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Berlin: Sprin- tional medicine in the USA – prevalence order 160mg kamagra super otc erectile dysfunction treatment calgary, costs ger-Verlag order online kamagra super erectile dysfunction 3 seconds, (1996) buy kamagra super master card erectile dysfunction pills available in stores. Introducing a placebo ting up and running a pharmacovigilance centre needle into acupuncture research. Ascertaining the minimally important differ- theory of acupuncture in musculoskeletal pain. On the evaluation of the evance and statistical signiﬁcance in health related clinical effects of acupuncture. Causes and treatment of low back status and well-being of patients with chronic pain. Green 2004 John Wiley & Sons, Ltd ISBN: 0-471-98787-5 6 B reast ancer DONALD A. Anderson Cancer Center, Houston, TX 77030, USA INTRODUCTION in situ (DCIS) increased by about sixfold, from about 5 cases per 100 000 women in 1980 to more More than 200 000 women in the United States than 30 per 100 000 in 1998. About Despite the increasing incidence of breast 40 000 women die from the disease each year. Although the risk mortality has decreased by almost 2% per year of breast cancer is substantially higher in older in the 1990s. Of this improvement in breast cancer survival to cases diagnosed in the US in 1998, 5% occurred increased use of screening mammography and to in women under the age of 35, 30% in women improvements in the treatment of breast cancer. These years saw the for- From 1940 to the early 1980s, breast cancer mation of strong advocacy groups that worked incidence in the US increased by a fraction to promote research in breast cancer. In addition, patient advocates the same period, the rate of ductal carcinoma have become highly educated about research Textbook of Clinical Trials. Green 2004 John Wiley & Sons, Ltd ISBN: 0-471-98787-5 88 TEXTBOOK OF CLINICAL TRIALS issues and many serve regularly alongside profes- 0 through Stage IV disease are 21%, 42%, 29%, sional scientists on various governmental boards 5% and 4%, respectively. Patient advo- examination has limited discrimination ability cates also serve on cooperative group committees because 70–80% of tumours are of a single type: that plan clinical trials in breast cancer, institu- inﬁltrating ductal carcinoma. PROGNOSIS Advocacy groups have worked to increase the number of women who participate in clinical tri- Breast cancer is heterogeneous. The Clinical Trial Initiative of the National cancers are slowly growing and their carriers Breast Cancer Coalition Fund (NBCCF) main- survive for many years and die of other causes. This heterogeneity registry, experts from the NBCCF ascertain that has implications for research in all phases of the it addresses an important, novel research ques- disease, beginning with screening and diagnostic tion related to breast cancer, and that its design methods through the evaluation of treatments for is scientiﬁcally rigorous and employs appropriate advanced disease. Stage IV disease is generally regarded to be incurable, with median STAGING survival in the range of 18 to 24 months, although a small fraction of patients with Stage IV disease Breast cancer is staged using a system developed achieve complete remission following systemic by the American Joint Committee on Cancer, chemotherapy, and survive for many years. The stage of disease, ranging from 0 node involvement is associated with a worse to IV, is based on combinations of these TNM prognosis, with ﬁve-year disease-free rates rang- rankings. Tumour grade, proliferative Stage 0 consists of ductal and lobular carci- activity and menopausal status play relatively noma in situ (DCIS, LCIS), non-invasive and minor roles. Although stage is an important prognostic Stages I to III are invasive stages in which the factor, it is of limited use as a determinant tumour is conﬁned to the breast or its immedi- of treatment outcome. Higher stage indicates larger primary of treatment are reasonably consistent across tumours or greater locoregional tumour involve- stages – although the absolute beneﬁt can be ment. Patients having evidence of distant metas- much greater for higher stage disease. In the US, the approxi- as indicators of general tumour aggressiveness, mate proportions of women diagnosed with Stage irrespective of type of therapy. BREAST CANCER 89 the best-studied predictive factor is oestrogen- breast cancer throughout the ﬁrst half of the cen- receptor (ER) status, which is an important tury, sometimes combined with radiotherapy. Tamoxifen and other selec- clinical trials to investigate alternative therapies tive oestrogen-receptor modulators (SERMs) are was proposed in the 1960s, controversy arose highly effective in patients with hormone- among breast cancer researchers as well as in sensitive breast cancer, but they have no other medical ﬁelds. Patients who beneﬁt from SERMs pioneers in the ﬁeld persisted in designing tri- may also beneﬁt from aromatase inhibitors. These early tri- 20% to 40% of breast tumours, and has been als compared various surgical and radiotherapy cited in numerous reports as conveying poor approaches. Rather, breast cancer came to be understood as a systemic disease that HISTORICAL PERSPECTIVE ON CLINICAL could beneﬁt from systemic therapy, and radi- TRIALS IN BREAST CANCER cal local therapies were no longer regarded as essential for prolonging survival. SURGERY AND RADIOTHERAPY CHEMOTHERAPY Scientiﬁc understanding of the biology of breast cancer has changed radically in the past 50 years. Cytotoxic agents for treatment of solid tumours Results of large randomised trials have played a were ﬁrst developed in the 1950s. From the nineteenth proved to be highly sensitive to several of these, century and up into the 1970s, breast cancer was when used as single agents in small trials. Subse- understood to be a local/regional disease that quently, combinations of these cytotoxic agents spread by direct extension along lymphatic path- were evaluated, one of the earliest being the ways to distant sites. This concept gave rise to the Cooper regimen (cyclophosphamide, methotrex- surgical methods promoted by W. This surgi- cancer cells to cytotoxic agents, the stage was set cal technique, known as radical mastectomy, for the rapid development of adjuvant chemother- remained the principal approach to treatment of apy once this concept was introduced in the 90 TEXTBOOK OF CLINICAL TRIALS 1970s. A randomised trial comparing surgery fol- most important advance in treating breast cancer. Small trials conducted HIGH-DOSE CHEMOTHERAPY WITH BONE in solid tumours in the early 1970s established MARROW TRANSPLANT OR STEM safety and dosing, and these were quickly fol- CELL SUPPORT lowed by Phase II trials of the agent in metastatic breast cancer. Subsequently, doxorubicin was An unresolved question in therapy of breast can- evaluated in combination with other agents, and cer that has presented an unusual challenge for randomised trials established that higher response the conduct of clinical trials is that of high- rates could be achieved in metastatic disease with dose chemotherapy supported by autologous bone combinations that included doxorubicin. These marrow transplant or peripheral blood progenitor successes prompted the introduction of various cells. Ten trials addressing the question of high- doxorubicin and other anthracycline-containing dose versus standard-dose chemotherapy have combinations as adjuvant therapy for primary been reported. Only two of the remaining eight trials tions continue to play a prominent role in the entered more than 200 patients. The available evidence suggests that high- dose therapy provides little or no beneﬁt for patients regardless of their disease stage. Early trials focused on ovarian ablation by Eight large randomised trials conducted since surgery or chemical means. The anti-oestrogen 1963 assessed the value of screening mam- agent tamoxifen was introduced in the 1970s, mography for reducing breast cancer mortal- at a time when there was high regard for the ity. These are of particular interest for the potential of cytotoxic agents, but little interest scrutiny they have undergone in recent years. Early small trials in the preponderance of evidence from the ran- metastatic breast cancer were equivocal and could domised trials indicates a beneﬁt associated with have led to abandoning the agent. After a series of large randomised trials, ity differences between the screened and non- tamoxifen is now regarded as standard therapy screened groups. Beginning in 1983, this group has col- lected data from virtually all major randomised PREVENTION trials conducted in early breast cancer, published Beginning in the 1990s, coinciding with the or not.
Do not switch from a generic to Dilantin buy cheap kamagra super online impotence caused by medication, or vice versa kamagra super 160 mg with amex erectile dysfunction vacuum pumps australia, ✔ If taking lamotrigine purchase kamagra super paypal top erectile dysfunction doctors new york, notify the physician immediately if a without discussing with the prescribing physician. CHAPTER 11 ANTISEIZURE DRUGS 193 comply with the prescribed regimen and attain seizure How Can You Avoid This Medication Error? The nurse holds all medica- drug (monotherapy) is recommended when possible. If tions, including her antiseizure medication, which is usually taken effective in controlling seizures, monotherapy has the ad- at midnight and 6 AM. If the first drug, in adequate dosage, fails to control seizures or causes unacceptable ad- verse effects, then another agent should be tried as PRINCIPLES OF THERAPY monotherapy. Most practitioners recommend sequen- tial trials of two to three agents as monotherapy before Therapeutic Goal considering combination therapy. When substituting one AED for another, the second Drug therapy is the main treatment of epilepsy for clients of all drug should be added and allowed to reach therapeutic ages. The goal is to control seizure activity with minimal ad- blood levels before the ﬁrst drug is gradually decreased verse drug effects. In most clients, treatment with a single AED is substituting oxcarbazepine for carbamazepine or vice sufﬁcient to meet this goal. In 20% to 30% of clients, however, versa, because the drugs are similar. In general, combination ther- When monotherapy is ineffective, a second, and some- apy is associated with more severe adverse effects, interactions times a third, drug may be added. Dosage forms may increase seizure control, client con- diagnosis is essential before drug therapy is started. For example, extended re- general, AEDs with activity against both partial-onset lease or long-acting dosage forms can maintain more and generalized seizures include lamotrigine, leve- consistent serum drug levels and decrease frequency of tiracetam, topiramate, valproic acid, and zonisamide. Most of the AEDs are available in oral Drugs considered most useful for partial seizures include tablets or capsules; a few are available as oral liquids carbamazepine, gabapentin, oxcarbazepine, phenobarbi- or injectable solutions. Cost should be considered because this may be a major ethosuximide is the drug of choice; clonazepam and factor in client compliance. For mixed seizures, a com- are generally effective and better tolerated than older bination of drugs is usually necessary. Most of these agents are approved for com- other factors, may vary among pharmacies and change bination therapy with other AEDs in clients whose over time. However, the following list of costs per seizures are not adequately controlled with a single month allow comparisons among AEDs and may be drug. Oxcarbazepine is approved for monotherapy of useful in clinical practice. Costs of older drugs are carbe- partial seizures; some of the other drugs are also thought mazepine ($54 to $81), ethosuximide ($105 to $158), to be effective as monotherapy. Adverse drug effects may be the deciding factor in valproate ($80 to $280). Costs of newer drugs are choosing an AED because most types of seizures can gabapentin ($139 to $354), lamotrigine ($196 to $289), be treated effectively by a variety of drugs. The use of levetiracetam ($105 to $315), oxcarbazepine ($97 to carbamazepine and valproic acid increased largely be- $358), tiagabine ($99 to $190), topiramate ($88 to $354), cause they cause less sedation and cognitive and psycho- and zonisamide ($100 to $201). Most of the newer AEDs reportedly cause uninsured clients, choosing less expensive drug ther- fewer adverse effects and are better tolerated than the apy regimens. In general, infants exposed to one AED have a signiﬁcantly higher Nursing Notes: Apply Your Knowledge risk of birth defects than those not exposed and infants exposed to two or more AEDs have a signiﬁcantly You are a nurse working in a clinic. His seizures have been well controlled on Drug Dosage phenytoin (Dilantin) 300 mg hs. The dosage of most drugs is determined empirically by ob- servation of seizure control and adverse effects. Usually, larger doses are needed for a single drug than for multiple drugs; for people with a large body mass 2. Periodic measurements of serum drug levels are rec- (assuming normal liver and kidney function); and in ommended, especially when multiple AEDs are being cases involving trauma, surgery, and emotional stress. Smaller doses are usually required when liver disease with particular drug dosages, seizure control, or ad- is present and when multiple drugs are being given. For most drugs, initial doses are relatively low; doses in relation to clinical responses because there are wide are gradually increased until seizures are controlled or variations among clients receiving similar doses, prob- adverse effects occur. Then, doses may be lowered to ably owing to differences in hepatic metabolism. In the minimum effective level, to decrease adverse ef- other words, doses should not be increased or decreased fects. Adverse effects are more likely to occur during solely to maintain a certain serum drug level. In addi- initiation of treatment and, if treatment is started too tion, the timing of blood samples in relation to drug ad- aggressively, clients may be unwilling to continue a ministration is important. For routine monitoring, blood particular medication even if doses are reduced in samples should generally be obtained in the morning, amount or frequency of administration. Several antiseizure drugs have the potential for caus- dosage of the one being added is gradually increased ing blood, liver, or kidney disorders. For this reason, it while the one being discontinued is gradually decreased. When fosphenytoin is substituted for oral phenytoin, the causes include incorrect diagnosis of the type of seizure, same total daily dosage (in PE) may be given IV or IM. For patients receiving carbamazepine or oxcarbazepine drug dosage, and too-frequent changes or premature therapy, either agent may be substituted for the other withdrawal of drugs. Additional causes may include drug without gradual reduction or titration of the dose. For overdoses (eg, theophylline) and severe electrolyte most patients, the equivalent oxcarbazepine dosage is imbalances (eg, hyponatremia) or use of alcohol or 50% higher than the carbamazepine dosage. Duration and Discontinuation of Therapy Antiseizure drug therapy may be discontinued for some Monitoring Antiepileptic Drug Therapy clients, usually after a seizure-free period of at least 2 years. The effectiveness of drug therapy is evaluated primar- drugs should be discontinued, studies indicate that medica- ily by client response in terms of therapeutic or adverse tions can be stopped in approximately two thirds of clients effects. CHAPTER 11 ANTISEIZURE DRUGS 195 Advantages of discontinuation include avoiding adverse drug CNS and cause drowsiness, their combination with any other effects and decreasing costs; disadvantages include recur- CNS depressant drugs may cause excessive sedation and other rence of seizures, with possible status epilepticus. They may also decrease the effects of drugs cannot be stopped completely, periodic attempts to de- numerous other drugs, mainly by inducing drug-metabolizing crease the number or dosage of drugs are probably desirable enzymes in the liver. Discontinuing drugs, chang- drugs are metabolized and eliminated more quickly. In some ing drugs, or changing dosage must be done gradually over 2 cases, larger doses of the affected drugs are needed to achieve to 3 months for each drug and with close medical supervision therapeutic effects.
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In immunosuppressed patients generic 160mg kamagra super with mastercard encore vacuum pump erectile dysfunction, HSV infection may result in the respiratory syncytial virus (RSV) is a highly contagious virus severe order kamagra super canada gas station erectile dysfunction pills, systemic disease buy discount kamagra super on line erectile dysfunction nclex questions. Herpes Zoster Epidemics of RSV infection often occur in nurseries, day care cen- Herpes zoster is caused by the varicella-zoster virus, which is highly ters, and pediatric hospital units during winter months. Most children in the United infects and destroys respiratory epithelium in the bronchi, bron- States are infected by early school age. It is spread by respiratory droplets and secre- pox on ﬁrst exposure and is spread from person to person by the (continued) 578 SECTION 6 DRUGS USED TO TREAT INFECTIONS BOX 39–1 SELECTED VIRAL INFECTIONS (Continued) tions, direct contact with an infected person, and contact with infection occurs but is usually less severe than primary infection. In older children, RSV infection produces much milder disease but RSV is the most common cause of bronchiolitis and pneumonia may be associated with acute exacerbations of asthma. These infants usually have wheezing, cough, respiratory symptoms of fever, cough, and nasal congestion. The infection is usually self-limited and re- most often in those with household or other close contact with chil- solves in 1 to 2 weeks. Antiviral therapy with ribavirin is used in dren, including pediatric health care workers. The mortality rate from RSV infection is low in chil- RSV infection may cause pneumonia requiring hospitalization. In dren who are generally healthy but increases substantially in those immunocompromised patients, RSV infection may cause severe with congenital heart disease or immunosuppression. Once inside host cells, viruses use cellular metabolic ac- pends on cell-mediated immunity (lymphocytes and tivities for their own survival and replication. Viral repli- macrophages) to eradicate the virus along with the cation involves dissolution of the protein coating and cell harboring it. Viral infection may occur without signs and symp- [DNA] or ribonucleic acid [RNA]). Then, host cell genes are coded to produce new viruses (eg, herpesviruses) can survive in host cells viruses. Also, autoimmune ing host cell mitosis and becomes part of the inherited diseases may be caused by viral alteration of host cells genetic information of the host cell and its progeny. Symptoms usually associated with acute viral infec- tase before replication can occur. When the cell is destroyed, the signs and symptoms vary with the type of virus and viruses are released into the blood and surrounding tis- body organs involved. Antibodies are Antiviral Drugs proteins that defend against microbial or viral invasion. They are very speciﬁc (ie, an antibody protects only Few antiviral drugs were available before the AIDS epi- against a speciﬁc virus or other antigen). Since then, numerous drugs have been developed to a person who has had measles, antibody protection (im- treat HIV infection and opportunistic viral infections that munity) develops against future infection by the measles occur in hosts whose immune systems are suppressed by virus, but immunity does not develop against other viral AIDS or immunosuppressant drugs given to organ transplant infections, such as chickenpox or hepatitis. Drug therapy for viral infections is still limited, the protein coat of the virus allows the immune sys- however, because drug development is difﬁcult. Viruses use tem of the host to recognize the virus as a foreign the metabolic and reproductive mechanisms of host cells for invader and to produce antibodies against it. This their own vital functions, and few drugs inhibit viruses with- system works well for most viruses but does not work out being excessively toxic to host tissues. Most of these for the inﬂuenza A virus, which can alter its protein agents inhibit viral reproduction but do not eliminate viruses covering so much and so often that the immune system from tissues. Available drugs are expensive, relatively toxic, does not recognize it as foreign to the body. Protection conferred by chemoprophylaxis is immedi- the viruses from reaching the bloodstream or, if they ate but lasts only while the drug is being taken. Subgroups of are already in the bloodstream, prevent their invasion antiviral drugs are described in the following sections; addi- of host cells. Once the virus has penetrated the cell, it tional characteristics and dosage ranges are listed in the is protected from antibody action and the host de- Drugs at a Glance tables. CHAPTER 39 ANTIVIRAL DRUGS 579 Drugs at a Glance: Drugs for Prevention or Treatment of Selected Viral Infections Routes and Dosage Ranges Generic/Trade Name Indications for Use Adults Children Herpes Virus Infections Acyclovir Oral mucocutaneous lesions Genital herpes, PO 200 mg q4h, ﬁve times daily <12 y: IV 250 mg/m2 q8h (Zovirax) (eg, cold sores, fever blisters) for 10 d for initial infection; 400 mg two times for 7 d Genital herpes daily to prevent recurrence of chronic infec- Herpes simplex encephalitis tion; 200 mg q4h ﬁve times daily for 5 d to Varicella (chickenpox) in immuno- treat recurrence compromised hosts Herpes zoster, PO 800 mg q4h ﬁve times daily Herpes zoster (shingles) in normal for 7–10 d and immunocompromised hosts Chickenpox, PO 20 mg/kg (maximum dose 800 mg) four times daily for 5 d Mucosal and cutaneous herpes simplex virus (HSV) infections in immunocompromised hosts (ICH), IV 5 mg/kg infused at constant rate over 1 h, q8h for 7 d Varicella-zoster infections in ICH, IV 10 mg/kg, infused as above, q8h for 7 d HSV encephalitis, IV 10 mg/kg infused as above, q8h for 10 d Topically to lesions q3h, six times daily for 7 d Cidofovir Treatment of CMV retinitis in IV infusion, 5 mg/kg over 1 h, every 2 wk Dosage not established (Vistide) persons with AIDS Famciclovir Acute herpes zoster Herpes zoster, PO 500 mg q8h for 7 d Dosage not established (Famvir) Genital herpes, recurrent Genital herpes, PO 125 mg twice daily for 5 d episodes Foscarnet Treatment of CMV retinitis in CMV retinitis, IV 60 mg/kg q8h for 2–3 wk, (Foscavir) persons with AIDS depending on clinical response, then Treatment of acyclovir-resistant 90–120 mg/kg/d for maintenance mucocutaneous HSV infections HSV infections, IV 40 mg/kg q8–12h for 2–3 wk in immunocompromised clients or until lesions are healed Reduce dosage with impaired renal function Ganciclovir CMV retinitis in immuno- CMV retinitis, IV 5 mg/kg q12h for 14–21 d, (Cytovene) compromised clients then 5 mg/kg once daily for 7 d/wk or Prevention of CMV disease in 6 mg/kg once daily for 5 d/wk or PO 1000 mg clients with organ transplants three times daily for maintenance or advanced HIV infection Prevention in transplant recipients, IV 5 mg/kg once daily 7 d/wk or 6 mg/kg once daily 5 d/wk Prevention in clients with HIV infection, PO 1000 mg three times daily Triﬂuridine Keratoconjunctivitis caused Topically to eye, 1% ophthalmic solution, 1 drop (Viroptic) by herpes viruses q2h while awake (maximum 9 drops/d) until re-epithelialization of corneal ulcer occurs; then 1 drop q4h (maximum 5 drops/d) for 7 d Valacyclovir Herpes zoster and recurrent geni- Herpes zoster, PO 1 g q8h for 7 d (Valtrex) tal herpes in immunocompetent Recurrent genital herpes, PO 500 mg q12h daily clients for 5 d Reduce dosage with renal impairment (creatinine clearance <50 mL/min) Vidarabine Keratoconjunctivitis caused by IV 15 mg/kg/d dissolved in 2500 mL of ﬂuid and (Vira-A) herpes viruses given over 12–24 h daily for 10 d Topically to eye, 3% ophthalmic ointment, applied q3h until re-epithelialization, then twice daily for 7 d Inﬂuenza Virus Infection Amantadine Prevention or treatment of PO 200 mg once daily or 100 mg twice daily 9 to 12 y: PO 100 mg (Symmetrel) inﬂuenza A infection Reduce dosage with renal impairment (creatinine twice daily clearance <50 mL/min) 1 to 9 y: PO 4. Drugs for Herpesvirus Infections causes granulocytopenia and thrombocytopenia in approxi- mately 20% to 40% of recipients. These hematologic effects Acyclovir, famciclovir, and valacyclovir penetrate virus- often occur during the ﬁrst 2 weeks of therapy but may occur infected cells, become activated by an enzyme, and inhibit viral at any time. Foscarnet and cidofovir should genital herpes, in which it decreases viral shedding and the du- be used cautiously in patients with renal disease. It does not eliminate inactive Triﬂuridine and vidarabine are applied topically to treat virus in the body and thus does not prevent recurrence of the keratoconjunctivitis and corneal ulcers caused by the herpes disease unless oral drug therapy is continued. Triﬂuridine should not be also used for treatment of herpes simplex infections in im- used longer than 21 days because of possible ocular toxicity. Prolonged or repeated courses of Vidarabine also is given IV to treat herpes zoster infections acyclovir therapy may result in the emergence of acyclovir- in patients whose immune systems are impaired and en- resistant viral strains, especially in immunocompromised cephalitis caused by herpes simplex viruses. Acyclovir can be given orally, intravenously (IV), or ap- be reduced with impaired renal function. IV use is recommended for severe genital herpes in nonimmunocompromised patients and any herpes infections in immunocompromised patients. Oral and IV Drugs for HIV Infection and AIDS acyclovir are excreted mainly in urine, and dosage should be de- (Antiretrovirals) creased in patients who are elderly or have renal impairment. Famciclovir and valacyclovir are oral drugs for herpes Four classes of drugs currently exist for the management zoster and recurrent genital herpes. Famciclovir is metabo- of HIV infection: nucleoside reverse transcriptase inhibitors lized to penciclovir, its active form, and excreted mainly in (NRTIs), nucleotide reverse transcriptase inhibitors, non- the urine. Valacyclovir is metabolized to acyclovir by en- nucleoside reverse transcriptase inhibitors (NNRTIs), and zymes in the liver and/or intestine and is eventually excreted protease inhibitors. As with acyclovir, dosage of these drugs must be viral replication in human host cells. In addition, foscarnet is used to treat acyclovir- Nucleoside Reverse Transcriptase Inhibitors resistant mucocutaneous herpes simplex infections in people with impaired immune functions. Valganciclovir and ganci- the NRTIs are structurally similar to speciﬁc DNA compo- clovir are used to prevent CMV disease, mainly in patients nents (adenosine, cytosine, guanosine, or thymidine) and thus with organ transplants or HIV infection. Ganciclovir ample, zidovudine, the prototype, is able to substitute for CHAPTER 39 ANTIVIRAL DRUGS 581 Drugs at a Glance: Drugs for Human Immunodeﬁciency Virus Infection and Acquired Immunodeﬁciency Syndrome Routes and Dosage Ranges Generic/Trade Name Characteristics Adults Children Nucleoside Reverse Transcriptase Inhibitors (NRTIs) Zidovudine Prototype NRTI PO 300 mg twice daily 3 mo to 12 y: 180 mg/m2 (AZT, ZVD, Retrovir) Well absorbed with oral q6h (not to exceed administration 200 mg q6h) Metabolized in the liver to an inactive metabo- Neonate born of HIV-infected lite, which is excreted in urine mother who took the drug Often causes severe anemia and granulocy- during pregnancy, labor, topenia, which may require stopping the and delivery, PO 2 mg/kg drug, giving blood transfusions, or giving ﬁl- q6h starting within 12 h grastim or sargramostim to hasten bone of birth and continuing marrow recovery until 6 wk of age. If unable May also cause peripheral neuropathy and pan- to take oral drug, give creatitis 1. Abacavir Well absorbed with oral administration PO 300 mg twice daily >3 mo: PO 8 mg/kg twice (Ziagen) Approximately 50% bound to plasma proteins daily (maximum dose, Metabolized to inactive metabolites that are ex- 300 mg twice daily) creted in urine and feces May cause serious hypersensitivity reactions Didanosine Used for patients who do not respond to or can- PO 200 mg twice daily <0. Efavirenz May cause CNS side effects PO 600 mg at bedtime ≥3 y and weight 10–40 kg (Sustiva) (22–88 lbs): PO 200– 400 mg, depending on weight Weight >40 kg: PO same as adults Nevirapine Well absorbed with oral administration and me- PO 200 mg once daily for Dosage not established (Viramune) tabolized in the liver 2 wk, then 200 mg twice Induces drug-metabolizing enzymes in the liver daily and increases metabolism of itself and other drugs Adverse effects include severe skin reactions and hepatotoxicity. Protease Inhibitors Amprenavir Well absorbed after oral administration PO 1200 mg (eight 150-mg 13–16 y and weight ≥50 kg: (Agenerase) Oral solution less bioavailable than capsules, capsules) twice daily PO same as adults thus the two dosage forms are not equivalent 4–12 y, or 13–16 y and on a milligram basis weight <50 kg: PO Highly bound to plasma proteins 20/mg/kg twice daily or Metabolized in liver; small amount of un- 15 mg/kg three times changed drug excreted in urine and feces daily (maximum daily May cause serious skin reactions dose, 2400 mg); Oral so- lution, 22.
The quantity charge per phase is deﬁned as the integral of the stimulus current over one half-cycle of the stimulus duration purchase kamagra super with a mastercard erectile dysfunction doctor nyc. In summary kamagra super 160mg low price erectile dysfunction doctor in kuwait, the measurements that have been made to date serve as useful guides for the threshold levels needed to stimulate retinal neurons; however kamagra super 160mg on-line doctor for erectile dysfunction in chennai, a quantitative relationship between minimum currents, electrode size, proximity, and pulse shape is still incomplete. What Is the Maximum Current That Can Be Used Before Impairing the Physiological Function of Retinal Cells? Among the early studies that have addressed this issue are the histopathological studies of long-term stimulation by Pudenz et al. Lilly (1961) demonstrated the relative safety of biphasic, charge- balanced waveforms compared with monophasic waveforms. They also showed that the threshold of tissue damage from electrical stimulation is primarily dependent on charge density and charge per phase (McCreery et al. Charge density is deﬁned as charge per phase divided by the electrochemically active electrode surface area. Since total charge density is responsible for the damage of tissue and electrodes, it has been hypothesized that there is a theoretical limit for how small electrodes can be (Brown et al. Using simple waveforms, conservative charge density limits for long-term stimulation with plati- num are 100 mC/cm2 and 1 mC/phase. For activated iridium oxide electrodes, the limit is 1 mC/cm2 and 16 nC/phase. Most of the studies that were done to determine these limits were performed with superﬁcial cortical electrodes (McCreery et al. Long-term in vivo retinal stimulation tests still need to be performed to deﬁne tissue damage thresholds. What Are the Optimum Conditions for Stimulating Retinal Neurons and What Is the Desired Response? One of the conditions for safe electrical stimulation of neural tissue is a reversible faradaic process. These reactions involve electron transfer across the electrode/neuron interface. These chemicals remain bound to the electrode surface and do not mix with the surrounding solution. It is also necessary to know the chemical reversibility of electrode materials and stimulation protocols. Chemical reversibility requires that all processes occurring at an electrode that are due to an electrical pulse, including H2 and O2 evolution, will be chemically reversed by a pulse of opposite polarity. The two basic waveforms used in electrical neural stimulation to achieve chem- ical reversibility are sinusoidal and pulsatile. The sinusoidal waveform is completely described by its amplitude and frequency. The pulsatile waveform is completely described by a square-ware pulse amplitude, that is, amplitude, duration, polarity, and repetition frequency (Gorman and Mortimer, 1983). Over time, any net dc current can lead to charge accumulation and irreversible electrolytic reactions. A biphasic current waveform consisting of two consecutive pulses of equal charge but opposite polarity avoids these problems. Studies with isolated rabbit retinas in both normal and rd mice showed that the electrophysiological response has the lowest threshold when a cathodic wave is used ﬁrst. These studies also showed that the response threshold was lower when a square-wave electrical stimulus was used (Shyu et al. Electrode Biocompatibility Because any future implantable device would be positioned against neural tissue for very long periods of time, potentially decades, a number of biocompatibility issues need to be addressed. The biocompatibility between an implanted medical device and the host tissue is as important as its mechanical dura- bility and functional characteristics. E¤ects of the implant on the tissue include inﬂammation, sensi- tivity reactions, infections, and carcinogenicity. E¤ects of the tissue on the implant are corrosion and other types of degradation. Sources of toxic substances are anti- oxidants, catalysts, and contaminants from fabrication equipment. Microfabricated electrodes were initially conceived in the early 1970s (Wise et al. In subsequent years, the dimensions of these electrodes have been decreased, using concurrent advances in the microelectronics industry. Today, micromachined silicon electrodes with conducting lines of 2 mm are standard (Hetke et al. Long-term implantation and in vitro testing have demonstrated the ability of silicon devices to maintain electrical charac- teristics for long-periods (Weiland and Anderson, 2000). Using simple waveforms, conservative charge density limits for long-term stimulation with plati- num are 100 mC/cm2. For activated iridium oxide electrodes, the limit is 1 mC/cm2 (Beebe and Rose, 1988). Platinum-iridium alloys are mechanically stronger then plat- inum alone. Most neural prostheses use platinum stimulating electrodes, the exception being the BION microstimulator (Advanced Bionics, Sylmar, California), which uses iridium oxide. Iridium oxide has been shown in vitro to have a safe stimulation limit of 3 mC/cm2 (Beebe and Rose, 1988). Recently, a titanium nitride, thin-ﬁlm electrode has demonstrated charge in- jection limits higher than both platinum and iridium oxide, with an in vitro limit of 22 mC/cm2 (Janders et al. Stabilizing the electrode array on the surface of the retina is an especially formida- ble problem. The biocompatibility and the feasibility of surgically implanting an elec- trode array onto the retinal surface have been examined at Johns Hopkins University Hospital. In one experiment, a 5 Â 5 electrode array (25 disk-shaped platinum elec- trodes in a silicone matrix) was implanted on the retinal surface using retinal tacks in each of four mixed-breed sighted dogs for a maximum period of 1 year. No retinal Stimulation of Large Retinal Tissue Areas 29 detachment, infection, or uncontrolled intraocular bleeding occurred in any of the animals. Retinal tacks and the retinal array remained ﬁrmly a‰xed to the retina throughout the follow-up period. It was concluded that implantation of an electrode array on the epiretinal side (i. Another method for attaching electrode arrays is by biocompatible adhesives. Nine commercially available compounds were examined for their suitability as intraocular adhesives: commercial ﬁbrin sealant, autologous ﬁbrin, Cell-Tak, three photocurable glues, and three di¤erent polyethylene glycol hydrogels. Hydrogels proved superior for intraocular use in terms of consistency, adhesiveness, stability, impermeability, and safety. IRP Experiments A number of in vivo and in vitro retinal stimulation studies have been performed in animals and humans at Johns Hopkins University Hospital. The next major step will be long-term implantation of active devices in animal models to examine the e‰cacy and safety of such devices. Speciﬁc parameters that will be examined during these experiments are the clinical appearance of the retina during the period of the implantation, and electrophysiolog- ical responses—electroretinogram (ERG) and visual-evoked potentials (VEP).