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By Z. Bram. Southern Methodist University.

If this persists beyond 4 cycles order lamictal 50 mg overnight delivery treatment 7th march, adjust dose or use a different combination of drugs order 50mg lamictal with visa medicine 94. Editorial comments • Avariety of estrogen/progestin combinations are available in the United States (see table in Appendix) purchase 100mg lamictal otc aquapel glass treatment. They are divided into monophasic therapy (single dosage of estrogen/progestin for specific time) 100mg lamictal fast delivery treatment whiplash, biphasic (increased progestin dose for “second phase”), and triphasic (three dosage regimens per month with variance of either estrogen or progestin dosage). Mechanism of action: Inhibits sodium and chloride reabsorption in proximal part of ascending loop of Henle. Contraindications: Hypersensitivity to sulfonamides, anuria, severe progressive renal disease, hepatic coma, severe elec- trolyte depletion. Ethambutol is administered in combination with the fol- lowing antituberculosis drugs: isoniazid, rifampin, pyrazinamide. Adjustment of dosage • Kidney disease: Creatinine clearance 30–60 mL/min: decrease dosage by 50%; creatinine clearance 10–30 mL/min: decrease dosage by 75%; creatinine clearance <10 mL/min: dose 3 times/wk. Contraindications: Optic neuritis (relative contraindication), hyper- sensitivity to ethambutol. Warnings/precautions • Use with caution in patients with the following conditions: cataracts, inflammatory conditions of the eye, renal disease, gout, diabetic retinopathy. Clinically important drug interactions: Ethambutol increases effects/toxicity of drugs that produce neurotoxicity. Discontinue if these occur, particularly when there are changes in color per- ception. If visual impairment occurs and is not identified, con- tinued treatment with ethambutol may lead to permanent blindness. Editorial comments • Ethambutol is not to be used as the sole therapy for tuberculo- sis as resistance can develop rapidly. Mechanism of action: Reversibly inhibits initiation and conduc- tion of nerve impulses near site of injection. Contraindications: Hypersensitivity for amide-type local anesthetic (eg, lidocaine), sensitivity to sodium metabisulfate (in preparations containing epinephrine). Any increase in heart rate and systolic pressure within 45 seconds (the epinephrine response) would indicate that the injection is intravascular. The necessary means must be available to manage this condition (dantrolene, oxygen, sup- portive measures). Editorial comments • Etidocaine is not recommended for obstetric or non-obstetric paracervical block. Mechanism of action: Inhibits cyclooxygenase, resulting in inhi- bition of synthesis of prostaglandins and other inflammatory mediators. Extended release tablets: 400–1000 mg once daily • Acute pain Ð Adults: 200–1000 mg q6–8h. Adjustment of dosage • Kidney disease: Creatinine clearance 10–50 mL/min: reduce dose by 25%; creatinine clearance ≤10 mL min: reduce dose by 50%. Contraindications: Hypersensitivity to etoposide; intrapleural or intrathecal route. Warnings/precautions: Use with caution in patients with low serum albumin, liver and kidney disease. Advice to patient • Use two forms of birth control including hormonal and barrier methods. Adverse reactions • Common: nausea and vomiting (30–40%), diarrhea (10%), anorexia (10–16%), reversible alopecia, mucositis. Clinically important drug interactions • Drugs that increase effects/toxicity of etoposide: calcium chan- nel blockers. Discontinue drug administration if platelets <50,000/mm3 or neutrophil count <500/mm3. Editorial comments • Use latex gloves and safety glasses when handling cytotoxic drugs. Adjustment of dosage • Kidney disease: Creatinine clearance 40–59 mL/min: dose q12h; creatinine clearance 20–30 mL/min: dose q24h; creati- nine clearance <20 mL/min: dose q48h. Advice to patient • Inform patient how to recognize early symptoms of herpes zoster infection, eg, itching, pain. Cimetidine (another H2 blocker) is considered compatible by American Academy of Pediatrics. Advice to patient • Change position slowly, in particular from recumbent to upright, to minimize orthostatic hypotension. Sit at the edge of the bed for several minutes before standing, and lie down if feeling faint or dizzy. Clinically important drug interactions • Drugs that increase effects/toxicity of calcium blockers: cime- tidine, β blockers, cyclosporine. Impaired renal function prolongs duration of action and increases tendency for toxi- city. Clinically important drug interactions: Other antihypertensive agents increase effects/toxicity of fenoldapam. Editorial comments: Fenoldapam has advantages over nitroprus- side because of its beneficial effects on renal function, particularly in patients with renal impairment. Increase in urine output will be maintained in patients on fenoldapam who are recovering from surgery (cardiac or noncardiac). Mechanism of action: Inhibits cyclooxygenase, resulting in inhi- bition of synthesis of prostaglandins and other inflammatory mediators. Mechanism of action: Binds to opiate receptors and blocks ascend- ing pain pathways. Adjustment of dosage • Kidney disease: Creatinine clearance 10–50 mL/min: give 75% of normal dose; creatinine clearance <10 mL/min: give 50% of normal dose. Contraindications: Hypersensitivity to narcotics of the same chem- ical class, management of acute or postoperative pain, use in outpatient surgeries. Warnings/precautions • Use with caution in patients with the following conditions: head injury with increased intracranial pressure, serious alco- holism, prostatic hypertrophy, chronic pulmonary disease, severe liver or kidney disease, postoperative patients with pul- monary disease, disorders of biliary tract. If nausea and vomiting per- sist, it may be necessary to administer an antiemetic, eg, droperidol or prochlorperazine. This drug can cause severe hypotension in a patient who is volume depleted or if given along with a phe- nothiazine or general anesthetic. Editorial comments • Transdermal fentanyl has become an important therapy for severe chronic pain. When such combination therapy is contem- plated, the dose of one or the other drugs should be reduced by 50% or more. Mechanism of action: Iron in ferrous sulfate replaces ferrous iron in formation of hemoglobin which is reduced in anemia. Eggs, coffee, tea, milk inhibit iron absorption and should be avoided when taking ferrous sulfate. Adverse reactions • Common: constipation, black stools, epigastric pain (15%), heartburn. Clinically important drug interactions • Drugs that increase effects/toxicity of ferrous sulfate: ascorbic acid (vitamin C). Advice to patient • Avoid driving and other activities requiring mental alertness or that are potentially dangerous until response to drug is known. Parameters to monitor: Efficacy of treatment: improvement of symptoms of rhinitis including sneezing, rhinorrhea, itchy/ watery eyes.

Poly- hedral niosomes are formed when cholesterol content is low in the same system (43) discount 50 mg lamictal with mastercard medications zyprexa. Polyhedral niosomes are thermoresponsive and release the encapsulated drug when heated above 35◦C (40) purchase lamictal 50 mg with amex treatment zap. This can be useful for sunscreen formulations in which the sunscreen can be released on exposure to sun (40) cheap lamictal 100 mg amex symptoms quitting weed. Niosomes have been shown to penetrate the skin and enhance the permeation of drugs (44) discount lamictal 25mg overnight delivery medications emts can administer. Span nio- somes showed significantly higher skin permeation and partitioning of enoxacin than those shown by liposomes and the free drug (44). The niosomes dissociate and form loosely bound aggregates, which then penetrate to the deeper strata (40). Furthermore, the skin penetration has been attributed to the flexibility of niosomes, and this is supported by the fact that a decrease in choles- terol content increases the drug penetration through the skin (45). In addition, adsorption and fusion of niosomes with the skin surface increase the drug’s thermodynamic activity, leading to enhanced skin penetration (46). In vitro studies have found that the chain length of alkyl Nanosystems for Dermal and Transdermal Drug Delivery 137 polyoxyethylene in niosomes did not affect the cell proliferation of human ker- atinocytes, but ester bond was found to be more toxic than ether bond in the surfac- tants (47). Generally, the droplet size of these systems is less than 100 nm and they flow easily (48). Nanoemulsion is transparent, stable, and spontaneously formed, whereas a macroemulsion is milky and nonstable that requires some energy to form (49). The formation of nanoemul- sion is dependent on a narrow range of oil, water, surfactant, and cosurfactant concentration ratios (48). A cosurfactant is commonly used to lower the interfacial tension and fluidize the interfacial surfactant (48–50). Nonionic and zwitterionic surfactants are the first line of choice for emulsion-based systems (51). Structurally, nanoemulsions biphasic with oil or water as the continuous phase, depending on the phase ratios (48). As nanoemulsion is in a dynamic state and the phases are inter- changeable, it is difficult to characterize these systems, unlike other disperse sys- tems. As these systems have water and oil phases, both hydrophilic and lipophilic drugs can be delivered using nanoemulsions (48,49). The surfactants in the system can act on the intercellular lipid structure and increase skin permeation (48). On the other hand, the oil phase may act as an occluding agent and can increase skin hydration (51). Drug release from the nanoemulsions depends on whether the drug is in the internal or external phase (52). Nanoemulsions have been found to pro- duce higher skin penetration than macroemulsions (53). In contrast, a comparative study of macroemulsions and nanoemulsions found no significant difference in the skin penetration of tetracaine (54). The emulsion droplets may collapse or fuse with the skin components, and thus the size of the emulsion may have a minimal effect on skin penetration. On the other hand, nanoemulsions have also been shown to penetrate through the hair follicles (55). Furthermore, the drug can be adsorbed, complexed, or conjugated to the surface of nanoparticles. Unlike the other systems discussed so far, these are relatively rigid nanosystems. Various types of biodegradable and nondegradable polymers can be used for the preparation of these nanosystems. Some of the polymers that have been used for topical or transdermal drug delivery include poly(lactide-co- glyocolide), polymethacrylate, poly(butyl cyanoacrylate), poly(E-caprolactone), and chitosan (56–60). Recently, poly(vinyl alcohol)–fatty acid copolymers and tyrosine- derived copolymers have also been used for preparing nanocapsules or nanoparti- cles for skin applications (61,62). Nanoparticles or nanocapsules can be prepared by either solvent evapora- tion or solvent displacement procedures (63). In solvent evaporation technique, the polymer is dissolved in an organic phase, such as dichloromethane or ethyl acetate. This organic phase is then dispersed in an aqueous phase containing the surfac- tant and emulsified by sonication or high-pressure homogenization. Subsequently, 138 Venuganti and Perumal the organic phase is removed by evaporation under reduced pressure or continu- ous stirring to form polymeric nanoparticles (63). In this method, a lipophilic drug is loaded in the polymeric matrix by dissolving the drug in the organic phase. In solvent displacement method, the polymer is dissolved in a water-miscible organic solvent and injected into an aqueous medium with stirring in the presence of the surfactant as a stabilizer (63). Water-miscible organic solvents such as ethanol, acetonitrile, and acetone are used. The rapid diffusion of the organic solvent through the aqueous phase with the dissolved polymer at the interface leads to the formation of nanoparticles. Only a few studies have investigated the size-dependent penetration of polymeric nanoparticles into the skin. On the other hand, there was a size- and time-dependent accumulation of particles in the follicular regions, where 20-nm particles accumulated more than the 200-nm particles. The 40-nm particles were found to penetrate deeper in the follicles and also further pen- etrate into the epidermal Langerhans cells present at the infundibulum of hair fol- licles. On the other hand, the larger particles (750 and 1500 nm) did not penetrate into the follicles. In this regard, hair follicles can be used as a reservoir for drug delivery to localize the drug to the hair follicles or deliver the drug to the surround- ing epidermal cells (4). This was found tape-stripping studies in human volunteers by using fluorescent-labeled poly(lactide-co-glycolide) nanoparticles (300–400 nm). The nanoparticles are slowly cleared from the hair follicles by sebum secretions and the migration of par- ticles to nearby cells and through the lymphatic system (4). The surface charge on the polymeric nanoparticles also influences their permeation through the skin. The authors attributed the higher penetration to the charge repulsion between the negatively charged skin lipids and the carboxylate groups in the negatively charged nanoparticles (66). The larger surface of the smaller 50-nm particles and the high charge density in 500-nm particles were attributed to their higher skin penetration (65). One of the distinct features of dendrimers is their large number of surface functional groups that can carry a high drug payload and also undergo multivalent interactions with the biological membranes (67). Due to their unique architecture, drugs can be encapsulated inside the core (nanocontainers), com- plexed, or conjugated to the surface functional groups (nanoshells). The surface functional groups in the dendrimers can be tailored for various drug delivery applications (67,68). The number of branches and surface functional groups increases with each dendrimer generation. Many studies have been reported with dendrimers in cell cultures and other routes of administration (68), but very few studies have explored dendrimers for skin mediated drug delivery. Cationic den- drimers were found to penetrate deeper (40–60 m) in the skin compared to other dendrimers (Fig. It has been found to increase the skin penetration of both hydrophilic and lipophilic drug molecules (70–73). The possible mechanisms include increased drug solubil- ity, increased skin partitioning, and the penetration-enhancing effect through their interaction with the skin lipids (70–73). However, further studies are required to clarify their mechanism of skin penetration.

If diarrhoea does not settle on antibiotic withdrawal or if pseudomembranous colitis is present: • Vancomycin 200mg lamictal with visa symptoms vitamin d deficiency, oral discount 100mg lamictal symptoms 7 days before period, 125 mg 6 hourly cheap 25 mg lamictal with mastercard medications for osteoporosis. In this setting polymicrobial infection with anaerobes and Enterobacteriaceae are usually found lamictal 100mg free shipping medicine mound texas. Primary or spontaneous bacterial peritonitis is much less common and usually complicates ascites in patients with portal hypertension. This is not usually polymicrobial but due generally to Enterobacteriaceae such as E. Spontaneous bacterial peritonitis is often culture-negative but is 9 3 diagnosed by ascitic neutrophil count >0. Switch to oral therapy when clinically appropriate according to culture or treat with: • Ciprofloxacin, oral, 500 mg 12 hourly. Clinical features: » pallor, » petechiae, » purpura, and » bleeding with frequent or severe infections. Stabilise patient, if necessary, with blood products before transport but after consultation with an expert. Do not treat with iron, folic acid or vitamin B12 unless there is a documented deficiency. Destruction may be due to: » Extracellular factors such as auto-immunity or mechanical factors, e. Coombs’ test (direct antiglobulin) is usually positive with autoimmune haemolysis. Efficacy of transfusion is limited by the shortened red cell survival due to haemolysis. In patients with cold agglutinins all transfusions must be given through a blood warmer to avoid cold-induced haemolysis. Common causes of iron deficiency are chronic blood loss or poor nutritional intake. Hypochromic microcytic anaemia Investigations Assess for a haematological response to iron therapy. After the haemoglobin has returned to normal, treatment should be continued for 6 months in order to replenish the iron stores adequately. Consider the following if there is failure to respond to iron therapy: » non-adherence, » continued blood loss, » wrong diagnosis, » malabsorption, and » mixed deficiency; concurrent folate or vitamin B12 deficiency. Macro-ovalocytes on blood smear; polysegmentation of neutrophils, thrombocytopenia with giant platelets. Intrinsic factor antibodies in vitamin B12 deficiency, and anti-parietal cell antibodies in pernicious anaemia. Give vitamin B12 and folic acid together until the test results are available as giving folic acid alone in patients with a B12 deficiency may precipitate a permanent neurological deficit. Folic acid deficiency • Folic acid, oral, 5 mg daily until haemoglobin returns to normal. Note: Response to treatment is associated with an increase in strength and improved sense of well-being. As there is an increase in red blood cell production, short-term iron and folic acid supplementation is also recommended. Consider the following if there is failure to respond: » co-existing folate and/or iron deficiency, » infection, » hypothyroidism, » myelodysplasia, » incorrect diagnosis,and » drug-induced, e. Prophylaxis Vitamin B12 is indicated for patients after total gastrectomy or ileal resection. The disease is characterised by various crises: vaso-occlusive, aplastic, megaloblastic and sequestration crises, and infection. The pain may be localised to a single long bone, typically in the juxta-articular area. Investigations The diagnosis is suspected from the history, peripheral blood examination, and/or screening tests for sickling. This is a medical emergency as these patients can rapidly develop features of severe sepsis (multi-organ failure and/or hypotension). Once culture results are available, adjust treatment to the most appropriate narrow spectrum agent. If fever develops after 48 hours of admission: Choice will depend on local susceptibility patterns. Note: Ertapenem is not recommended because it is not effective for pseudomonas species which are important pathogens in this setting. Investigations Evidence of cytopenia, with normal B12 and folate levels and substantial morphological dysplasia on the blood smear. Bone marrow examination confirms dysplasia of the blood elements and the presence of cytogenetic abnormalities. A careful and detailed history, thorough examination and review of relevant laboratory investigations will allow differentiation between these three categories, as the management of each of these groups differs significantly. Early consultation with a haematologist or a clinician with expertise in the handling of such patients is advisable. Patients with a chronic bleeding tendency should be advised to wear a medic alert bracelet which clearly mentions the type of disorder he/she suffers from, e. Complications include haemarthrosis with later chronic arthropathy, intracranial haemorrhage, soft tissue and muscle haematomas. Pain/tingling in a joint suggests bleeding into the joint in a known haemophiliac. Ideally, patients should attend a specialised haemophilia centre with a dedicated multi-disciplinary health care team. Head trauma, severe nose 60-100% 3–4 days or until bleeds, any internal bleeding, the wound has major operations, any trauma healed well. Note: Desmopressin is not effective in type 3 and the majority of type 2 von Willebrand’s disease. Platelet transfusions may be given if surgery is required or in life-threatening bleeding. Platelet transfusions Platelet transfusions are only indicated in acute active bleeding uncontrolled by other means or before procedures. In an adult, 1 mega-unit of single donor, leucocyte depleted platelets is usually sufficient to control the bleeding initially. Platelet transfusions have limited benefit in this condition as platelets are rapidly destroyed by the immune system. This condition presents with: » anaemia, » thrombocytopenia, often with purpura but not usually severe bleeding, » acute renal insufficiency that may be associated with anuria and may require acute dialysis, » neurologic abnormalities, and » fever. If the patient is bleeding, replace haemostatic factors with cryoprecipitate or fresh frozen plasma. If the patient is not actively bleeding and platelet count > 20 000, then platelet transfusion is not necessary. Replacement therapy for thrombocytopenia should consist of 1 apheresis single donor unit / megaunit (expected platelet count increment 30–50 x 9 9 10 /L) or 6 random donor units (expected increment 50–60 x 10 /L), ideally 9 aiming to raise the platelet count > 50 x 10 /L. Perform frequent estimation of the platelet count and coagulation screening tests. Differential diagnosis include: » cellulitis, » superficial thrombophlebitis, » chronic venous insufficiency, » lymphoedema, » popliteal (Baker’s) cyst, » internal derangement of the knee, and » calf muscle pull or tear Diagnosis is primarily clinical and confirmed with imaging studies, e. Ultrasonography should be repeated after a week but may be omitted if D-dimer is negative. Units of unfractionated heparin Volume of heparin in mL (25 000 units/mL) Weight (kg) Loading 12 hourly Loading 12 hourly dose dose (units) dose dose (units) (mL) (mL) 35 kg 11 000 units 8 750 units 0. Thrombolytic therapy is indicated only in patients with angiographically confirmed early pulmonary embolism where haemodynamic stability cannot be achieved. Although the risk of bleeding is small, in the following patients prophylaxis should only be used under exceptional circumstances: » active bleeding, » intraocular, intracranial or spinal surgery, » lumbar puncture or epidural anaesthesia within 12 hours, » renal insufficiency, » coagulopathy, or » uncontrolled hypertension. Heparin induced thrombocytopenia A severe immune-mediated drug reaction occurring in 1–5% of patients receiving heparin (unfractionated or low molecular weight heparin) therapy.

Melphalan* Pregnancy Category-D Schedule H Indicatons Breast carcinoma purchase lamictal 50 mg visa medications diabetes, multple myeloma cheap lamictal 200 mg treatment uveitis, advanced ovarian carcinoma purchase 200mg lamictal free shipping medicine x topol 2015, malignant melanoma lamictal 200 mg discount medicine 230, polycythaemia vera. Alternatvely 10 mg daily for 7 days (total dose 70 mg), repeat if required afer blood counts partcularly neutrophils and platelets. Contraindicatons Pregnancy (Appendix 7c); hypersensitvity; myelosuppression; lactaton. Adverse Efects Nausea, vomitng, oral mucosits, hyperuricaemia, bone marrow suppression, alopecia, thromboembolism, leucopenia; menstrual irregularites; haemolytc anaemia. Contraindicatons See notes above and consult literature; hypersensitvity; pregnancy (Appendix 7c) and lactaton (Appendix 7b). Precautons See notes above and consult literature; monitor blood count; uric acid levels; renal impairment and hepatc impairment (Appendix 7a); interactons (Appendix 6c). Dose Oral Choriocarcinoma: 15 to 30 mg daily for 5 days repeat 3 to5 full courses afer 1 week. Intramuscular route 15 to 30 mg daily for 5 days, repeat 3 to5 courses afer 1 week. Leukaemia, maintenance afer remission: 30 mg/m2 body surface area (max upto 15 mg twice a week). Contraindicatons See notes above and consult literature; severe renal and hepatc impairment; alcohol liver disease; severe leucopenia; thrombocytopenia; pregnancy (Appendix 7c) and lactaton (Appendix 7b). Precautons See notes above and consult literature; bone marrow depression; renal and hepatc impairment (Appendix 7a); interactons (Appendix 6a, 6c, 6d). Mitomycin* Pregnancy Category-D Indicatons Adrenocarcinoma, lymphosarcoma and seminoma, superfcial bladder cancer (adjuvant therapy). Contraindicatons Pregnancy (Appendix 7c); bone marrow depression; severe anaemia; thrombocyto- penia; lactaton. Precautons It causes delayed bone-marrow toxicity and therefore it is usually administered at 6-weekly intervals. Cauton in handling because it is irritant to tssues, thrombocytopenia; necrosis; leucopenia. Note: Irritant to tssues Paclitaxel* Pregnancy Category-D Schedule H Indicatons Metastatc ovarian and breast cancer. Dose Intravenous infusion Adult- 175 mg/m2 body surface area over 3 h, repeat every 3 weeks. Anthistamines, cortcosteroids or H2 antago- nist may be required during treatment. Contraindicatons Hypersensitvity; severe hepatc impairment; lactaton; pregnancy (Appendix 7c). Dose Oral 50 mg daily to start with initally, increased to 250 to 300 mg individual doses. Contraindicatons See notes above and consult literature; hypersensitvity; pregnancy (Appendix 7c) and lactaton (Appendix 7b). Precautons See notes above and consult literature; ulceraton; haemorrhage; leucopenia: renal and hepatc impairment (Appendix 7a); interactons (Appendix 6a). Adverse Efects See notes above and consult literature; leucopenia; anaemia; thrombocytopenia; hypotension; retnal haemorrhage. Thalidomide is adminis- tered in combinaton with dexametha- sone in 28-day treatment cycles. Dexamethasone is 40 mg daily adminis- tered orally on days 1-4, 9-12, and 17-20 every 28 days. Dosing with thalidomide should contnue untl signs and symptoms of actve reacton have subsided, usually a period of at least 2 weeks. Tapering of medicaton should be atempted every 3 to 6 months, in decre- ments of 50 mg every 2 to 4 weeks. Contraindicatons Hypersensitvity, pregnancy (Appendix 7C) and lactaton, interactons (Appendix 6c). Adverse Efects Teratogenicity, Drowsiness/somnolence, peripheral neuropathy, constpaton, dizziness, bradycardia, orthostatc hypoten- sion, hypersensitvity, and neutropenia. Vinblastne* Pregnancy Category-D Schedule H Indicatons Disseminated Hodgkin’s and Non-Hodgkin’s lymphomas; advanced testcular carcinoma, breast carcinoma; palliatve treatment of Kaposi’s sarcoma; trophoblastc tumours; Leterer-Siwe disease; Histolytc lymphoma. Contraindicatons See notes above and consult literature; hypersensitvity; severe granulocytopenia; lactaton (Appendix 7b). Note: Irritant to tssues Vincristne* Pregnancy Category-D Schedule H Indicatons Acute lymphoblastc leukaemia; neuroblas- toma, Wilm’s tumour, Hodgkin’s and Non- Hodgkin’s lymphomas; rhabdomyosarcoma, Ewing’s sarcoma; mycosis fungoides. Precautons See notes above and consult literature; uric acid neuropathy; branchospasm; hepatc impairment (Appendix 7a); pregnancy (Appendix 7c). Specifc expertse, diagnostc precision, individualizaton of dosage or special equipment are required for their proper use Immunosuppressive drugs are used in organ transplant recipi- ents to suppress rejecton; they are also used as second-line drugs in chronic infammatory conditons. Careful monitoring of blood counts is required in patents receiving immunosuppressive drugs and the dose should be adjusted to prevent bone- marrow toxicity. It is useful when cortcosteroid therapy alone has proven inadequate or for other conditons when a reducton in the dose of concurrently administered cortcosteroids is required. It is metabolized to 6-mercaptopurine and, as with mercap- topurine, doses need to be reduced when given with allop- urinol. The predominant toxic efect is myelosuppression, although hepatc toxicity also occurs. Cyclosporine is a potent immunosuppressant which is virtu- ally free of myelotoxic efects, but is markedly nephrotoxic. It is partcularly useful for the preventon of graf rejecton and for the prophylaxis of graf-versus-host disease. The dose is adjusted according to plasma-cyclosporine concentratons and renal functon. Cortcosteroids such as prednisolone have signifcant immu- nosuppressant actvity and can also be used to prevent rejec- ton of organ transplants. Dose Oral Adult and child over 3 months-Renal transplantation: initially 5 mg/kg body weight daily. Contraindicatons Hypersensitivity to azathioprine and mercaptopurine; lactation (Appendix 7b). Precautons Monitor for toxicity throughout treatment; full blood counts necessary every week (or more frequently with higher doses and in renal or hepatic impairment) for first 4 weeks of treatment and at least every 3 months thereafter; reduce dose in elderly; renal impairment; liver disease (Appendix 7a); interactions (Appendix 6c, 6d); lactation (Appendix 7b); pregnancy (Appendix 7c). Patients should be warned to report im- mediately any signs or symptoms of bone marrow suppression, for example unex- plained bruising or bleeding, infection. Adverse Efects Hypersensitvity reactons including malaise, dizziness, vomitng, fever, muscular pains, arthralgia; rash; hypotension or intersttal nephrits call for immediate withdrawal; haematological toxicity includes leukopenia and thrombocytopenia (reversible upon withdrawal); liver impairment, cholestatc jaundice; hair loss; increased susceptbility to infectons and colits in patents also receiving cortcosteroids; nausea; rarely, pancreatts, pneumonits, hepatc veno- occlusive disease; microcystosis. Dose Oral and intravenous infusion Adult and child over 3 months-Initally 5 mg/ kg b. Organ transplant: 10 to 15 mg/kg body weight 2 to 4 h before transplantaton, fol- lowed by 10 to 15 mg/kg body weight for 1 to 2 weeks post operatvely. Decrease there- afer gradually to 2 to 6 mg/kg body weight for maintenance (adjust according to blood cyclosporine concentraton and renal func- ton), if required 1/3rd corresponding oral dose can be administered by intravenous infusion over 2 to 6 h. Intravenous infusion Bone marrow transplantaton; 3 to 5 mg/kg body weight by intravenous infusion over 2 to 4 h from day before transplantaton. Adverse Efects Dose-related and reversible increases in serum creatnine and urea unrelated to tssue rejecton; burning sensaton in hands and feet during inital therapy; electrolyte disturbances including hyperkalaemia, hypomagnesaemia; hepatc dysfuncton; hyperuricaemia; hypercholesterolaemia; hyperglycaemia, hypertension (especially in heart transplant patents); increased incidence of malignancies and lymphoproliferatve disorders; increased susceptbility to infectons due to immunosuppression; gastrointestnal disturbances; gingival hyperplasia; hirsutsm; fatgue; allergic reactons; thrombocytopenia (sometmes with haemolytc uraemic syndrome), also mild anaemia; tremors; convulsions, neuropathy; dysmenorrhoea or amenorrhoea; pancreatts, myopathy or muscle weakness; cramps, gout, oedema; headache; gingival hypertrophy; renal dysfuncton; hypertrichosis; paresthesia; renal toxicity; gastrointestnal symptoms. Tacrolimus Pregnancy Category-C Indicatons Prophylaxis of organ rejecton in patents receiving allogeneic liver, kidney, or heart transplants. Precautons Monitoring of blood trough serum concentratons for preventaton of organ rejecton and to reduce drug related toxicity, pregnancy (Appendix 7c); interactons (Appendix 6c, 6d). Adverse Efects Nephrotoxicity; neurotoxicity; hyperglyc- emia, hypertension, hyperkalemia, and gas- trointestnal disturbances.

No reliable objective criteria have yet been developed which will unequivocally identify the hypnotic state cheap 200mg lamictal treatment non hodgkins lymphoma. In the absence of reliable objective criteria cheap lamictal 100mg amex treatment 247, it becomes necessary to describe hypnosis in terms of the subjective events which the hypnotized individual experiences discount 25mg lamictal visa medications like gabapentin. This distortion may affect any and all modalities of perception in regard to both external and internal events purchase 200 mg lamictal with visa treatment erectile dysfunction. Although this distortion of reality may be extremely real to the subject and his -170- behavior appropriate to it, considerable evidence suggests that at some level the individual continues to remain aware of the world as it really exists. Another attribute of the hypnotic state is that the subject experiences it as discontinuous from his normal waking experience. It is inappropriate in this context to review in detail the many theories proposed to account for the clinical observations. We shall briefly consider some of the theoretical views most generally held, since their implications differ markedly regarding the degree to which the state increases the susceptibility of a person to purposeful influence. Primarily of historical interest are the views of Mesmer (13) and his latex followers, who held that hypnosis, or the Mesmeric trance, results from a flow from the hypnotist to the subject of a force called animal magnetism. This view is important because it is the basis of the lingering lay opinion that hypnosis is in some way an overpowering of a weak mind by a superior intellect. There is no presentday investigator who would defend this position, and in fact it is contradicted by recent evidence. Since the time of Braid (14) in 1843, the view has been widely held that hypnosis is a state of artificially induced sleep. More recently, Pavlov (56) proposed a similar view when he maintained that cortical inhibition, sleep, and hypnosis are essentially identical. This view is currently held throughout those parts of the world where Pavlovian theory is accepted as a creed. This position implies that hypnosis is a state characterized by a profound neurophysiological alteration and that the subject in trance is somehow passively compelled to respond when appropriate suggestions are given. To the American investigator there appears to be overwhelming experimental evidence against this view. For example, Bass (4) has shown that the patellar reflex, which disappears in sleep, is not diminished in hypnosis. However, there are two Russian papers (50) which contradict these findings, claiming that the characteristic rhythm of hypnosis resem- -171- bles that of drowsiness and light sleep. Although this position seems reasonable in view of the similarity of the two conditions, it tells us little about the actual nature of hypnosis. The implicit assumption of this theory-that hypnosis is a sign of pathology — is not generally accepted today. The Nancy school, especially Bernheim (9), revolutionized thinking about the hypnotic state by introducing the concept of suggestion and suggestibility. This orientation has been supported most notably by Hull (32), who, in a major monograph on hypnosis, concluded that hypnosis is primarily a state of heightened suggestibility. These views focus upon a trait in the subject, suggestibility, which is heightened by hypnotic induction techniques. Hull also relates the phenomenon to a habit, insofar as it becomes increasingly easy for a subject to achieve a state of hypnosis once he has been able to do so. Although the concepts of suggestion and suggestibility provide a bridge between hypnosis and the normal waking state, they do not offer explanations of the causes of the state or of the ongoing processes of hypnosis. Welch (77) has attempted to explain hypnosis and its induction by an ingenious application of conditioning theory, utilizing the concept of abstract conditioning. He has pointed out that trance induction proceeds from suggestions which are almost certain to take effect to those that are more likely to be resisted. Several suggestions for experimental testing of this theory have never been followed up. In contrast to the foregoing views, which focus either on the hypnotist or on some trait of the subject, several more recent approaches have been concerned with the interaction between the subject and the hypnotist. Schilder (63), White (83), and Sarbin (61) have all in one way or another emphasized the social relationship which exists in the hypnotic situation and especially the needs of the subject in this context. He emphasizes that hypnosis takes place because the subject wishes to play the role of the hypnotized subject as currently defined by the subject and the hypnotist. Although other concepts are of necessity evoked to explain various phenomena in hypnosis, the actual occurrence of the trance state is related to the wish of the subject to enter hypnosis. This writer is a proponent of this approach, and the critical comments in this report are undoubtedly colored by this viewpoint. It is important to recognize that almost no experimental work has been done that would support the validity of these various theoretical views, although there is some evidence already mentioned which tends to refute some of them. The general acceptance of the motivational view is based on the clinical impression of both experimentalists and clinicians that it accounts best for the major portion of the clinical data. Trance is commonly induced in situations where the subject is motivated a priori to cooperate with the hypnotist, for example, to obtain relief from suffering, to contribute to a scientific study, or (as in a stage performance) to become, temporarily at least, the center of attraction. Almost all the currently available knowledge about hypnosis has been derived from these situations, and it is well to keep in mind the source of these data when one attempts to evaluate the possible utility of hypnosis in situations differing from these. There is a small body of evidence stemming from the criminal cases in which hypnosis has allegedly played a role, which are radically different from those where hypnosis is normally observed. Because these situations may be more relevant to the questions of hypnosis in interrogation, this body of knowledge deserves particular attention and is discussed subsequently. Hypnosis in the Interrogation Situation The Induction of Hypnosis The initial problem in utilizing hypnosis for interrogation is to induce trance. Another arises when the subject is seeking psychiatric help and hypnosis is induced in the course of a clinical interview with no explicit mention of the process. The third situation involves a trance spontaneously entered by individuals who are observing trance induction in another subject. The older literature is replete with statements that hypnosis may readily be induced by giving suggestions to sleeping subjects in a low but insistent voice; the subject becomes gradually more responsive to the suggestions until eventually he enters a somnambulistic state of hypnosis [ Bernheim (9), Braid (14), Binet and Fere (12), etc. As so often the case in hypnosis literature, the statements appear to have been carried over from one textbook to another without any critical evaluation. He found considerable similarity between compliance to suggestions given during sleep and reactions to customary hypnotic techniques. It should be pointed out that, in his study, Barber requested permission from the subjects to enter their rooms at night and talk to them in their sleep. Several of them remarked that this was hypnosis, and one may reasonably assume that most, if not all, of the subjects perceived that trance induction was the purpose of the study. This study, therefore, tells us little about what would happen if a truly naive sleeping subject were exposed to such a situation. Casual experimentation by the author failed to demonstrate the feasibility of this technique. The sample consisted of only four subjects, three of whom awakened to ask belligerently what was taking place, whereas the fourth continued to sleep. Whether any increase in suggestibility over the normal waking state occurs has never been established. In another context, the trance phenomena seen among primitive people frequently occur in ceremonies involving prolonged stimulation by rhythmic drums. Many authors have emphasized the importance of monotonous rhythmic verbal suggestions, especially during the induction stage of hypnosis. Recently, Kroger and Schneider (38) have proposed the use of an electronic aid which gives a repetitive signal approximating the alpha range of ten cycles per second as an adjunct. Certainly, the use of such techniques or even of monotonous rhythmic speech is by no means necessary in order to induce hypnosis. All sophisticated discussions of hypnotic trance induction recognize that a successful response to a suggestion will facilitate further successful responses to suggestions.

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