By D. Givess. University of Memphis.
The day-to-day variability purchase 30 gm v-gel free shipping, for a symp- tomatic asthmatic discount v-gel 30gm without prescription, can be considerable cheap v-gel 30 gm with mastercard. Studies in which treatments are fixed through- using the mean of all values over a prespecified out the period under investigation v-gel 30 gm line. An arm in period, as long as possible, generally provides 372 TEXTBOOK OF CLINICAL TRIALS us with a measure that has proven to be useful also of symptom scores and of the use of rescue in many clinical studies. Because of the intrinsic variability in measure is to use FEV1 measurements obtained at the underlying disease it is important to compute visits to the clinic. Though each individual FEV1 means over long periods, preferably the full measurement so obtained is much more reliable treatment period. This means that, for some drugs than a single PEF measurement, the overall mean at least, the mean will contain data from a period over a treatment period of daily recorded PEF of onset of action, though the effect of that will measurements obtained in the morning is, in our be minor in long-term studies. Simi- When using FEV1 obtained at visits to the larly it might be useful to compute the percentage clinic as primary variable in a long-term clinical of days with no rescue medication. Thus it is important that ally, one approach to the analysis of the data is to FEV1 is measured at approximately the same time compute the sum of the symptoms (as the nasal of day on each visit. To obtain maximal efficiency index score), but an alternative is to analyse them we also need to schedule the patients for visits simultaneously in a multivariate analysis. The possibility of enforcing this will very to define a patient to have control of the asthma, if much determine the effectiveness of the FEV1 there are no symptoms and the patient did not use variable in discriminating between treatments. The percentage of such days In COPD studies lung function is also of with asthma control can be a useful summary interest, but for this disease the symptomatic measure for some patient populations, typically benefit is stressed more. A variant of this is to define night sleep, breathlessness, coughing and chest mild exacerbations, or episodes, of asthma from tightness seem to be accepted symptoms to diary cards by looking for worsening of lung include in diary cards. The exact criteria for such blockage, rhinorrhea, sneezing and/or itchy nose episodes probably need to be adjusted to the which sometimes are combined into the nasal patient population under study, and to the study index score, which is the sum of them. In order to avoid spurious events, it might addition to this, eye symptoms are recorded as be a good idea to define an event to have occurred a secondary variable. The most readily available for two consecutive days in order to be labelled objective measure in the clinical trial setting is an episode. From an analysis point of view we either the Peak Nasal Inspiratory Flow (PNIF) or can analyse time to first such exacerbation or Peak Nasal Expiratory Index. As already indicated, asthmatic patients, especially PEF, and the dis- in fixed dose studies period mean values are often ease asthma in general. When we interpret diary computed, not only of PEF measurements, but card data, obtained over a longer period, we must RESPIRATORY 373 interpret it on a group mean level. A discussion General health status scales such as the Sick- on individual responders is virtually meaning- ness Impact Profile with 136 items26 have been less. This cannot be tionnaires and single-item measures of health assessed on the basis of diary card data, since has also been proposed. The Nottingham Health the underlying disease is, by definition, vary- Profile with 45 items and SF-36 (a Measures ing – what seems to be a clear response could of Sickness short-form general health survey) well be a period of good asthma control totally are now widely used and validated. The SF-36 unrelated to drug effect (in some cases a study Health Status Questionnaire is based on 36 items effect) and the converse. This is obvious once selected to represent eight health concepts (phys- one has inspected placebo data in a long-term ical, social and role functioning; mental health; study. However this does not exclude that one can health perception; energy/fatigue; patin; and gen- define responders according to some criteria and eral health). This is It is perhaps the most comprehensive question- true irrespective of whether the dose in question naire for evaluation of quality of life in airways refers to the investigational drug or to some diseases and allows for direct numerical compar- concomitant drug (as e. The measure consists of 50 Asthma and COPD are chronic disorders that (76 responses) items that produce three domain can place considerable restrictions on the physi- scores and one overall score. The domains are: cal, emotional and social aspects of the lives of symptoms (severity and frequency), activity (that patients. Quality of life may be use- ful for assessing the degree of morbidity, e.
We are grateful to everyone who contributed to these studies buy v-gel 30 gm line, and to our colleagues and their publishers who have allowed us to reproduce Figures from their papers generic v-gel 30 gm otc. Finally buy 30gm v-gel, the authors would like to thank INSERM and NH&MRC for support of their work cheap 30gm v-gel mastercard. The principle is based on the selective investigation of different spinal path- the apparent simplicity of the monosynaptic projec- ways. Whatever the pathway investigated, its activa- tion of Ia afferents to homonymous motoneurones. We will consider successively: (i) the initial of changes in the spinal circuitry in human sub- findings; (ii) the principles underlying the mono- jects is therefore to be able to assess changes in synaptic reflex testing method; (iii) the basic motoneurone excitability quantitatively, using valid methodology of the H reflex; (iv) limitations related reproducible methods. All may be, and many have been, used Initial studies in studies on patients, but here the methodology should be simple and rapid. Animal studies This initial chapter is technical and non-specialist readers could bypass it, referring back if they need The monosynaptic reflex depends on the projec- to clarify how results were obtained or understand tion of muscle spindle Ia afferents to homonymous the advantages and limitations of a particular tech- motoneurones and was used in the early 1940s as nique. However, the chapter is required reading for a tool for investigating changes in excitability of those who want to understand fully the particular the motoneurone pool (Renshaw, 1940;Lloyd, 1941). During the 1940s and The monosynaptic reflex: H reflex early 1950s this method was used to reveal impor- and tendon jerk tant features of the input to spinal motoneurones. Ia afferents from muscle spindle primary endings (dotted line) have monosynaptic projections to motoneurones (MNs) innervating the corresponding muscle (homonymous MNs). The H reflex is produced by electrical stimulation of Ia afferents, and bypasses muscle spindles. The tendon jerk is elicited by a tap that stretches muscle spindles and therefore also depends on the sensitivity to stretch of primary endings, a property that may be altered by the activity of efferents (however, see Chapter 3,pp. The pathway of presynaptic inhibition of Ia terminals (see Chapter 8)is represented. Thissug- The monosynaptic reflex arc geststhatthemonosynapticreflexmethodproduces reliable results. Pathway Ia fibres from muscle spindle primary endings have Human studies monosynaptic excitatory projections to motoneu- rones innervating the muscle from which the affer- Percutaneous electrical stimulation of the posterior ents emanate (homonymous projections, Fig. The H reflex is produced by electrical knownastheHoffmannreflexorHreflex(Magladery stimulation of Ia afferents, which have a lower elec- &McDougal, 1950). After the pioneer investigations of Paillard (1955), the H reflex, which The H reflex, tendon jerk and short-latency is the equivalent of the monosynaptic reflex in ani- spinal stretch reflex mal studies, became the main tool in many motor control investigations and diagnostic studies per- Thesearealldependentonmonosynapticexcitation formed on human subjects (for reviews, see Schiep- from homonymous Ia afferents. Chapter 3): (i) the electrically induced afferent The monosynaptic reflex 3 (a) Test reflex alone: Test EPSP MNs (b) Test reflex conditioned by an excitatory input Conditioning + test EPSPs MNs (c) Test reflex conditioned by an inhibitorory input Conditioning IPSP + test EPSP MNs Fig. The dotted horizontal line represents the threshold for discharge of the MNs. Only the smallest MNs (black) are fired by the test Ia volley, and the excitability of subliminally excited MNs decreases from the smallest to the largest (as indicated by the decreasing tone of grey). There is summation of the conditioning (thin lines) and test (thick lines) EPSPs. As a result, MNs which had just failed to discharge in the control reflex are raised to firing threshold and the size of the reflex is increased. There is summation of the conditioning IPSP (thin line) and of the test EPSP (the test EPSP is also reduced by changes in the membrane conductance, see p. As a result, MNs which had just been recruited in the control reflex cannot be discharged, and the size of the reflex is reduced. Note that the excitability of the MNs in the subliminal fringe of excitation is also modified by the conditioning input. Basic methodology This orderly recruitment of motoneurones is pre- served when they receive a variety of excitatory and Hreflexes cannot be recorded with equal ease in dif- inhibitoryinputs(thoughnotall,seepp. In most healthy that facilitation will initially affect those motoneu- subjects at rest,Hreflexes can usually be recorded ronesthatjustfailedtodischargeinthecontrolreflex only from soleus (Hoffmann, 1918), quadriceps (dark grey motoneurones in Fig. In the control situation, the test Ia volley elicited by stimulation of constant intensity causes some motoneurones to discharge producing the control General experimental arrangement test reflex (black motoneurones in Fig. If motoneurones are now facilitated by chair with the examined limb loosely fixed in a posi- a subthreshold conditioning volley, motoneurones tion avoiding stretch of the test muscle (see Hugon, thathadjustfailedtofireinthecontrolreflexwilldis- 1973;Burkeetal. Thus,thelowerlimbiscom- monly explored with the hip semi-flexed (120◦), the charge when the conditioning and test EPSPs sum- kneeslightlyflexed(160◦)andtheankleat110◦ plan- mate (Fig. Theupperlimbisexploredwiththeshoul- der in slight abduction (60◦), the elbow semi-flexed tioning inhibitory post-synaptic potentials (IPSPs), (110◦), and the forearm pronated and supported by the test Ia volley will not be able to discharge the motoneurones that had been recruited last into the arm of the chair.
Oprelvekin has been given to a few children with In some clients with preexisting hepatic impairment generic v-gel 30gm on line, sar- adverse effects similar to those observed in adults purchase v-gel 30 gm without prescription. Val- indicate that tachycardia occurs more often in children and ues declined to baseline levels when the drug was stopped or that larger doses are needed (eg order 30gm v-gel fast delivery, a dose of 75 to 100 mcg/kg its dosage reduced order v-gel 30 gm. Hepatic function tests are recommended in children produces similar plasma levels to a dose of every 2 weeks in clients with preexisting impairment. Long-term effects on growth and de- With aldesleukin, hepatic impairment occurs during ther- velopment are unknown. This impairment may be increased if other hepatotoxic Little information is available about the use of interferons in drugs are taken concomitantly. Interferon alfacon-1 (Infergen) is not recommended patic impairment may delay metabolism and elimination of for use in children. Interfer- ons alfa-2b, alfacon-1, and alfa-n1 are contraindicated in Use in Older Adults clients with decompensated liver disease (ie, signs and symp- toms such as jaundice, ascites, bleeding disorders, or de- In general, hematopoietic and immunostimulant agents have creased serum albumin), autoimmune hepatitis, a history of the same uses and responses in older adults as in younger adults. Worsening of liver disease, with jaundice, hepatic adverse effects, especially if large doses are used. Oprelvekin encephalopathy, hepatic failure, and death, has occurred in should be used with caution in clients with a history of or risk these clients. The drugs should be discontinued in clients with factors for atrial fibrillation or flutter; these arrhythmias oc- signs and symptoms of liver failure. In addition, older adults are more likely to have fluid retention, with resultant symptoms of peripheral edema, dyspnea on ex- Home Care ertion, and dilutional anemia. Darbepoetin alfa (Aranesp), epoetin alfa (Epogen), filgrastim (Neupogen, Neulasta), oprelvekin (Neumega), and the inter- Use in Renal Impairment ferons are often self-administered or given by a caregiver to chronically ill clients. The home care nurse may need to teach Except for darbepoetin alfa and epoetin alfa, which are used to clients or caregivers accurate drug preparation and injection treat anemia in clients with chronic renal failure, little informa- techniques, as well as proper disposal of needles and sy- tion is available about the use of hematopoietic and immuno- ringes. Assistance may also be needed in obtaining appropri- stimulant drugs in clients with renal impairment. Renal function tests For example, epoetin alfa is not effective unless sufficient are recommended every 2 weeks in clients with preexisting iron is present, and most clients need an iron supplement. When an iron preparation is prescribed, the home care nurse With aldesleukin, renal impairment occurs during therapy. With fil- This impairment may be increased if other nephrotoxic drugs grastim, the nurse may need to help the client and family with are taken concomitantly. In addition, drug-induced renal im- techniques to reduce exposure to infection. CHAPTER 44 HEMATOPOIETIC AND IMMUNOSTIMULANT DRUGS 667 NURSING Hematopoietic and Immunostimulant Agents ACTIONS NURSING ACTIONS RATIONALE/EXPLANATION 1. Administer accurately For hospitalized clients, the drugs may be prepared for adminis- tration in a pharmacy. Give darbepoetin alfa intravenously (IV) or subcutaneously Outpatients may be taught self-administration techniques. Give epoetin alfa IV or SC; do not shake the vial; and dis- For clients with chronic renal failure on hemodialysis, epoetin alfa card any remainder of multidose vials 21 d after opening. For patients with- out an IV line or who are ambulatory, the drug is injected SC. Shaking can inactivate the medication; the manufacturer does not ensure sterility or stability of multidose vials after 21 days. With aldesleukin, review institutional protocols or the man- This drug has limited uses and is rarely given. With interferons, (1) Read drug labels carefully to ensure having the correct Available drugs have similar names but often differ in indications drug preparation. With intravesical Bacillus Calmette-Guérin (BCG): (1) Reconstitute solution (see Drugs at a Glance: Hematopoi- Reconstituted solution should be used immediately or refrigerated. Then, allow to ambulate but ask to retain solution for a total of 2 h before urinating, if able. The goal is usually to achieve and maintain a hematocrit between 30% and 36% (with epoetin) or hemoglobin of no more than 12 g/dL (with darbepoetin). With epoetin, it takes 2–6 wk for the hematocrit to change after a dosage change. With oprelvekin, observe for maintenance of a normal or Platelet counts usually increase in approximately 1 wk and con- near-normal platelet count when used to prevent thrombocy- tinue to increase for approximately 1 wk after the drug is stopped.