By B. Barrack. Springfield College. 2018.
The presence of these sequences near the translocation break-points may facilitate recombination purchase aldactone 100mg otc blood pressure when to go to er. Teniposide gave mainly negative responses in a range of assays in prokaryotes and lower eukaryotes buy discount aldactone 25mg on-line blood pressure 360. Teniposide caused about a twofold increase in the frequency of revertant colonies in S. In several of these bacterial tests, toxicity but not mutagenicity occurred at a dose of 250 μg/plate, which is higher than those studied in mammalian cells. Teniposide induced the formation of quadriradial chromosomes and affected accurate chromosomal segregation in Chinese hamster ovary cells. Fluorescence in- situ hybridization techniques revealed that about 40% of the rearrangement sites in teniposide-induced quadriradial and triradial chromosomal configurations in Chinese hamster Don cells involved a telomere-like block of base sequences (Fernández et al. Teniposide induced micronuclei and chromosomal aberrations in the bone marrow of mice. The drug induced sister chromatid exchange in V79 Chinese hamster cells and mutation and somatic recombination in Drosophila melanogaster in the wing spot test. It did not induce mutations at the Hprt locus in mouse lymphoma L5178Y cells, although it had weak effects at the same locus in Chinese hamster ovary cells. It induced primarily small colony mutants at the Tk locus in L5178Y cells; these mutants are usually caused by chromosomal mutations, and teniposide induced a series of deletions and duplications in the Aprt gene of Chinese hamster ovary cells. Cytogenetic changes were measured in bone marrow and embryonic tissue from pregnant mice given a single intraperitoneal injection of 1. Treatment on day 7 or 8 increased the frequency of embryonic cells with structural aberrations, one-fourth or more of which were stable, consisting of chromosomes with metacentric or submetacentric markers. Teniposide increased the percentage of embryonic cells with numerical aberrations, but this was statistically significant only on day 8. Most of the aberrations were hypo- ploidy (usually monosomy) and hyperploidy (usually trisomy) (Sieber et al. Whether cellular damage results in mutation or apoptosis depends on a number of factors (Ferguson & Baguley, 1994). Teniposide-induced apoptosis has been demons- trated in various cell types including unstimulated mouse splenic lymphocytes (Roy et al. Polyploidy induced by teniposide was demonstrated by flow cytometry techniques in Chinese hamster ovary cells (Zucker et al. In general, the effects of teniposide in mammalian cells in vitro occurred in the absence of exogenous metabolic activation. Various metabolic species of teniposide have been identified, but their mutagenic properties have not been studied. Most of the mutational events reported in mammalian cells, including point mutations, chromosomal deletions and exchanges and aneuploidy, can be explained by this activity. Teniposide does not inhibit bacterial topoisomerases and may not mutate bacterial cells by the same mechanism as mammalian cells. It possesses readily oxidizable functions: Teniposide formed phenoxy radical intermediates in the presence of horseradish peroxidase or prostaglandin synthase (Haim et al. The first is that teniposide itself causes the translocations, perhaps through a cytotoxic action. The second possibility for the role of teniposide in causing translocations is that it selects for cells that already have translocations. Chemotherapy has profound effects on the kinetics of the marrow: it causes cell death, forcing many marrow stem cells to divide, which might select for the rare stem cells with a translocation (Knudson, 1992). In the case–control study, the use of other potentially leukaemogenic agents was adjusted for in the analysis; however, the possibility cannot be excluded that interaction occurred between teniposide and those agents. It is unlikely that the large excess risk for acute myeloid leukaemia can be explained fully by misclassification or phenotypic change of the initial haematological malignancy. Other cohort studies have also reported strongly increased risks for acute myeloid leukaemia after treatment of various primary malignancies with teniposide-containing regimens that also included alkylating agents or teniposide-containing regimens in combination with etoposide. In these studies, the possibility cannot be excluded that the excess risk for leukaemia was partly or wholly due to the other agents. About 45% of a radiolabelled dose of teniposide was excreted in the urine, 4–14% occurring as the parent drug. In mice, the pharmacokinetics of teniposide differs from that of etoposide, a closely related drug, with lower clearance, a larger volume of distribution and a longer terminal elimination half-time.
This gives rise to typical side-effects associated with cancer chemotherapy such as hair loss and acute gastrointestinal disturbances order aldactone 25mg line pulse pressure 82. In the early 1900s Paul Ehrlich (who has been described as the father of drug delivery and therapeutics) pioneered the idea of the “magic bullet” approach generic aldactone 25mg line heart attack nightcore, whereby therapy “could learn to aim”. The inherent premise of this concept is to try to improve therapy by targeting the drug to the site of action, thereby removing unwanted toxic sideeffects and minimizing drug wastage. It generally involves the transformation of a lipid-soluble drug (which can cross membranes and thus reach its site of action) into a more polar, water-soluble compound which can be rapidly eliminated in the urine. Metabolic processes have considerable implications for successful drug delivery: • Metabolic activity may result in premature degradation of the active moiety, prior to its arrival at the active site. Metabolic activity may also constitute a considerable biochemical barrier to drug absorption. As described above, extensive enzymatic degradation of labile drugs in the gastrointestinal tract can severely limit their oral bioavailability. Specific tubular uptake processes exist for carbohydrates, amino acids, vitamins etc. Drugs may pass from the tubule into the plasma if they are substrates for the uptake processes, or if they are lipid soluble (this process is highly dependent on the prevailing pH, see Section 1. Depending on the drug and the disease state, the timing of therapy may be optimal as either zero-order controlled release, or variable release. Considerable advances in controlling drug release from delivery systems have been made; such systems are described in detail in Chapters 3, 4 and 16. By effective management of the dose size and the dose frequency, it is possible to achieve therapeutic steady-state levels of a drug by giving repeated doses. An example of the type of plasma profile obtained after repeated oral dosing of a drug is shown in Figure 1. However, multiple oral dosing is associated with disadvantages: • The drug concentration does not actually remain constant in the plasma, but fluctuates between maximum (peak) and minimum (trough) values (Figure 1. These fluctuations in plasma concentration may mean that drug levels may swing too high, leading to toxic side-effects; alternatively drug levels may fall too low, leading to a lack of efficacy. An alternative approach to overcome these limitations is to use a delivery system which provides zero-order controlled release of the drug (Figure 1. Zero-order controlled release offers the advantage of improved control over drug plasma levels: the peaks and troughs of conventional therapy are avoided and constant plasma levels are attained. The risk of side- effects is minimized since possible toxic peak drug plasma levels are never obtained and the total amount of drug administered is lower than with frequent repeated dosing. There is also a reduction in symptom breakthrough which can occur if plasma concentrations drop too low. Furthermore, patient compliance is also improved as a result of the reduction in the number and frequency of doses required to maintain therapeutic efficacy. For example, the problem of dosing through the night is eliminated since the drug is slowly released in vivo. A wide variety of drug delivery systems have been developed to achieve zero-order controlled release and are discussed further in the relevant chapters. Situations in which changing levels of response may be required include: Circadian rhythms Biological processes are frequently associated with rhythms of a predictable period. Some of these rhythms have periods of less than a second, others are ultradian (a period ranging from a few minutes to a 31 Figure 1. The intensity of the disease state and associated symptomatology may vary over a 24 h period. For example, in hypertension, blood pressure is lower during the night and increases early in the morning, therefore optimal therapy should facilitate maximum drug levels in the morning. Approximately 80% of insulin-dependent diabetics experience the dawn phenomenon, a rapid rise in serum glucose levels in the dawn hours. At this time interval, the insulin dose should be increased to meet the biological need. Variation in the pharmacokinetics of a drug may also occur (chronopharmacokinetics) which is directly related to the time of day that the drug is administered. The responsiveness of the biological systems (chronopharmacodynamics) may also vary depending on the time of day that the drug is administered, thereby possibly resulting in altered efficacy and/or altered intensity of side-effects.
These drugs are all widely dis- bladder buy aldactone 25 mg without prescription blood pressure medication gluten free, stimulating tributed purchase 25 mg aldactone otc blood pressure monitors at walmart, metabolized in the liver, and excreted in urine. Urinary tract antispasmodics relieve smooth muscle spasms by in- This anticholinergic ef- hibiting parasympathetic activity, which causes the detrusor and fect is what makes oxy- urinary muscles to relax. Flavoxate and oxybutynin also exhibit butynin useful in the many anticholinergic effects. Pharmacotherapeutics Urinary tract antispasmodics are used for patients with overactive bladders who have symptoms of urinary frequency, urgency, or in- continence. Urgent symptoms Trospium is also indicated for patients with overactive bladders who have symptoms of urge urinary incontinence, and oxybutynin acts as an antispasmodic for uninhibited or reflex neurogenic bladder. Adverse reactions to urinary tract antispasmodics Possible adverse reactions to urinary tract • constipation antispasmodics include: • nausea • blurred vision • vomiting • headache • weight gain • somnolence • pain • urinary retention • acute and secondary angle-closure • dry mouth glaucoma. This type of erectile dysfunction usually stems from vascular and neurologic conditions. Drugs used for erectile dys- function include alprostadil, sildenafil, tadalafil, and vardenafil. The majority of these drugs—including sildenafil, tadalafil, and vardenafil—are given orally, metabolized in the liver, and excreted in feces. An exceptional drug Alprostadil is the exception: it’s administered directly into the cor- pus cavernosum, metabolized in the lungs, and excreted in urine. Pharmacodynamics Sildenafil, tadalafil, and vardenafil selectively inhibit the phospho- diesterase type 5 receptors, which causes an increase in blood lev- els of nitric oxide. Alprostadil acts locally, promoting smooth muscle relaxation, which causes an increase in blood flow to the corpus cavernosum and produces an erection. Adverse reactions to erectile dysfunction drugs Adverse reactions to erectile dysfunction • headache drugs include: • dizziness • decreased supine blood pressure and car- • flushing diac output • dyspepsia • increased risk of cardiovascular events, in- • vision changes cluding myocardial infarction, sudden cardiac • prolonged erections (more than 4 hours), death, ventricular arrhythmias, cerebrovascu- which can result in irreversible damage to lar hemorrhage, transient ischemic attack, and erectile tissue Sometimes we just hypertension • penile pain (with alprostadil). Sildenafil is also indicated for potentially serious the treatment of pulmonary arterial hypertension. Drug interactions Erectile dysfunction drugs may interact with other drugs in the following ways: • Nitrates and alpha-adrenergic blockers used in combi- nation with erectile dysfunction drugs may cause severe hypotension and potentially serious cardiac events. For example, ethinyl estradiol may be combined with desogestrel, drospirenone, lev- onorgestrel, norethindrone, norgestimate, or norgestrel. Ethinyl estradiol or ethynodiol diacetate may also be used alone as a contraceptive. Patch power Some forms of hormonal contraceptives are available in a trans- dermal patch form. These contraceptives are absorbed through the skin but have the same distribution, metabolism, and excre- tion as orally administered contraceptives. The primary mechanism of action of combination hormonal con- traceptives (estrogen and progestin) is the suppression of go- nadotropins, which inhibits ovulation. Estrogen suppress- es secretion of follicle-stimulating hormone, which blocks follicular development and ovulation. Progestin suppress- es the secretion of luteinizing hormone, which prevents ovulation, even if the follicle develops. Progestin also thickens the cervical mucus; this interferes with sperm migration and causes endometrial changes that prevent implantation of a fertilized ovum. Pharmacotherapeutics The primary purpose for taking hormonal contraceptives is the prevention of pregnancy in women. The combination of ethinyl estradiol and norgestimate is also used to treat moderate acne in females younger than age 15. A patient taking these drugs with a hormonal contracep- tive needs to use a barrier contraceptive. Adverse reactions to hormonal contraceptives Potentially serious adverse reactions to hormonal contraceptives in- clude arterial thrombosis, thrombophlebitis, pulmonary embolism, my- ocardial infarction, cerebral hemorrhage or thrombosis, hypertension, gallbladder disease, and hepatic adenomas. Other adverse reactions include: • acne • bleeding or spotting between menstrual periods • bloating • breast tenderness or enlargement • changes in libido • diarrhea • difficulty wearing contact lenses • unusual hair growth • weight fluctuations • upset stomach • vomiting. When caring for a patient taking a hydrochlorothiazide, you should monitor the patient for: A.
Under Germany’s “alternative” industrial perspective cheap aldactone 100mg fast delivery arteria heel, plant extracts were not assemblies of active substances but potent mixtures acting on a whole and complex system of bodily regulations aldactone 100 mg overnight delivery arrhythmia lidocaine. Mass production was thus considered as a means to achieve cheaper, innovative, and more reliable “biological” therapies. Madaus’s innovation strategy was primarily – as in the case of Dausse - linked to the mechanization of processes. The most important changes, those for which Madaus submitted numerous patent applications, had to do with the machine- based treatment of fresh plants. The company continued to sell dried extracts of entire plants organs, but gradually transformed their presentation into massively produced pills. Its so-called “Teep” (for Tee-Pulver) preparations were obtained by mincing and grinding the plant with sugar (Figure ) followed by drying under a fow of warm air. This raw “0” preparation was stored in dry storage rooms for later mixing with additional sugar in order to get the dosage of plant material sought for the Teep pills, which were produced with exactly the same type of pressing machine used in all pharmaceutical companies. Madaus considered the Teep preparations better, not only because they were less expensive and more stable than the classic “soft” plant preparations, but more importantly because the Teep process preserved the mixture of substances found in the fresh plants. Numerous experiments were therefore conducted at the company’s chemical and biological laboratories in order to document the quality of Teep preparations. A series of analyses presented in 1935 compared Teep with various presentations of “entire” plant material, i. For all the families of substances investigated (hormones, proteins, vitamins, enzymes, saponins, oils, cellulose, pigments, carbohydrates, pectin, and waxes) the results suggested that the Teep & Co, Radebeul/Dresden, Sächsisches Hauptstaatsarchiv Dresden, 11610, Nummer 114. Courtesy of Madaus In complement to its “coffee-table” annual report, Madaus also published a Lehrbuch der Biologischen Heilmittel, many aspects of which are quite similar to Dausse’s pharmacological textbook, beginning with its organization into sections focusing on one type of plant after another. The chapter on Atropa belladonna, for instance, listed its location, morphology, composition, physiological effects, toxicological symptoms, therapeutic uses, indications, and mode of preparation. Differences were nonetheless signifcant: a) indications were rooted in long-term history with references to old medical treaties dating back to the sixteenth century; b) lay therapeutic experience was given a signifcant place, as for instance in the evaluation of a “Bulgarian cure” promoted in the newspapers by a certain Iwan Raeff as a secret remedy, which G. Madaus evaluated on the basis of what he thought of the interactions between the alkaloids of Atropa belladonna and the rest of the material included in the cure; c) toxicology did not mean animal experimentation for modeling the dose-response relationship but the reporting of clinical cases; d) homoeopathic conditions were central in the defnition of proper uses. Madaus, “Die Schädigung von Heilpfanzen bei ihrer Verarbeitung zum Heimittel”, Jahrbuch Dr. Madaus evaluation of the capacity of Teep preparation to preserve plant substances. Turning popular medicine into scientifc-industrial medicine required important connections with the practices of “school medicine. The sensitive experience of the plant connoisseurs with their knowledge of forms, odors, texture, and tastes was complemented with both chemical and physiological tests. Kuhn’s guidance thus spent considerable amounts of time investigating the composition of Teeps made out of various plants such as Mint, Valeriana, Viscum album, Digitalis, Lycopodium, Oleander, Aloe, Arnica, etc. Much of this investigation consisted in straightforward quality-control procedures. For instance, in December 1939, following complaints that a given lot had acquired a suspicious color, Kuhn and his colleagues determined the content of various Arnica Teeps. Although the quantity of oils that could be extracted with ether was highly variable, all the preparations analyzed presented a normal arnica smell and the 50 Professional and Industrial Drug Regulation in France and Germany: same yellow deposit. Controlling the plants collected in the wild during the spring and summer collection campaigns or harvested at the Madaus farm was a demanding activity that could occasionally result in changes in the production practices. While developing the Teep procedure for this plant, Madaus chemists actually noticed that one of the active components of the plant, an alkaloid called hypericin, occasionally disappeared from the fnal mixture with sugar. This was traced back to a rapid loss of solubility during extraction, for reasons that remained unknown, but was attributed to a physical or enzymatic alteration of hypericin. The Teep-preparation protocol was therefore modifed to accelerate the mixture, no longer leaving the brew of minced plants stand for hours in the open air. Nonetheless, even if for Madaus the relation to the botanical understanding of specifcity and classifcation was essential, its use of chemistry with orthodox pharmacology was far from marginal. This is eloquently testifed by Kuhn’s attempts to standardize the composition of Belladonna extracts on the basis of specifc molecular analysis. Admitting that the potency of the plant was due to the mixture of atropine and a few related alkaloids, Madaus chemists screened the pharmaceutical literature to design an innovative combination of extraction steps and physical measurements, which resulted in a quantitative assessment of the three most important alkaloids of the plant, i. The main conclusion of this inquiry – in contrast to received pharmacological knowledge – was that the most potent varieties were not enriched with atropine but with another alkaloid, scopolamine.