By C. Pyran. University of Massachusetts Medical School. 2018.

Nitrogen mustard de- cell cycle and their cytotoxic effects are similar to those of rivatives (eg buy panmycin 250mg mastercard, cyclophosphamide) interfere with cell division the alkylating agents generic panmycin 500mg mastercard. They bind to DNA so that DNA and and the structure of DNA during all phases of the malignant RNA transcription is blocked purchase 250mg panmycin with amex. As a result purchase panmycin 500mg line, they have a broad spectrum of activ- row depression and GI upset discount panmycin 500mg mastercard. They are most effective in hematologic malignancies but also cause cardiotoxicity and tissue necrosis if extravasation also are used to treat breast, lung, and ovarian tumors. Nitrosoureas also interfere with DNA replication and RNA synthesis and may inhibit essential enzymatic reactions of can- Plant Alkaloids cer cells. They are cell cycle nonspecific and have been used in clients with gastrointestinal (GI), lung, and brain tumors. They Plant alkaloids include derivatives of camptothecin (eg, topote- are highly lipid soluble and therefore enter the brain and cere- can), podophyllotoxin (eg, etoposide), taxanes (eg, pacli- brospinal fluid more readily than other antineoplastic drugs. These They cause delayed bone marrow depression, with maximum drugs vary in their characteristics and clinical uses. As a result, the drugs are given less often than other drugs, and complete blood counts (CBCs) are needed weekly for at least 6 weeks after a dose. Nursing Notes: Apply Your Knowledge Platinum compounds are cell cycle–nonspecific agents that inhibit DNA, RNA, and protein synthesis. Adverse Your patient, Sally Moore is receiving an antineoplastic drug that effects include severe nausea and vomiting, nephrotoxicity, is known to cause bone marrow depression, with a nadir (lowest point) 12 days after administration. Carboplatin is most often used to treat en- marrow depression and appropriate nursing assessments. What dometrial and ovarian carcinomas and it produces bone marrow teaching would be appropriate for this patient? Oxaliplatin (Eloxatin) was 918 SECTION 11 DRUGS USED IN SPECIAL CONDITIONS Camptothecins (also called DNA topoisomerase inhibitors) It may cause severe bone marrow depression. Ibritumomab is inhibit an enzyme required for DNA replication and repair. They have activity in several types of cancers, including col- It is used with rituximab and may cause severe bone marrow orectal, lung, and ovarian cancers. Dose-limiting toxicity is depression and fatal infusion-related reactions. Common adverse Podophyllotoxins act mainly in the G2 phase of the cell effects include infusion reactions (hypoxia, acute respiratory cycle and prevent mitosis. Etoposide is used mainly to treat tes- distress syndrome, myocardial infarction, ventricular dys- ticular and small cell lung cancer; teniposide is used mainly for rhythmias, cardiogenic shock) and lymphopenia. Miscellaneous Cytotoxic Agents Taxanes inhibit cell division (antimitotic effects). Miscellaneous agents vary in their sources, mechanisms of Dose-limiting toxicity is neutropenia. L-Asparaginase Vinca alkaloids are cell cycle–specific agents that stop (Elspar) is an enzyme that inhibits cellular protein synthesis mitosis. These drugs have similar structures but different anti- and reproduction by depriving cells of required amino acids. Hydroxyurea acts in the S phase of the cell to treat non–small cell lung cancer. It is used to treat leukemia, vere tissue damage with extravasation (leaking of medication melanoma, and advanced ovarian cancer. Procarbazine inhibits DNA, RNA, vinblastine and vinorelbine are more likely to cause bone and protein synthesis. It marrow depression, and vincristine is more likely to cause is a monoamine oxidase inhibitor and may cause hypertension peripheral nerve toxicity. Monoclonal Antibodies Miscellaneous biotherapy agents include interferons (see Monoclonal antibodies (see Chap. Researchers also conjugate Imatinib is a tyrosine kinase inhibitor that inhibits cell pro- monoclonal antibodies with radioisotopes, toxins, chemother- liferation and increases cell death in chronic myelogenous apeutic agents, and drug-filled liposomes to increase their leukemia. It is also used to treat a rare type of cancer called effectiveness and deliver antineoplastic drugs to specific areas gastrointestinal stromal tumor and is being investigated for of the body. It is given orally and its side effects Cancer cells have more growth factor receptors than healthy include edema, cramps, nausea, and anemia. For example, 20% to 30% of women with breast cancer have an excessive number of HER2 receptors. A monoclonal Hormones and Hormone Inhibitors antibody, trastuzumab (Herceptin), was developed specifi- cally to bind with HER2 receptors and inhibit malignant cell Hormones interfere with protein synthesis and inhibit tumor growth.

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Do not regard writing block as a sign of failure; it is a sign that we are taking trouble to produce something worth while (see process of writing) buy cheap panmycin 500mg. This is particularly true of major projects trusted panmycin 500mg, such as scientific papers purchase 500 mg panmycin with mastercard, major reports panmycin 250mg on line, or theses buy panmycin 250 mg with mastercard. Here the prizes go to the persistent rather than to the clever or the knowledgeable. So, whenever possible, groups of writers should join together to give support and encouragement. After all, if it works for slimming, it should do so for writing, which is much easier. There should be about half a dozen members in the group, and they should meet regularly, perhaps every two or three months. Members of the group should be roughly at the same stage in terms of writing experience, otherwise it will become an opportunity for 141 THE A–Z OF MEDICAL WRITING political manoeuvring and showing off. It is worth taking care over the kind of things you will allow members to talk about. Which journals will they target and who will the co-authors be (see writing goals; brief setting)? Agree on the deadlines that you will have to meet if the targets are to be achieved. This is a good way of maintaining motivation, and ensuring that deadlines do not slip. Difficulties will surely emerge, whether they be technical ones such as using a particular piece of software, or more delicate ones such as persuading the professor to return the paper you sent him three months ago. It is surprising how much expertise can be found in a group of six people. Sharing problems and solutions will encourage the group to keep moving towards its targets. Every so often, and at least once a year, the group should celebrate its success. Some may wish to set a league table of celebrations, so that the greater the success the better the party! A final caution: these meetings should be used as an opportunity to discuss whether the work in hand is being produced, and not to discuss the work itself. If you allow the group to start getting involved in this you will usually end up with the work of those who have met their targets being criticized by those who have not. It will institutionalize the false feedback loop and ensure that the group misses its targets. Writing This whole book is about writing but there are main sections such as advice on writing; bad writing; books, writing of; books, writing of chapters in; concise writing; defensive writing; efficient writing; free writing; research into writing; science writing. Writing for different audience Not a specialist technique but the skill that goes right to the heart of effective writing. Writing goals Writing, when done well, takes up a tremendous amount of time. When you start 142 WRITING GOALS on a major writing project, do so because you want it to achieve some- thing and not because you rather feel you should. This means spending time working out – and writing down – your writing goals. Why do you need to write: to advance your career, to tell people about the interesting things you are doing, to see your name in print, to make money? The answer(s) should give you some idea of what you need to do: if you want to advance your career, you need one or two original papers in major journals; if you want to tell people what you are doing then perhaps a feature article in Pulse or Hospital Doctor – or a newsletter for patients. Now decide on – and also write down – your objectives: what you need to do to meet these goals. A much-loved mnemonic in this regard is SMART; we go one step further with SMARTER. What will be the criterion by which you will consider yourself to have succeeded? When and how will you review what you have done and see whether you are meeting the goals, and indeed whether the goals remain the same? For the price of committing yourself to paper, you can transform your dread of writing into well thought-out, rational, goal-related behaviour. Yellow marker test Over the years I have found this simple test an extremely useful tool for understanding the structure of a piece of writing. Take the highlighter and identify those sentences that you think are more important than the others.

Thirdly by preventing modern medicine cheap panmycin 250 mg with visa, which successfully identifies a future pathological mishappenings while the pathological cause of disease panmycin 250 mg on line, chooses a method current problem is being solved order panmycin 250 mg fast delivery. Suppression of symptoms like cough buy panmycin 250mg on line, While the aetiology buy 500 mg panmycin, epidemiology and natural diarrhoea or dyspnoea helps the sick individual course of a disease affect the design of clinical to survive. The aim Prevention in the modern biological sense of treatment is the re-establishment of balance; frequently refers to an immunological mecha- once balance is re-established, either naturally or nism through which the individual becomes more through herbal intervention, well-being will be resistant to future attacks of similar pathologi- re-established. Chinese medicine is often the control of adverse Clinical trials for Chinese medicine or herbal symptoms. The ultimate goal is maintaining the medicine therefore could follow the line of well-being of the biological system. The aeti- thought for scientific planning on data collection ological consideration is therefore not directed and subsequent data meta-analysis. However, the towards the actual cause of the disease (of which pre-treatment data would be confined mainly to the herbal expert has no idea), but a general symptomatology. Other parameters would carry conceptual state of the biological balance of the little weight for the herbal expert; but could human bodily functions. The ancient healers cor- still be included for more scientific knowledge related this conceptual state with the Taoist phi- in clinical trials. Any loss of balance GENERAL CONSIDERATIONS FOR CLINICAL led to ailment and disease. TRIALS ON HERBS The aim of treatment is therefore to main- tain the balance. Yin and Yang includes other In the modern scientific world, only up-to-date contrasting opposing forces like cold and heat, methodologies should be adopted. The set of COMPLEMENTARY MEDICINE 67 common methodologies for conducting clinical and metabolic pathways before clinical tests be trials on modern medicine has been logical, conducted. What is the chemistry of specific useful and has made wonderful contributions to herbs? What are the pathways of action and the clinical testing of new drugs and new meth- metabolic degradation? A lot of work of data and the use of statistics have revealed has been done in the past 50 years on this basic the trustworthiness of certain accumulated expe- understanding and not much has come out. Each rience, while at the same time the fallacies of and every herb contains so much complicated some even well accepted and widely practised chemistry that many years of research might methods. Actually at least four The common methodology of random selec- hundred herbs are popular and possess records tion, blinding and placebo control, followed by of therapeutic action and impressive efficacy. In the demand thorough knowledge on just this popular design of the trial, good clinical practice should proportion of herbs is not practical, not to speak be the aim. However, due to the nature of the of the less commonly used extra one to two herbs, which come from different origins and thousand varieties. Strictly encounter situations where basic principles that speaking, since herbs are agricultural products, cannot be strictly kept. The sites of production have THE OLD APPROACHES different weather, different soil contents, and the methods of plantation are also different. At the The herbal experts fervently respect case reports moment, maybe over 50% of popular Chinese and anecdotal reports, particularly when results herbs are produced on special farms in China. Once good demands that environmental and nurturing proce- results are known to be possible, the expert could dures be uniformly ensured. Procedures include try to achieve equally good results by wisely soil care, watering, fertilisers, pest prevention and manipulating the varieties of treatment. When such procedures are not uniform In this chapter, we do not endorse this and there are no means to ensure a common prac- traditional approach. We do want to apply modern tice, good agricultural practice is not possible. These different After all, the development of this system of species may have different detailed chemical con- healing depends solely on anecdotal analysis. Herbal experts have extensive experience Good clinical practice insists that the pre- and knowledge about some special correlations scribed drug for the clinical trial should be between the effectiveness of particular herbs and thoroughly known and uniform.

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The following five treatments were on a multiplicative scale panmycin 500 mg on line, we need to compute the 26 22 18 14 10 6 2 −2 A 6 µg A 12 µg A 24 µg −6 B 50 µg Placebo −10 0 Time since treatment administration (hours) Figure 22 panmycin 500mg discount. Geometric mean values purchase panmycin 250mg visa, expressed as percent increase from the baseline measurement generic panmycin 250 mg with mastercard, of FEV1 measurements over 12 hours for individual treatments RESPIRATORY 383 area all the way down to zero generic 500mg panmycin otc. To do this, we fit (weighted linear could integrate over the baseline measurement, regression to keep track of the uncertainties of but then the area could be negative and we would the means31) a straight line to drug A means be forced to do the final analysis on the original vs. As a consequence we find that 24 µgofdrugA as a single dose has + period + ln(FEV1,base) greater bronchodilating effect over 12 hours than 50 µgofdrugB. A more statistically we get a reasonable compromise between these sound approach would be to rephrase the two extremes. To find this out we compare them, from highest to lowest dose, with placebo. Mean 95% Confidence Here is the result in tabular form: Treatment ratio limits 24 µgofdrugA 1. We see that treatments clearly have a duration in excess the mean effect is 15–21% larger than it of 12 hours. So we can claim that 6 µg is an effective dose of drug A, without Effects of anti-asthma drugs are in general not compromising the significance level (see the confined to the lungs. Since the drugs are cleared through the effect as the reference treatment, 50 µgof bloodstream they will therefore have systemic 384 TEXTBOOK OF CLINICAL TRIALS 2. Treatment mean values for 12-hour average FEV1 with fitted log-linear dose–response curve for drug A and estimation of Deq relative to 50 µgofdrugB effects (albeit perhaps not measurable). In con- With this model in mind we can use cortisol trast to the anti-asthmatic effects, these effects in plasma as an index of the systemic burden can be measured both in healthy volunteers and of therapeutically given GCS. We can however not we can compare the pharmacodynamic systemic measure it timepoint by timepoint and compare effects of different GCSs by comparing their to measurements without drug, since the level effects on endogenous cortisol levels. This has the of cortisol is determined as a balance between added advantage over drug plasma concentrations production and elimination (with a half-life of that it accounts for differences in potency in about 1. We therefore need to study a done by negative feedback on the HPA axis). The cortisol levels in plasma have It is important to state at this point that we a diurnal rhythm which is very pronounced, so do not study endogenous cortisol levels because the most appropriate study to do is to give they themselves represent a dangerous side- repeated doses of the GCS until a new steady effect. The most useful variable to study is RESPIRATORY 385 the area under the curve for those 24 hours. In steady state, when there is a 24-hour periodicity, Mean 95% Confidence Treatment ratio (%) limits p this is proportional to the amount produced during 24 hours. This result does not tell much about how the Example: Comparison of Plasma Cortisol drugs compare. To do that we can fit parallel Dose–Response Curves non-linear dose–response curves to the mean effect data, adjusting for precision by using a We want to compare two inhaled steroids (with weighted non-linear regression. Each treatment period obtain that the relative dose potency is estimated consists of 4 days, and there was a washout to be 3. Each steroid was given in estimated to be about four times more potent than three doses: 200, 400 and 1000 µg b. Or put in other words: to achieve the Blood samples were measured every second hour same average depression in cortisol, we can use during the last 24 hours in each treatment period a four times larger dose of A than of B. The effect of the fact that the study is open We cannot extrapolate these results to patients is hard to assess. There is a basic difference between a of the drugs is associated with more stress than healthy volunteer and an asthmatic – the latter the administration of the other, this might bias has an ongoing inflammatory process. However, this seems unlikely, and that the dynamic system regulating cortisol is doing the study open has the benefit that fewer disturbed (compared to healthy) and we can inhalations are required on each occasion. So a typical patient might have a It is done on the logarithm of the concentrations larger ED50 than a typical healthy volunteer. By with standard factors for a crossover study: sub- the same token we can expect different patients ject, treatment and period. Estimated dose–response mean value curves for treatments A (to the right) and B (to the left) and in healthy volunteers, i. Thus the to claim that the relative effect of two GCS, pivotal confirmatory trials for the airway diseases as measured by the potency ratio, ρ, should asthma, COPD and rhinitis are parallel group, differ between patients and healthy volunteers, or diary card studies typically spanning from a between different categories of patients for that month up to a year. If such differences turn out to be the case, the reason must be that the systemic dose differs Asthma Trials between healthy volunteers and patients, and For asthma the typical study length for an efficacy then, most likely, between patients of different study seems to be 3 months, though occasionally degrees of severity in their disease. As already discussed, there is a continuous scale of severity of each of PHASE III STUDIES the respiratory diseases. The severity of asthma can be classified into a few groups, each of which DOCUMENTING EFFICACY AND SAFETY has its recommended medical treatment.

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