopheles female mosquito bites a human, along with the sting the sporozoites of the malarial parasite enter the blood stream and within a short period enter the liver cells. Ultimately, the cells of the liver rupture and innumerable merozoites enter blood and then enter the red blood corpuscles. In this stage some of the merozoites get converted into gametocytes (Male and female). When a female Anopheles mosquito bites a malarial patient and sucks the blood, gametocytes also reach the stomach of the mosquito and there, in the stomach new sporozoites develop, which enter the blood stream of another person through the sting of the mosquito. The rest of the merozoites, which are present in the blood cells continue with the process of development, division and growth. Eventually, these red cells also rupture and innumerable merozoites are released in the blood stream and enter other red cells. This is also the cause of anemia (pallor or decrease in the hemoglobin levels) after frequent bouts of malaria. Thus, malarial parasites continue their life cycle in female anopheles mosquito and humans and keep the disease as well as themselves alive. Once the shivering stops, the body temperature rises (fever) and the patient feels warm. In addition to this headache, body ache, nausea, vomiting and dry cough may occur. These malarial parasites infect all the stages of the red blood corpuscles (Vivax infects only the newly formed blood cells) 1 to 2% of the total blood cells get infected. Thus the number of infected blood cells is considerably more and the resulting anemia is also more severe. These infected blood cells clog the capillaries causing unconsciousness (Cerebral malaria). When the patient is able to take the tablets orally, then the same is administered accordingly. Besides this pyrimethamine, tetracycline, doxycycline can also be given in less serious cases. Blood Test for Confirmation of Diagnosis: If the required blood test is carried out carefully, malarial parasites are normally seen in the blood cells in a peripheral smear. In falciparum malaria, the proportion of malarial parasite being more they can be seen very easily in the blood test, but in vivax type of malaria the numbers being less, many times they cannot be seen. It is better to collect the blood sample when the patient has fever, but this can also be done later. Many a times the blood tests are negative in a patient who has self medicated himself and has taken 2 to 4 tablets of chloroquin. The doctor has to treat the patient solely on the basis of the symptoms or repeat Q. If the fever is not cured even then, further investigations should be done to find out the exact cause and treatment given accordingly. It is said that in our country the main reason for the seizures in younger generation is the infection of a parasite named cysticercus, which occurs due to eating meat or unwashed salads. In this case along with the medicines to control the seizures, albendezole or praziquantel are also given in a proper dose by the neurologist. Avoiding meat and salads or if possible eating after washing properly and heating at low temperature can help avoid this disease. Tetanus: this disease occurs due to the toxin produced by a gram positive organism known as clostridium tetani. This poisonous chemical (exotoxin) excites the muscles and the nerves causing tetanus. Finally, it starts affecting the respiratory system and the swallowing muscles and seizures also start. Sometimes when the tetanus limits itself to the wounds, the chances of recovery are more, but in the full blown cases of tetanus, the death rate is around 60% despite treatment. Treatment: the treatment begins by giving Hyper Immune Globulin (3000 to 10000 units). Penicillin is the most reliable antibiotic for tetanus, which is given for 10 to 14 days. The patient is kept in a dark room and diazepam is given intravenously in proper dose to prevent seizures and spasms. Sometimes, neuromuscular blocking is done after keeping the patient on a ventilator. There can be problems like irregular blood pressure, fever, or heart trouble due to the irregularities of the involuntary nervous system, which also have to be treated carefully. These are the general guidelines for the prevention of tetanus because every individual/case has different factors and thus it is for the doctor to decide the treatment for each individual case. This disease is unfortunately still prevalent in our country because of poor hygiene, illiteracy and ignorance. The lack of cleanliness and proper medical services in the villages, thousands of lives, to such a preventable disease. Poliomyelitis: this viral infection of the brain is caused by enterovirus and damages the anterior horn cell of the brain and the spinal cord, which results in handicap. Fortunately, rigorous vaccination drives have nearly eradicated this disease from the face of the earth. The treatment is basically supportive and there is no specific treatment available. Avoiding intramuscular injections to small children during fever can prevent many polio cases. Rabies: Rabies is a, dangerous viral disease affecting the brain, which is contracted by the bite of any warm-blooded animal like a dog, monkey, fox etc. This disease can occur anytime between 30 to 60 days or even after 6 months of animal bite. In the initial stage there are certain behavioral changes and the patient stays excited and then he may suffer from paralysis etc. It is advisable that rabies vaccine and anti-serum be used in each and every case of animal bite. Summary: the discussion on various infectious diseases of the brain demonstrates that the infectious diseases of the body and the brain occur due to weakened immunity poor and therefore it is necessary to boost the immune system. An appropriate nutritional diet, with, adequate fruit and vegetable consumption, exercise, cleanliness, drinking boiled water etc. In addition to that, if there is a patient suffering from these infections in the office or at home one should be very careful. The doctors sometimes prescribe an antibiotic or some other medicine to the relatives of such a patient in order to avoid the disease; such medicines should be. Also, intake of unhygienic and non-nutritious food and beverages should be avoided. Due to the dwindling of these cells, which are the most important defence mechanism of the body, the entire immune system of the body gets affected and the immunity power of the body gradually decreases. Disposable syringes and needles should be used for injections and injections should be avoided for common diseases unless absolutely essential. The patient gets fever, muscular pain, swelling of lymph glands, red spots on the skin, swelling in the throat etc. After this phase various symptoms are seen like swelling of the lymph glands, continuous or frequent fever, ulceration in the mouth and throat, splenomegaly, prolonged coughing, weight loss etc. This test is a screening test and if it is positive, confirmation is done with the help of Western Blot test. Damage to the nerves of the nervous system result in neuritis caused by infectious organisms like Herpes etc. Polymyositis and other such muscle related diseases in which the muscles become weak. As a result the quality of the patients life can be improved, the infectious diseases can be prevented and the patient can move around and can remain mentally sound. Many a times the doctors use a combination of three medicines whose average monthly expense is around Rs. The irony is that in spite of this expenditure, the disease is neither completely cured nor controlled. Therefore, if the diagnosis of these organisms is done in an early stage and treated immediately these infections can be cured. They cause various common and specific symptoms depending on their size, type, location, properties and histology. Improvement in the surgical techniques and anesthesia, developments in stereo tactic and the micro neurological techniques, remarkable advances in radiation as well as chemotherapy have brightened the future of patients of brain tumors. Out of these many, are cases of cancer -that originate in the brain (primary) like glioma or spread from other parts of the body to the brain. Increased Intracranial pressure: Increase in the size of the tumor increases the pressure inside the skull (a fixed vault) as well as on the brain, causing symptoms like headache on both sides, nausea-vomiting, blackouts, uneasiness and diplopia. All cases of headache do not indicate brain tumor, only in 1 % of the cases, the cause of headache is brain tumor.

At 13 years old cirrhotic arthritis definition order 75 mg indocin with mastercard, the patient can be reassured if she has not yet completed sexual maturation arthritis tools buy indocin 25mg with mastercard. If breast development has not yet begun arthritis relief for wrists order indocin 50 mg, consider non-functioning ovaries since estrogen is necessary for breast development inflammatory arthritis diet remedies indocin 25mg low price. Most common etiology is Turner syndrome ("streak gonads") x rays of arthritis in fingers order indocin 25 mg online, so look for characteristic stigmata: short stature arthritis relief for dogs generic indocin 75mg visa, webbed neck, broad chest with wide-spaced nipples, etc. External genital exam this is crucial, since an examination of the introitus can identify an imperforate hymen. Look for clinical signs of hormonal abnormalities that commonly affect menses (see historical points above). Unless there has been no breast development at all, the most likely diagnosis in this patient is normal puberty, as her hypothalamic-pituitary-ovarian axis is still undergoing maturation. As discussed above, other diagnoses to consider include pregnancy, hyperandrogenism, thyroid disease, hyperprolactinemia, imperforate hymen, malnutrition, and excessive exercise. Unless history or physical exam suggests any of these, they are less likely in this patient. In the absence of pubertal delay or any significant history or physical exam findings suggestive of the diagnoses listed above, no further workup is needed for this patient as this is most likely normal puberty. Very high levels point to a problem with ovarian production of estrogen (lack of feedback inhibition) and very low levels point to a problem with the pituitary or hypothalamus ability to send a signal to the ovary. If any of the other diagnoses mentioned in the differential were suspected, relevant labs should be obtained. Again, in this patient, it would not be necessary until she fits the definition of primary amenorrhea. Diagnosis: the differential diagnosis is listed in the "Clinical Reasoning" section above. If this 13 year old is otherwise healthy and has breast development, the diagnosis in this case is normal pubertal development. A fourteen-year-old female well known to your practice makes an appointment to see you alone regarding a desire for contraception. While many states provide minors with the ability to obtain contraception without the involvement of parents, it is important to encourage the patient to discuss sexuality and sexual decision-making with her parents. Trying to keep contraception hidden makes compliance more challenging and may put an adolescent at higher risk for pregnancy. In addition, adolescents often lack a clear understanding of consequences and may not view sexual activity as a risk behavior. Involving adults can help provide perspective regarding health outcomes resulting from sexual activity. Discussions about contraception with this adolescent should include a conversation about alternative ways to express intimacy and affection besides sexual intercourse. If she still plans to have sex or wants to be prepared in case the opportunity arises, a discussion regarding the advantages and disadvantages of various methods should be pursued. Condoms, combined estrogen/progesterone methods (oral contraceptive pills, the transdermal patch, the intravaginal ring), and progesterone-only methods (intramuscular injections of depot medroxyprogesterone acetate, or Depo-Provera) are commonly used forms of birth control in the younger adolescent population. She should consider ease of use, ability to adhere to the contraceptive regimen, privacy of method, and side effects when choosing a form of birth control. Although children generally cannot receive medical care without the consent of their parents, adolescents under the age of 18 years are given the ability consent to their own health care in certain situations. While it is preferred to have a parent involved, it has been shown that some adolescents may not seek care for certain problems, such as sexual health, if a parent must be involved, thereby placing them at risk for negative health outcomes. Often they are able to consent to any health care if they are pregnant, are a parent, are married, or are fully and legally emancipated from their parents. In this case, the patient (in most states) would be able to seek contraception from her physician without her parents being involved. As they transition from childhood to adulthood, adolescents need to develop a sense of independence and autonomy from their parents. The ability to talk with a physician alone and in confidence not only reinforces this developmental task, but it also helps the physician build rapport with the adolescent, while also providing an opportunity for teens to talk about or seek care for issues they feel uncomfortable addressing with parents. Stressing the concept of privacy rather than secrecy, the concept of confidentiality should be discussed openly with adolescents and their parents from the initial visit. Everyone should be aware from the outset that when a parent is asked to leave the room during a visit, the content of the discussion will remain confidential between adolescent and heath care team, with a few exceptions such as concerns for self-harm. While it would be ideal for this adolescent to discuss contraception and sexual decision-making with a parent, she can opt to keep the discussion confidential. Your responsibility to the parent is to protect the welfare of the adolescent and act in her best interest. If you have concerns that she may be in an unsafe relationship, you may need to violate the confidentiality for the ultimate benefit and protection of the patient. But discussions about contraception, and even the decision to initiate contraception, can remain confidential (although you should make sure you know the specific confidentiality and consent provisions in your own state, as the specifics vary from state to state). It is important, however, to recognize that there are challenges to confidentiality when it comes to accessing services such as contraception or testing for sexually transmitted infections, especially with respect to payment. If the health care provider cannot guarantee confidentiality when providing contraception or sexual health services, he or she should be aware of other places in the community. P a g e 199 Suggestions for Learning Activities Do a role-play scenario with the adolescent, in which confidentiality is discussed, including the limits to confidentiality. Discuss birth control options available to adolescents, and the relative advantages and disadvantages of each method in the adolescent population. Have the students investigate the laws in their own state regarding circumstances in which adolescents may consent to their own health care. Confidential health care for adolescents: Position paper of the Society for Adolescent Medicine. P a g e 200 Issues Unique to Adolescence, Case #11 Written by Christy Peterson, M. A sixteen year old girl presents with fever and acute lower abdominal pain but denies urinary urgency or frequency. Definition for Specific Terms: Urinary urgency- A sudden compelling need to urinate. Urinary frequency- the need to urinate an increased number of times during the day or at night, in normal or decreased volumes. Review of Important Concepts: One of the most important concepts to take away from this case is that a pelvic exam is required when a sexually active female presents with abdominal pain regardless of the presence of fever. Historical Points Fully describe the pain: where, when, constant vs intermittent, severity, nature, onset, what are you doing when it comes, association with eating, associated symptoms, radiation of the pain, what makes it better, what makes it worse. Associated symptoms: vaginal bleeding, vomiting, diarrhea, vaginal discharge, and back pain are important associated symptoms to discuss. Patient Confidentiality: the question already discusses the most important question that you need to answer for this situation, "is she sexually active. Consider that many adolescents withhold information from their parents especially in the area of sexuality. Thus a private conversation (chaperone as needed) will increase your ability to get accurate information in the history. Other social history: this patient is involved in one high risk activity and this fact increases the likelihood that she would also engage in other risky behaviors. She is 16 and in most states a 16 year old has reached the age at which the courts consider her to be able to consent to sexual relations. However, it is still ok to ask her how old her partner is and whether or not she was forced to have sex with him. P a g e 201 Physical Exam Findings 1st question: Is the patient stable or unstable? Also consider admission for dehydration or vomiting to the point of not being able to keep oral medications down. Assess for signs of acute abdomen which include extreme tenderness to even light palpation or movement, rebound tenderness, high pitched bowel sounds, and absence of bowel sounds after three minutes of auscultation. Whether or not there is cervical motion tenderness is an important decisive point. A swab of the lining of the vaginal wall can also provide material for a wet prep. If he is over the age of 18 and she is more than 2 years younger than him this is statutory rape in most states. Paradise, Jan E and Linda Grant, Pelvic Inflammatory Disease in Adolescents Pediatrics in Review 1992 13:216-223. P a g e 203 Issues Unique to Adolescence, Case #12 Written by Christy Peterson, M. A fifteen year-old female comes to your clinic with complaints of bilateral leg pain. On physical examination, you notice that she has lost fifteen pounds since her last visit one year ago and she has missed her last six periods. Refusing to maintain body weight at or above minimum for normal according to age and height. Amenorrhea Amenorrhea- Cessation of menstruation when otherwise expected to occur. The pain that the child has may be muscle pain which can be caused by electrolyte disorders like hypokalemia, hypocalcemia and hypercalcemia. P a g e 204 Review of Important Concepts: Historical Points Fully expand on the pain; (where, when, timing, onset, description, intensity, when in relation to exercise, what makes it worse, what makes it better, related symptoms. Ask family members about trips to the bathroom after meals or requests to be excused from family meals and preference to eat alone. Vitals: Are there any signs of hypovolemia like a drop in blood pressure on standing? Perform orthostatic blood pressure and pulse measurements, lying, sitting and standing. Lymph: Check axillary nodes and inguinal nodes as well as cervical and supraclavicular for any signs of lymphadenopathy or any signs of cancer to explain the weight loss? Clinical Reasoning What information in this patient scenario do you find concerning and how would you approach her evaluation? The fact that the pain is bilateral would lead you to look for a muscular source rather than the bones. This muscular pain could be from overuse or excessive exercise but a systemic cause is more likely. One likely cause of the pain, if you suspect anorexia nervosa, is hypokalemia, however labs may be normal. If you diagnose anorexia ask yourself, "Does the patient need to be admitted to the hospital? Have the patient set a weight goal, keep a food diary and return within one month. Abnormal values require a second thought about the diagnosis or admission to the hospital. Disordered eating, Anorexia/Bulimia with myopathy from electrolyte disturbances is the number one possibility but the history must support this and even in the face of typical history, a full physical exam and labs are necessary to determine the need or lack thereof for hospital admission and to rule out other causes. Female athletic triad may be present along with the eating disorder and again the muscle pain could be from electrolyte disturbances. Otherwise pain is not typically part of the female athletic triad unless there is a fracture. The fracture could be from decreased bone mineral density and could only be caused by repetitive stress on the weakened bone (stress fracture) but bilateral stress fractures are highly unlikely. Exercise related leg pain (shin splints) is possible but even in the presence of excessive exercise this would be a diagnosis of exclusion. The history would be of pain more at night and the pain would be at least lessened by movement of the legs. Suggestions for Learning Activities: Have students discuss the next step after diagnosis of anorexia. P a g e 207 Issues Unique to Adolescents, Case #13 Written by Rachel S-D Fortune, M. A previously healthy sixteen-year-old girl presents for a routine health care supervision visit with her mother. Definitions for Specific Terms: Confidentiality- the ethical principle or legal right that a physician or other health professional will hold secret all information relating to a patient, unless the patient gives consent permitting disclosure. A person must be of sufficient mental capacity and of the age at which he or she is legally recognized as competent to give consent (age of consent). Legal issues Please be familiar with your local laws regarding what treatments a teen can consent to on her-own behalf. Although your patient has legal rights to obtain care on her own, some parents are not comfortable with this and will be resistant to you talking to their child alone. Setting the stage the medical provider needs to be very clear with the patient as to what the provider can keep confidential in the medical setting. The provider should not give the teen the impression that everything they discuss can be kept confidential. Generally speaking, the provider should use a statement such as this: "Many things that we discuss can be kept between you and me. However, if you tell me that you or someone else is in danger, or doing something very dangerous, I will have to share that information with your parents or guardian. If you disclose to me that you have been abused then I need to report this information too". This confidentiality disclosure should be given while the parent or guardian is still in the room if they are there for the appointment. A mandated reporter is someone who is bound by the law to report cases of abuse and neglect. As a medical provider, if your patient tells you about abuse or neglect, you are required to inform your local child protection services. Approaches to the challenging parent Remember to remain objective and calm, even if the parent is becoming upset. Share with the parent that talking to the patient alone is standard of care for all adolescents and recommended by the American Academy of Pediatrics and the Society for Adolescent Health and Medicine, as well as all P a g e 208 other medical agencies that deal with the medical care of teenagers.

Question What is the underlying problem here that has not been completely defined? Answer this patient has a significant haemolytic anaemia arthritis in the knee and yoga trusted 25 mg indocin, which is of recent onset and is thus most likely to be due to his treatment with prophylactic antimalarial drugs arthritis pain herbal remedies trusted 25mg indocin. The lack of this enzyme often only becomes clinically manifest when the red cell is stressed arthritis in back and running generic indocin 50 mg amex, as in the presence of an oxidant such as chloroquine (other common drugs that precipitate haemolysis include primaquine arthritis cervical fusion generic 25 mg indocin, dapsone arthritis in dogs what to give order indocin 75 mg visa, sulphonamides does acupuncture help arthritis in fingers purchase 50mg indocin otc, the 4-quinolones, nalidixic acid and ciprofloxacin, nitrofurantoin, aspirin and quinidine). The patient should be asked whether anyone in his family has ever experienced a similar condition, as it is inherited as an X-linked defect. Patients whose ethnic origins are from Africa, Asia, southern Europe (Mediterranean) and Oceania are more commonly affected. Stopping the chloroquine and treating with folate and iron should improve the anaemia and symptoms. In addition to surgery, radiotherapy and chemotherapy, attention to psychiatric and social factors is also essential. Accurate staging is important and where disease remains localized cure, using surgery or radiotherapy, may be possible. If the tumour is widespread at presentation, systemic chemotherapy is more likely to be effective than radiotherapy or surgery, although these may be used to control local disease or reduce the tumour burden before potentially curative chemotherapy. In approximately 50% of human cancers, genetic mutations contribute to the neoplastic transformation. Some cancer cells overexpress oncogenes (first identified in viruses that caused sarcomas in poultry). Oncogenes encode growth factors and mitogenic factors that regulate cell cycle progression and cell growth. Alternatively, neoplastic cells may overexpress growth factor receptors, or underexpress proteins. The overall effect of such genetic and environmental factors is to shift the normal balance to dysregulated cell proliferation. Unlike normal adult somatic cells, neoplastic cells are immortal and do not have a programmed finite number of cell divisions before they become senescent. The element of cell replication responsible for this programme is the telomere, located at the end of each chromosome. Telomeres are produced and maintained by telomerase in germ cells and embryonic cells. Telomerase loses its function in the course of normal cell development and differentiation. In healthy somatic cells, a component of the telomere is lost with each cell division, and such telomeric shortening functions as an intrinsic cellular clock. Approximately 95% of cancer cells re-express telomerase, allowing them to proliferate endlessly. These drug effects are not confined to malignant cells, and many anti-cancer agents are also toxic to normal dividing cells, particularly those in the bone marrow, gastrointestinal tract, gonads, skin and hair follicles. There are two main groups of cytotoxic drugs, classified by their effects on cell progression through the cell cycle (see Figure 48. Because of this, their dose­cytotoxicity relationships follow first-order kinetics (cells are killed exponentially with increasing dose). Cytotoxic drugs are given at very high doses over a short period, thus rendering the bone marrow aplastic, but at the same time achieving a very high tumour cell kill. Their dose­cytotoxicity curve is initially exponential, but at higher doses the response approaches a maximum (see Figure 48. Until the kinetic behaviour of human tumours can be adequately characterized in individual patients the value of this classification is limited. The distinction between cell cycle phase-non-specific and phase-specific drugs, although clear-cut in animal and in vitro experiments, is also probably an over-simplification. E 2F Log % cells surviving Log % cells surviving div ve Glucocorticosteroids is (a) Dose (b) Dose Figure 48. Acquired tumour drug resistance results from the selection of resistant clones as a result of killing susceptible cells or from an adaptive change in the neoplastic cell. The ability to predict the sensitivity of bacterial pathogens to antimicrobial substances in vitro produced a profound change in the efficacy of treatment of infectious diseases. The development of analogous predictive tests has long been a priority in cancer research. Such tests would be desirable because, in contrast to antimicrobial drugs, anticancer agents are administered in doses that produce toxic effects in most patients. Unfortunately, currently, clinically useful predictive drug sensitivity assays against tumours do not exist. Cytotoxic cancer chemotherapy is primarily used to induce and maintain a remission or tumour response according to the following general principles. It often entails complex regimens of two to four drugs, including pulsed doses of a cytotoxic agent with daily treatment with agents with different kinds of actions. Knowing the details of such regimens is not expected of undergraduate students and graduate trainees in oncology will refer to advanced texts for this information. This is less immunosuppressive and generally more effective than continuous low-dose regimens. Key points Principles of cytotoxic chemotherapy · · · · · · Cytotoxic drugs kill a constant percentage of cells ­ not a constant number. Cells have discrete periods of the cell cycle during which they are sensitive to cytotoxic drugs. The most frequent adverse effects of cytotoxic chemotherapy are summarized in Table 48. This is usually delayed for one to two hours after drug administration and may last for 24­48 hours or even be delayed for 48­96 hours after therapy. It may also be necessary to give the patient a supply of as-needed medication for the days after chemotherapy. No prophylactic anti-emetic treatment is 100% effective, especially for cisplatin-induced vomiting. Careful attention to the correct intraluminal location of vascular catheters for intravenous cytotoxic drug administration is mandatory. Second malignancy Sometimes vomiting may be anticipatory and this may be minimized by treatment with benzodiazepines. It is often routine to use two- or three-drug combinations as prophylactic anti-emetic therapy. Support with blood products (red cells and platelet concentrates) and early antibiotic treatment (see below) is crucial to chemotherapy, since aplasia is an anticipated effect of many effective regimens. However, many resume normal menstruation when treatment is stopped and pregnancy is then possible, especially in younger women who are treated with lower total doses of cytotoxic drugs. Sperm storage before chemotherapy can be considered for males who wish to have children in the future. Reproductively active men and women must be advised to use appropriate contraceptive measures during chemotherapy, as a reduction in fertility with these drugs is not universal and fetal malformations could ensue. It is best to avoid conception for at least six months after completion of cytotoxic chemotherapy. Polymorph count/mm3 5000 1000 500 Secondary fall 100 0 3 9 15 21 03 Therapy 9 15 21 27 33 39 45 51 57 Therapy Figure 48. This malignancy is also approximately 20 times more likely to develop in patients with ovarian carcinoma treated with alkylating agents with or without radiotherapy. This delayed treatment complication is likely to increase in prevalence as the number of patients who survive after successful cancer chemotherapy increases. Key points Adverse effects of cytotoxic chemotherapy Immediate effects: ­ nausea and vomiting. Classical signs of infection ­ other than pyrexia ­ are often absent in neutropenic patients, and constant vigilance is required to detect and treat septicaemia early. Broad-spectrum antibiotic treatment must be started empirically in febrile neutropenic patients before the results of blood and other cultures are available. Combination therapy with an aminoglycoside active against Pseudomonas and other Gram-negative organisms. Alternatively, monotherapy with a third- or fourth-generation cephalosporin active against -lactamase-producing organisms. Pneumocystis carinii) can occur; details of the treatment for such infections are to be found in Chapters 43, 45 and 46. This may be ameliorated in the case of doxorubicin by cooling the scalp with, for example, ice-cooled water caps. The reactive ethyleneimine ion forms spontaneously due to cyclization in solution. If a tumour is sensitive to one alkylating agent, it is usually sensitive to another, but cross-resistance does not necessarily occur. The pharmacokinetic properties of the different drugs are probably important in this respect. For example, although most alkylating agents diffuse passively into cells, mustine is actively transported by some cells. Cyclophosphamide is highly effective in treating various lymphomas, leukaemias and myeloma, but also has some use in other solid tumours. It is converted to active metabolites in the liver (see above); these are excreted by the kidneys. Absorption from the gastro-intestinal tract is excellent (essentially 100% bioavailabilty). Renal excretion of one of its metabolites, acrolein, causes the haemorrhagic cystitis that accompanies high-dose therapy. It is also a weak monoamine oxidase inhibitor and may precipitate a hypertensive crisis with tyramine-containing foods (Chapter 20). Because mesna is excreted more rapidly (t1/2 is 30 minutes) than cyclophosphamide and ifosfamide, it is important that it is given at the initiation of treatment, and that the dosing interval is no more than four hours. Cisplatin is markedly effective for testicular malignancies and several other solid tumours, including carcinoma of the ovary, lung, head and neck, and bladder may also respond well. Because of the efficacy of platinum compounds and the toxicity of cisplatin, there has been a search for less toxic analogues, yielding carboplatin and oxaliplatin. The comparative pharmacology of carboplatin and oxaliplatin is summarized in Table 48. Mechanism of action Mesna protects the uro-epithelium by reacting with acrolein in the renal tubule to form a stable, non-toxic thioether. Adverse effects these include the following: · severe nausea and vomiting; · nephrotoxicity (especially cisplatin) which is dose-related and dose-limiting. Low potential for ototoxicity and neuropathy Pharmacokinetics Activation slower than cisplatin t1/2 2­3 h, 60­70% excreted in the urine in first 24 h Additional comments Anti-tumour spectrum similar to that of cisplatin Oxaliplatin i. Folinic acid circumvents this biosynthetic block and thus non-competitively antagonizes the effect of methotrexate. Plasma disappearance of cisplatin is multiphasic and traces of platinum are detectable in urine months after treatment. Drug interactions Additive nephrotoxicity and ototoxicity occurs with aminoglycosides or amphotericin. Determinants of methotrexate toxicity these consist of: · a critical extracellular concentration for each target organ; · a critical duration of exposure that varies for each organ. For bone marrow and gut, the critical plasma concentration is 2 10 8 M and the time factor is approximately 42 hours. The severity of toxicity is proportional to the length of time for which the critical concentration is exceeded and is independent of the amount by which it is exceeded. Folinic acid rescue bypasses the dihydrofolate reductase blockade and minimizes methotrexate toxicity. Some malignant cells are less able to take up folinic acid than normal cells, thus introducing a degree of selectivity. Rescue is commenced 24 hours after methotrexate administration and continued until the plasma methotrexate concentration falls below 5 10 8 M. Monitoring of the plasma methotrexate concentrations has improved the safe use of this drug and allows identification of patients at high risk of toxicity. Unfortunately, the pathways blocked by antimetabolites are not specific to neoplastic cells. Methotrexate is also an immunosuppressant (Chapters 26 and 50) and is used to inhibit cellular proliferation in severe psoriasis (Chapter 51). There are several different dosage schedules, several of which require co-administration of folinic acid (see Figure 48. Adverse effects these include the following: myelosuppression; nausea and vomiting; stomatitis; diarrhoea; cirrhosis ­ chronic low-dose administration (as for psoriasis) can cause chronic active hepatitis and cirrhosis, interstitial pneumonitis and osteoporosis; · renal dysfunction and acute vasculitis (after high-dose treatment); · intrathecal administration also causes special problems, including convulsions, and chemical arachnoiditis leading to paraplegia, cerebellar dysfunction and cranial nerve palsies and a chronic demyelinating encephalitis. Renal insufficiency reduces methotrexate elimination and monitoring plasma methotrexate concentration is essential under these circumstances. Acute renal failure can be caused by tubular obstruction with crystals of methotrexate. Diuresis (3 L/day) with alkalinization (pH 7) of the urine using intravenous sodium bicarbonate reduces nephrotoxicity. Renal damage is caused by the precipitation of methotrexate and 7-hydroxymethotrexate in the tubules, and these weak acids are more water soluble at an alkaline pH, which favours their charged form (Chapter 6). About 80­95% of a dose of methotrexate is renally excreted (by filtration and active tubular secretion) as unchanged drug or metabolites. Other weak acids including furosemide and high-dose vitamin C compete for renal secretion. Dose reduction is required for hepatic dysfunction or in patients with a genetic deficiency of dihydropyridine dehydrogenase. Pharmacokinetics Methotrexate absorption from the gut occurs via a saturable transport process, large doses being incompletely absorbed. After intravenous injection, methotrexate plasma concentrations decline in a triphasic manner, with prolonged terminal elimination due to enterohepatic circulation. This terminal phase is important because toxicity is related to the plasma concentrations during this phase, as well as to the peak methotrexate concentration.

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Comment Although highly effective in causing diuresis in patients with resistant oedema, combination diuretic treatment with loop, K -sparing and thiazide diuretics can cause acute prerenal renal failure with a disproportionate increase in serum urea compared to creatinine. Case history A 73-year-old man has a long history of hypertension and of osteoarthritis. Three months ago he had a myocardial infarction, since when he has been progressively oedematous and dyspnoeic, initially only on exertion but more recently also on lying flat. He continues to take co-amilozide for his hypertension and naproxen for his osteoarthritis. The blood pressure is 164/94 mmHg and there are signs of fluid overload with generalized oedema and markedly elevated jugular venous pressure. Why would it be hazardous to commence furosemide in addition to his present treatment? Comment the patient may go into prerenal renal failure with the addition of the loop diuretic to the two more distal diuretics he is already taking in the co-amilozide combination. Case history A 35-year-old woman has proteinuria (3 g/24 hours) and progressive renal impairment (current serum creatinine 220 mol/L) in the setting of insulin-dependent diabetes mellitus. In addition to insulin, she takes captopril regularly and buys ibuprofen over the counter to take as needed for migraine. She develops progressive oedema which does not respond to oral furosemide in increasing doses of up to 250 mg/day. Amiloride (10 mg daily) is added without benefit and metolazone (5 mg daily) is started. Her blood pressure is 90/60 mmHg, heart rate is 86 beats/minute and regular, and she has residual peripheral oedema, but the jugular venous pressure is not raised. Hydrochlorothiazide reduces loss of cortical bone in normal postmenopausal women: a randomized controlled trial. Since the introduction of insulin, the therapeutic focus has broadened from treating and preventing diabetic ketoacidosis to preventing long-term vascular complications. Type 2 diabetes ­ where insulin resistance and a relative lack of insulin lead to hyperglycaemia ­ not only causes symptoms related directly to hyperglycaemia (polyuria, polydipsia and blurred vision ­ see below), but is also a very powerful risk factor for atheromatous disease. Glucose intolerance and diabetes mellitus are increasingly prevalent in affluent and developing countries, and represent a major public health challenge. Addressing risk factors distinct from blood glucose, especially hypertension, is of paramount importance and is covered elsewhere (Chapters 27 and 28). In this chapter, we focus mainly on the types of insulin and oral hypoglycaemic agents. It lowers blood glucose, but also modulates the metabolic disposition of fats and amino acids, as well as carbohydrate. It is secreted together with inactive C-peptide, which provides a useful index of insulin secretion: its plasma concentration is low or absent in patients with type 1 diabetes, but very high in patients with insulinoma (an uncommon tumour which causes hypoglycaemia by secreting insulin). C-peptide concentration is not elevated in patients with hypoglycaemia caused by injection of insulin. Diabetes mellitus (fasting blood glucose concentration of 7 mmol/L) is caused by an absolute or relative lack of insulin. However, concordance in identical twins is somewhat less than 50%, so it is believed that genetically predisposed individuals must also be exposed to an environmental factor. Viruses (including Coxsackie and Echo viruses) are one such factor and may initiate an autoimmune process that then destroys the islet cells. In type 2 diabetes there is a relative lack of insulin secretion, coupled with marked resistance to its action. The circulating concentration of immunoreactive insulin measured by standard assays (which do not discriminate well between insulin and pro-insulin) may be normal or even increased, but more discriminating assays indicate that there is an increase in proinsulin, and that the true insulin concentration is reduced. Type 2 diabetes is rarely if ever associated with diabetic ketoacidosis, although it can be complicated by non-ketotic hyperosmolar coma or, rarely (in association with treatment with a biguanide drug such as metformin, see below), with lactic acidosis. An increased concentration of glucose in the circulating blood gives rise to osmotic effects: 1. Diabetic neuropathy causes a glove and stocking distribution of loss of sensation with associated painful paraesthesiae. Approximately one-third of diabetic patients develop diabetic nephropathy, which leads to renal failure. Macrovascular disease is the result of accelerated atheroma and results in an increased incidence of myocardial infarction, peripheral vascular disease and stroke. There is a strong association (pointed out by Reaven in his 1988 Banting Lecture at the annual meeting of the American Diabetes Association) between diabetes and obesity, hypertension and dyslipidaemia (especially hypertriglyceridaemia), and type 2 diabetes is strongly associated with endothelial dysfunction, an early event in atherogenesis (Chapter 27). In young type 1 patients there is good evidence that improved diabetic control reduces microvascular complications. It is well worth trying hard to minimize the metabolic derangement associated with diabetes mellitus in order to reduce the development of such complications. Education and support are essential to motivate the patient to learn how to adjust their insulin dose to optimize glycaemic control. This can only be achieved by the patient performing blood glucose monitoring at home and learning to adjust their insulin dose accordingly. A common strategy is to combine injections of a short-acting insulin before each meal with a once daily injection of a long-acting insulin to provide a low steady background level during the night. Follow up must include structured care with assessment of chronic glycaemic control using HbA1c and regular screening for evidence of microvascular disease. This is especially important in the case of proliferative retinopathy and maculopathy, because prophylactic laser therapy can prevent blindness. By contrast, striving for tight control of blood sugar in type 2 patients is only appropriate in selected cases. Tight control reduces macrovascular complications, but at the expense of increased hypoglycaemic attacks, and the number of patients that needs to be treated in this way to prevent one cardiovascular event is large. In contrast, aggressive treatment of hypertension is of substantial benefit, and the target blood pressure should be lower than in non-diabetic patients (130 mmHg systolic and 80 mmHg diastolic, see Chapter 28). In older type 2 patients, hypoglycaemic treatment aims to minimize symptoms of polyuria, polydipsia or recurrent Candida infection, and to prevent hyperosmolar coma. Animal insulins have been almost entirely replaced by recombinant human insulin and related analogues. For example, a lysine and a proline residue are switched in insulin lispro, which consequently has a very rapid absorption and onset (and can therefore be injected immediately before a meal), whereas insulin glargine is very slow acting and is used to provide a low level of insulin activity during the 24-hour period. Insulin is usually administered by subcutaneous injection, although recently an inhaled preparation has been licensed for use in type 2 diabetics. It is administered intravenously in diabetic emergencies and given subcutaneously before meals in chronic management. Formulations of human insulins are available in various ratios of short-acting and longer-lasting forms. The small dose of soluble insulin controls hyperglycaemia just after the injection. When starting a diabetic on a two dose per day regime, it is therefore helpful to divide the daily dose into two-thirds to be given before breakfast and one-third to be given before the evening meal. If the patient engages in strenuous physical work, the morning dose of insulin is reduced somewhat to prevent exercise-induced hypoglycaemia. Insulin is also required for symptomatic type 2 diabetics in whom diet and/or oral hypoglycaemic drugs fail. Unfortunately, insulin makes weight loss considerably more difficult because it stimulates appetite, but its anabolic effects are valuable in wasted patients with diabetic amyotrophy. Insulin is needed in acute diabetic emergencies such as ketoacidosis, during pregnancy, peri-operatively and in severe intercurrent disease (infections, myocardial infarction, burns, etc. Insulin requirements are increased by up to one-third by intercurrent infection and patients must be instructed to intensify home blood glucose monitoring when they have a cold or other infection (even if they are eating less than usual) and increase the insulin dose if necessary. Vomiting often causes patients incorrectly to stop injecting insulin (for fear of hypoglycaemia) and this may result in ketoacidosis. Patients for elective surgery should be changed to soluble insulin preoperatively. This is continued post-operatively until oral feeding and intermittent subcutaneous injections 287 of insulin can be resumed. A similar regime is suitable for emergency operations, but more frequent measurements of blood glucose are required. Patients with type 2 diabetes can sometimes be managed without insulin, but the blood glucose must be regularly checked during the post-operative period. Conservation of K is even less efficient than that of Na in the face of acidosis and an osmotic diuresis, and large amounts of intravenous K are often needed to replace the large deficit in total body K. Fat is mobilized from adipose tissue, releasing free fatty acids that are metabolized by -oxidation to acetyl coenzyme A (CoA). In the absence of glucose breakdown, acetyl CoA is converted to acetoacetate, acetone and -hydroxybutyrate (ketones). There are therefore a number of metabolic abnormalities: · Sodium and potassium deficit A generous volume of physiological saline (0. When blood glucose levels fall below 17 mmol/L, 5% glucose is given in place of N-saline. Potassium must be replaced and if the urinary output is satisfactory and the plasma potassium concentration is 4. Bicarbonate treatment to reverse the extracellular metabolic acidosis is controversial, and may paradoxically worsen intracellular and cerebrospinal fluid acidosis. Key points Type 1 diabetes mellitus and insulin · Type 1 (insulin-dependent) diabetes mellitus is caused by degeneration of -cells in the islets of Langerhans leading to an absolute deficiency of insulin. Even with insulin treatment, such patients are susceptible to microvascular complications of retinopathy, nephropathy and neuropathy, and also to accelerated atherosclerotic (macrovascular) disease leading to myocardial infarction, stroke and gangrene. Management includes a healthy diet low in saturated fat (Chapter 27), high in complex carbohydrates and with the energy spread throughout the day. Regular subcutaneous injections of recombinant human insulin are required indefinitely. Regular selfmonitoring of blood glucose levels throughout the day with individual adjustment of the insulin dose is essential to achieve good metabolic control, which reduces the risk of complications. Fluid loss is restored using physiological saline (there is sometimes a place for halfstrength, 0. Magnesium deficiency is common, contributes to the difficulty of correcting the potassium deficit, and should be treated provided renal function is normal. In this hyperosmolar state, the viscosity of the blood is increased and a heparin preparation (Chapter 30) should be considered as prophylaxis against venous thrombosis. Pharmacokinetics Insulin is broken down in the gut and by the liver and kidney, and is given by injection. It is metabolized to inactive and peptide chains largely by hepatic/renal insulinases (insulin glutathione transhydrogenase). Insulin from the pancreas is mainly released into the portal circulation and passes to the liver, where up to 60% is degraded before reaching the systemic circulation (presystemic metabolism). The kidney is also important in the metabolism of insulin and patients with progressive renal impairment often have a reduced requirement for insulin. There is no evidence that diabetes ever results from increased hepatic destruction of insulin, but in cirrhosis the liver fails to inactivate insulin, thus predisposing to hypoglycaemia. Mechanism of action Insulin acts by binding to transmembrane glycoprotein receptors. It is treated with an intravenous injection of glucose in unconscious patients, but sugar is given as a sweet drink in those with milder symptoms. Glucagon (1 mg intramuscularly, repeated after a few minutes if necessary) is useful if the patient is unconscious and intravenous access is not achievable. Insulin-induced post-hypoglycaemic hyperglycaemia (Somogyi effect) occurs when hypoglycaemia. The situation can be misinterpreted as requiring increased insulin, thus producing further hypoglycaemia. Local or systemic allergic reactions to insulin, with itching, redness and swelling at the injection site. Insulin resistance, defined arbitrarily as a daily requirement of more than 200 units, due to antibodies, is unusual. Changing to a highly purified insulin preparation is often successful, a small starting dose being used to avoid hypoglycaemia. Most type 2 diabetic patients initially achieve satisfactory control with diet either alone or combined with one of these agents. The small proportion who cannot be controlled with drugs at this stage (primary failure) require insulin. Subsequent failure after initially adequate control (secondary failure) occurs in about one-third of patients, and is treated with insulin. Its anorectic effect aids weight reduction, so it is a first choice drug for obese type 2 patients, provided there are no contraindications. It must not be used in patients at risk of lactic acidosis and is contraindicated in: renal failure (it is eliminated in the urine, see below); alcoholics; cirrhosis; chronic lung disease (because of hypoxia); cardiac failure (because of poor tissue perfusion); congenital mitochondrial myopathy (which is often accompanied by diabetes); · acute myocardial infarction and other serious intercurrent illness (insulin should be substituted). Plasma creatinine and liver function tests should be monitored before and during its use.

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