By Z. Mojok. Westminster Theological Seminary in California. 2019.
While it would order hydrochlorothiazide 25 mg online, once again order discount hydrochlorothiazide on line, be unrealistic to expect that the complex dynamics of these three periods can be rendered by relational maps buy hydrochlorothiazide 25mg on line, Figure 7 (see also Figure 5) shows that using this kind of map, we can at least visualize their existence. First, while the map displays a neat chronological sequence, we can also see on the top and the bottom of the map a cluster of years and substances that correspond, respectively, to the beginnings of chemotherapy and to the most recent period, characterized by the emergence of targeted therapies. The map, thus, displays the coordinates of the chemo-therapeutic space generated by an evolving set of substances and regimens during the last forty years. In what follows, we will provide a closer look at the structuring of this space during the second (Section 4) and third (Section 5) period. Such a view centers on individual compounds as the fulcrum of the trialists’ activities and assigns an unchanging ontology to substances. In this section, we provide detailed examples of why these two assumptions are problematic. Baker, The Chemotherapy Program of the National Cancer Institute: History Analysis and Plan. The Committee also made higher-order decisions: what kinds of substances should be procured? Selected staff members were charged with the promotion of specifc compounds and functioned as part of an advocate system widely used in the pharmaceutical industry at the time. Despite the representation of the process as a linear array, substances did not always follow a straight line from the beginning to the end of the evaluation process. A minor administrative scuffe in the late 1970s offers some insight into the tortuous routes sometimes taken. In it, DeVita noted that “[w]e are sometimes too concerned with the precise defnition of the decision point rather than the concept of dropping a compound, holding it static to develop more data, or, moving it along”, and went on to recall that: “[w]e are here to facilitate drug fow through the system, and when we have a clear interest, forward motion through several decision points is quite appropriate, particularly for unusual drugs. In order to examine the dynamics of regimens in the 1970s and 1980s, we have 37 Ibid. Determining whether or not to use a given regimen, at which stage of a disease – frst occurrence, relapse, metastasis – and in conjunction with what other modalities – surgery and/or radiotherapy – engendered an array of questions that contributed to the defnition of the feld of clinical cancer research as a new style of practice. Even before entering a regimen, a substance underwent a primary “historical/chemical” information test: could it be deemed an analogue of a substance already in use? If so, clinical evaluation differed from the evaluation of new substances insofar as “the analogue must always be compared in some way to its parent clinical [note that it doesn’t say: chemical] structure while the new drug stands alone and need only search for its role in competition with currently available regimens”. Yet none of these end-points could normally be tested by themselves: most substances in use were already in a given regimen that included other compounds so that activity, for example, was not absolute but relative to a given combination. A different and more complex strategy emerged in the case of analogues designed to diminish acute or chronic toxicity. The frst is that the unit category is not, as mentioned above, the substance but the regimen. The Phase distinctions, in other words and somewhat counter- intuitively, sometimes describe the trajectory of a compound synchronically, not diachronically. Anderson Hospital and Tumor Institute listed a series of tumors (breast, melanoma, etc. The integration of the different modalities was based on the “recognition that surgery and radiotherapy [had] reached a plateau in their ability to cure solid tumors”,52 a statement that must be understood in the context of an era when chemotherapy was rarely a frst line therapy. As Carter and Soper explained: the primary treatment in solid tumors without disseminated disease is surgery and/or radiotherapy. Chemotherapy is relegated to secondary or tertiary use after the local modalities fail and the disease is advanced and disseminated. Since the secondary or tertiary therapy is rarely curative in any tumor, including hematologic malignancies, it is understandable that chemotherapy in solid tumors has not been curative although it has produced tumor regression, palliative beneft and some survival gains. Any comparison of the results of chemotherapy in solid tumors and in hematologic malignancies should take into consideration the differences in the fow of treatment as well as the dissimilarities between the two tumor types. This relatively straightforward strategy amounted to testing drugs and regimens in late-stage patients and moving the successful ones forward until they reached the front line. For instance, the standard treatment fow for breast cancer patients consisted of four stages corresponding to the disease trajectory: an initial “curative” stage consisting of mastectomy and radiotherapy, followed by hormonal manipulation, oophorectory and/or estrogen for primary recurrent disease, hormonal manipulation and/or chemotherapy for secondary recurrent or advanced disseminated disease and, fnally, chemotherapy for advanced- late disease. The novel approach was to test chemotherapy drugs and regimens in patients from this last stage, determine the optimum drug combination in patients with secondary recurrent or advanced disseminated disease and use a combined modality approach that would henceforth include chemotherapy in patients from the frst two stages. Soper, Integration of Chemotherapy into Combined Modality Treatment of Solid Tumors. An interesting complication, in this respect, is that as soon as a given regimen becomes the recommended standard therapy, it is unethical to perform placebo-controlled trials to assess variants of or alternatives to that regimen. For a controversy between two prominent trialists touching on this issue see Jean L. Substances could thus be ranked in relation to the number of tumors in which they had been “adequately” or “inadequately” tested. For example, in 1974, single agents had undergone many more trials in breast cancer than in bladder cancer. Of the 29 known active agents, 24 had received an “adequate trial” in breast cancer while only two had been so tested in bladder cancer. Although individual agents may each have shown effectiveness in a human tumor, their combination was largely empirical. The empiricism, however, was also perceived as a form of bounded rationality insofar as it followed rules of thumb that had been shown to hold for the most successful combination regimens, namely that each drug in the combination should be active when used alone against the tumor, that the drugs should have different mechanisms of action, and that their toxic effects should not overlap, so that each could be given near its maximum tolerated dose. A legitimate question, therefore, is whether and, if so, to what extent commercial producers of individual substances were involved, in addition to clinical researchers, in the priority setting exercise. Initially, commercial producers were not as involved in 55 Carter and Soper, Integration of Chemotherapy , op. As recently as the 1980s, the market for cytotoxic drugs was “quite small when compared to such conditions as hypertension or peptic ulcer”. By drawing too sharp a boundary between clinical investigators and pharmaceutical companies,theaforementionedquestionbetraysanunnecessarilyrigid,dichotomousunderstanding of the relations between public and private organizations. Although the development of hybrid confgurations transgressing public/private boundaries between and within organizations has become screamingly evident in recent years in domains such as genomics and bioinformatics,65 this phenomenon characterizes emergent techno-scientifc networks more in general66 and there are clear indications that it was also at work in development of new chemotherapy substances and regimens, both from the perspective of public institutions and of commercial producers. Smith Doerr, Interorganizational Collaboration and the Locus of Innovation: Networks of Learning in Biotechnology. Cooper reported a spectacular 90% complete response rate in advanced breast cancer patients who had developed resistance to hormone therapy (Cooper, 1969). Cooper’s regimen created considerable buzz and, almost immediately, six different Cooperative Oncology groups set out to test variations of the regimen. A brief glance at the fate of these combinations and their varying rationales shows that despite the many attempts to impose order on the system – the multiple arrays, the logics, the phases and the charts and diagrams – clinical cancer research defes simple description for clinical trials are always more than simple tests of drug effcacy. The interpretation of trial results invariably takes place within the context of past, present and future trials.
Contraindicatons Hypersensitvity to penicillins (see notes above); serious infectons (see notes above) hydrochlorothiazide 25mg without a prescription. Adverse Efects Hypersensitvity reactons including urtcaria order hydrochlorothiazide now, serum sickness reacton; joint pain buy line hydrochlorothiazide, rash, angioedema, anaphylaxis (see notes above); nausea and diarrhoea; epigastric distress, skin eruptons; haemolytc anaemia. Piperacillin + Tazobactam Pregnancy Category-B Schedule H Indicatons Nosocomial pneumonia, infectons following burns, urinary tract infectons. Precautons Pregnancy (Appendix 7c), lactaton; prolonged treatment may increase super infectons, interactons (Appendix 6c). Adverse Efects Hypersensitvity reactons like rash, fever, bronchospasm, vasculits, serum sickness, exfoliatve dermatts, Steven’s-Johnson syndrome, and anaphylaxis. Procaine Benzyl Penicillin (Procaine Penicillin G) Pregnancy Category-B Schedule H Indicatons Syphilis; anthrax; childhood pneumonia; diphtheria carrier state; cellulits; mouth infectons; bites. Dose Intramuscular and intravenous injecton or infusion Adult- Streptococcal infecton and pyroderma: single dose 12 lac units. Precautons History of allergy (see notes above); renal failure; pregnancy (Appendix 7c). Adverse Efects Hypersensitvity reactons including urtcaria, fever, joint pains, rashes, angioedema, anaphylaxis, serum sickness-like reacton, haemolytc anaemia, intersttal nephrits (see also notes above); neutropenia, thrombocytopenia, coagulaton disorders and central nervous system toxicity (associated with high doses and severe renal failure); Jarisch-Herxheimer reacton (during treatment for syphilis and other spirochaete infectons, probably due to release of endotoxins); rarely, non-allergic (embolic- toxic) reactons; pain and infammaton at injecton site. Storage The consttuted soluton should be used immidiately afer preparaton but in any case within the period recommended by the manufacturer. Roxithromycin Pregnancy Category-B Schedule H Indicatons Susceptble infectons; pneumonia, acute bronchits, sinusits, pharyngits, tonsillits, genital infecton. Precautons Hepatc dysfuncton; paediatrics (reduce dose); interactons (Appendix 6d); pregnancy (Appendix 7c). Adverse Efects Diarrhoea; vomitng; nausea; transient rise in liver transaminase; skin rash; gastralgia. Contraindicatons Hypersensitvity to sulfonamides; porphyria; severe renal hepatc impairment, blood dyscrasias, elderly. Adverse Efects Nausea, vomitng, diarrhoea, headache; hypersensitvity reactons including rashes, pruritus,photosensitvityreactons,exfoliatve dermatts and erythema nodosum; rarely, erythema multforme (Stevens-Johnson syndrome) and toxic epidermal necrolysis; systemic lupus erythematosus, myocardits, serum sickness; crystalluria-resultng in haematuria, oliguria/anuria; blood disorders including granulocytopenia, agranulocytosis, aplastc anaemia, purpura-discontnue immediately; also reported, liver damage, pancreatts, antbiotc-associated colits, eosinophilia, cough and shortness of breath, pulmonary infltrates; aseptc meningits, depression, ataxia, tnnitus, vertgo, dizziness, hallucinatons, and electrolyte disturbances; convulsions, hypoprothrombinemia, methaemoglobinemia, anorexia, pancreatts. Dose Adult- 250 mg every 6 h, increase to 500 mg every 6 to 8 h in severe infectons. Non-gonococcal urethrits: 500 mg every 6 h for 7 to 14 days (21 days if failure or relapse afer course is seen). Contraindicatons Depositon of tetracyclines in growing bone and teeth (by binding to calcium) causes staining and occasionally dental hypoplasia and they should not be given to children under 12 years, or to pregnant (Appendix 7c) or lactatng women (Appendix 7b). However, doxycycline may be used in children for treatment and post-exposure prophylaxis of anthrax when an alternatve antbacterial cannot be given (unlicensed indicaton). With the excepton of doxycycline and minocycline, the tetracyclines may exacerbate renal failure and should not be given to patents with kidney disease; hypersensitvity; interactons (Appendix 6c, 6d) Precautons Used with cauton in patents with hepatc impairment or those receiving potentally hepatotoxic drugs. Tetracyclines may increase muscle weakness in patents with myasthenia gravis and exacerbate systemic lupus erythematosus; antacids and aluminium, calcium, iron, magnesium and zinc salts decrease the absorpton of tetracyclines; milk also reduces the absorpton of tetracyclines, demeclocyclines and oxytetracycline; cerebrovascular sensitsaton, maculopapular rashes, increased blood urea nitrogen, anaemia. Other rare side-efects include hepatotoxicity, pancreatts, blood disorders, photosensitv- ity (partcularly with demeclocycline) and hypersensitvity reactons (including rash, exfoliatve dermatts, Stevens-Johnson syn- drome, urtcaria, angioedema, anaphylaxis, pericardits). Headache and visual distur- bances may indicate benign intracranial hypertension (discontnue treatment); bulg- ing fontanelles have been reported in in- fants; anaemia. Trimethoprim Pregnancy Category-C Schedule H Indicatons Urinary-tract infectons; bronchits. Precautons Renal impairment; lactaton (Appendix 7b); predispositon to folate defciency; elderly; blood counts on long-term therapy (but practcal value not proven); neonates (specialist supervision required); pregnancy (Appendix 7c). Adverse Efects Rashes, pruritus; depression of haematopoiesis; gastrointestnal disturbances including nausea and vomitng; rarely, exfoliatve dermatts and toxic epidermal necrolysis, photosensitvity and other allergic reactons including angioedema and anaphylaxis; aseptc meningits; erythema, multforme, elevaton of transaminase and bilirubin. Precautons Avoid rapid infusion (risk of anaphylactoid reactons, see Adverse efects); rotate infusion sites; renal impairment (Appendix 7d); elderly; history of deafness-avoid; plasma-vancomycin concentraton measured afer 3 or 4 doses (earlier if renal impairment), blood counts, urinalysis and renal functon tests-use only in hospital setng; monitor auditory functon and plasma-vancomycin concentratons in elderly or in renal impairment; lactaton (Appendix 7b); pregnancy (Appendix 7c); interactons (Appendix 6c); Pseudomembranous colits. Adverse Efects Nephrotoxicity including renal failure and intersttal nephrits; ototoxicity (discontnue if tnnitus occurs); blood disorders; nausea, chills, fever, eosinophilia, anaphylaxis, rashes, including exfoliatve dermatts, erythema multforme (Stevens-Johnson syndrome), toxic epidermal necrolysis and vasculits; phlebits; on rapid infusion, severe hypotension (with shock, cardiac arrest), wheezing, dyspnoea, urtcaria, pruritus, fushing of the upper body (‘red man’ syndrome), pain and muscle spasm of back and chest; hypotension, pruritus, haematopoitc febits. Diethylcar- bamazine is efectve against both adult worms and larvae; a single weekly dose is normally efectve as prophylaxis. During individual treatment, partcularly of persons with heavy micro- flaraemia (>50 000 microflariae/ml blood), a conditon simu- latng meningoencephalits occasionally occurs. This probably results from sludging of moribund microflariae within cere- bral capillaries. The frequency of meningoencephalits associ- ated with diethylcarbamazine therapy of loiasis is reported as 1. Permanent cerebral damage is common among patents who survive and this possibility should be considered when deciding on treatment. Treatment of heavily infected patents should thus begin at low dosage and cortcosteroid and anthistamine cover should be provided for the frst 2 to 3 days. Lymphatc Filariasis: Lymphatc flariasis is caused by infecton with Wuchereria bancrofi (bancrofian flariasis), Brugia malayi or B. Indi- vidual treatment with diethylcarbamazine which has both microflaricidal and macroflaricidal actvity is efectve. Total cumulatve dosages of 72 mg/kg are generally recommended for Wuchereria bancrofi infectons with half this dose used for Brugia malayi and B. In all cases treat- ment is best initated with smaller doses for 2-3 days to avoid the danger of immunological reactons. Rigorous hygiene to the afected limbs with adjunctve measures to minimize infecton and promote lymph fow is important for reducing acute episodes of infammaton. In communites where flariasis is endemic, annual administra- ton of single doses of albendazole 400 mg with either diethyl- carbamazine (6 mg/kg) or ivermectn (200 µg/kg) is efectve for interruptng transmission; this treatment is contnued for at least 5 years. Trials in India and China have shown that the consistent use for 6-12 months of table salt containing diethyl- carbamazine 0. Dose Oral Adult and child- 11 mg/kg body weight daily in three divided doses on the frst day. Thereafer increase gradually to 6 mg/kg body weight given afer food daily for two to three days. Contraindicatons Pregnancy (delay treatment untl afer delivery); infants, elderly, debilitated (usually excluded from mass treatment programmes; see also Precautons); cardiac disease, hypersensitvity, impaired renal functon. Precautons Renal impairment; cardiac disorders; other severe acute diseases-delay diethylcarbamazine treatment untl afer recovery; risk of meningoencephalits in severe infecton (see notes above). Adverse Efects Headache, dizziness, drowsiness, nausea and vomitng; immunological reactons, within a few hour of the frst dose, subsiding by ffh day of treatment and including fever, headache, joint pain, dizziness, anorexia, malaise, nausea and vomitng, urtcaria and asthma in asthmatcs (similar to Mazzot reacton), induced by disintegratng microflariae; microencephalits (with heavy microflaraemia, see notes above); reversible proteinuria; enlargement of lymph nodes.
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Preparation and in vitro evaluation of liposomal/ niosomal delivery systems for antipsoriatic drug dithranol. It is vital that the regulatory process be coherent and avoid mistakes made in developing regulatory frameworks for recent innovations, such as nanotechnology and agricultural biotechnology, to ensure the development of new uses, as well as public conﬁdence (1). Although standards of care have been established, accurate prediction of the effects, both therapeutic and toxic, of a given therapeutic system on a given patient is frustrated by a host of cellular resistance mechanisms that yield disappointing differentials between in vitro predictions and in vivo results (2).