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Recent reports have been made concerning the very beneficial action of thuja on papilloma of the larynx and affections of that character in the post nasal region purchase cheap nifedipine on-line fetal arrhythmia 34 weeks. Moreau Brown has reported a number of cases satisfactorily treated with this remedy buy nifedipine 30mg without prescription hypertension 20 year old male. The same writer uses this agent in the treatment of growths in the posterior nares buy generic nifedipine 20 mg on-line blood pressure medication used to treat acne. He treats chronic enlargement of the tonsils with this remedy and has succeeded in reducing many severe cases to the normal size discount nifedipine 20 mg blood pressure medication beginning with m. He has treated some cases of disease of the turbinated bones with the same remedy. He believes that in all cases of normal hypertrophy, where there is no diathesis, underlying the difficulty, in the post nasal region, this remedy is of inestimable value. The use of thuja persistently in these cases is as effectual as it is when used in the same manner for syphilitic ulcerations. Mix thoroughly by drawing a quantity into the syringe, and forcing it back repeatedly for a few times, then draw up about two drams of the dilute mixture in the barrel of the syringe to be ready for use. Introduce a large exploring needle into the sac of the tunica vaginalis testis and allow the fluid to escape. Then in order to cause the liquid to enter every crevice of the sac of the hydrocele, pinch and knead the scrotum with the fingers quite vigorously. The pain induced is quite considerable for at least half an hour, then the patient goes about his business and usually no additional treatment is required. The non-alcoholic preparation is combined with vaseline or other unctuous substance and applied once or twice daily. However severe the case, he had no case especially where there was severe granulation of the lids that was so stubborn but that he could benefit it with a mild solution of thuja. It is applied directly to the growth as often as possible without inducing inflammation. Walker for many years has injected small tumors with thuja full strength, twenty drops for the first injection, increasing the subsequent injection every day or two until in some cases he has used as high as half an ounce. The agent is especially advised in the treatment of urinary disorders of the aged and young. It gives satisfaction in the treatment of nocturnal eneuresis when the difficulty is of functional origin. It is also valuable when there is dribbling of urine, loss of control from paralysis of the sphincter, perhaps, in the aged, where urinary incontinence is present, with severe coughs, lack of control when coughing or sneezing. Sometimes in severe cases of nocturnal eneuresis, it is accompanied with belladonna or rhus aromatica with good results. In old men with chronic prostatitis, with constant dribbling of the urine, this agent is valuable. It tones the muscular structure of the bladder and exercises a desirable influence over the mucous structures of the entire urinary apparatus. It also stimulates secretion within the tubules of the kidneys by its direct influence. Where there is irritability of the bladder from the presence of uric acid, or Ellingwood’s American Materia Medica, Therapeutics and Pharmacognosy - Page 436 other precipitates in the urine, or where there is chronic rheumatism or gout, the agent is serviceable. The agent is useful in urethral caruncle, and as a remedy for gleet, when granular urethritis is present. The remedy is valuable in the treatment of disorders of the mucous lining of the bronchial tubes. It is beneficial in ulcerative forms of sore throat, where the secretions are fetid in character. It may be inhaled in chronic bronchitis, bronchorrhea; bronchitis, with offensive discharge; chronic nasal catarrh. A number of cases of spermatorrhea have been cured since our previous report on this remedy. It is beneficial when the urine seems to burn or scald in the passing, when there is local soreness in the urethra or neck of the bladder, when the bladder tolerates but little urine at a time, and the patient must rise frequently during the night. Homeopathists give thuja where the rectum is diseased; where there is a slimy discharge streaked with blood with dark blotches on the adjoining tissues; where there is itching and constant inclination without power to expel feces; sharp sticking pains in the rectum. In cases of verucca on the genitalia or rectum, this agent is advantageously used, especially if preceded by a mild escharotic. In prolapsus of the rectum, especially in cases depending upon paralysis, this agent, may be diluted and injected. The injection of thuja into nevi that are of a non-pulsating character, or those not too venous in structure, has been recently practiced. One case was cured in three weeks, where the nevus looked like a ring worm, and was of a fiery red color. One physician cured a case of ulcerated stomach with thuja in four-drop doses, alternated with sub-nitrate of bismuth every two hours. Anything warm produced great Ellingwood’s American Materia Medica, Therapeutics and Pharmacognosy - Page 437 distress. Another physician advised the agent in pruritus, whether of the anus or vulva, especially when accompanied by fissures. Another physician reports a case of extreme prolapsus of the bowel in a child which he cured with a five per cent solution of thuja. A wet dressing was applied and a small quantity of the remedy was injected into the bowel. A greatly enlarged and relaxed uterus in a woman of fifty with severe metrorrhagia was treated with injections of thuja. A doctor reports the cure of a urinary fistula by giving two drops of thuja internally every four hours. The use of the oil of thuja in confluent smallpox given internally and applied externally was advised by Dr. Thuja will prove an excellent remedy for all forms of sore mouth, especially if combined with echinacea and a mild antiseptic astringent. Gibbs reports a case where a number of varicose enlargements about the ankle of an old washer woman broke down. He made a 50 per cent solution of thuja and applied it freely with bandages, covering the whole with roller bandages, and produced a cure. Ellingwood’s American Materia Medica, Therapeutics and Pharmacognosy - Page 438 Therapy—Trifolium has been used as a cancer remedy by virtue of specific alterative properties said to exist in it. It is given where a cancerous diathesis is known to be present, and its use is persisted in for months. Improvement in objective phenomena is reported from a number of excellent observers. The agent is also prescribed in irritable conditions of the larynx and air passages, especially if evidenced by spasmodic cough. It has served a good purpose in whooping cough, in the cough of measles, and in general bronchial or pulmonary irritation. Lambert is of the opinion that trifolium has a direct action in improving the nutrition of the brain. He thinks it is demanded when the patient is overworked; when there is general mental failure, with loss of memory of words, or when there is confusion of ideas of functional causes; also when there is weakness of the lower extremities, or of the feet from deficient capillary circulation.
The most ethical and legally sound approach is to provide information that may be verified directly with the medical litera- ture proven 20 mg nifedipine arrhythmia greenville sc. Ultimately cheap nifedipine 30 mg with mastercard blood pressure medication hctz, the clinical conclusion/treatment is that social and illicit substance use during pregnancy is contraindicated because of the associated maternal and embryo fetal risks discount 30 mg nifedipine fast delivery hypertension benign essential. The need for services to assist pregnant substance users is being recognized order 20 mg nifedipine mastercard pulse pressure 30, and pro- grams exist in most areas. For assistance in locating such a treatment program, the physi- cian can contact their local substance abuse service, or their state’s commission on sub- stance abuse that accredits treatment facilities. Ideally, the pregnant substance user should be managed by the obstetrician in conjunction with a program designed to promote absti- nence or at least to reduce the substance use during pregnancy. The medical positions of abstinence and treatment are the only appropriate ones clinically and legally. One’s medical mal- practice insurance provider is often the most economical and efficient source of legal infor- mation as this service is often included as a provision of a medical malpractice policy. Drug injec- tion sites on the upper forearm (‘track marks’) are strong evidence of a serious substance use problem, but this is not frequently observed. Substances of abuse usually have an anorectic effect and often result in poor weight gain during pregnancy. Other possible signs of substance use during pregnancy include new-onset ‘spontaneously arising’ heart murmur and hypertension not associated with preeclampsia. Heart murmurs occur with increased frequency among women who are Clinical evaluation 301 chronic substance users. Heart murmurs also occur in association with bacterial endocarditis or a history of this disease. Chronic substance use can induce hypertension in the nonpregnant adult, although not all have been studied for hypertensive effects dur- ing pregnancy. Cocaine, heroin, and tobacco use is known to be associated with hyper- tension during pregnancy (Abel, 1980a,b; Little et al. In addition, abruptio placentae or a history of this serious complication is also an indication that substance use may be a factor. Risk of abruptio placentae may be as high as 1–2 percent among substance abusers compared to 0. A history of stillbirths may, along with other risk fac- tors, be a clue to the obstetrician that substance abuse is a complicating factor. Hidden risks of substance abuse: impurities All substances of abuse, even alcohol, may be contaminated by certain impurities. Amphetamine and methampheta- mines may contain impurities, such as lead oxides (Allcott et al. Leaded gasoline is sometimes used as the solvent, resulting in lead contamination in the extraction of cocaine paste from cocoa leaves. If not fully reacted, cyanide may be contained in the final product because illicit laboratories are usually crudely equipped for purification, with no quality control. Lead and cyanide poisoning have resulted from the use of illic- itly manufactured substances and are associated with significant maternal–fetal morbid- ity and mortality. Drugs avail- able as tablets or capsules (for example, codeine, methadone, morphine, benzodi- azepines, pentazocine) contain a significant amount of the tablet/capsule vehicle agent (usually more than 97 percent), typically microcrystalline cellulose. Inhalants are aromatic (benzene ring-containing) substances, such as toluene or gaso- line, that may also contain lead or nitriles that can cause toxicity. Even marijuana may contain dangerous vegetable contaminants such as nightshade, poison sumac, poison ivy, and poison oak, all of which may cause serious pulmonary-cardiac morbidity or even death when smoked. Other drugs and chemicals as dilutants Other substances are used by dealers to ‘cut’ or dilute illicit drugs to increase their prof- its. Amphetamines are diluted, 302 Substance abuse during pregnancy sometimes heavily, with certain antihistamines or ephedrine. Heroin is known to have been cut with diverse compounds: talcum, confectioner’s sugar, and even finely ground sawdust. Perhaps the most notorious case of the dilutant being more dangerous than the substance of abuse is cutting heroin with warfarin, leading to a cluster of warfarin embryopathy cases that were never published. Some of these dilutants were teratogenic and these and others may cause serious maternal and/or placental complications, espe- cially when used parenterally. Opiates are the exception because methadone replacement/maintenance therapy is available for such drugs as heroin. Regimens used as an adjunct to assist in withdrawal include a benzodiazepine plus an antidepressant (e. A differ- ent pharmacological strategy is suppression of alpha-adrenergic action with drugs, such as clonidine, and to alleviate withdrawal symptoms, frequently with a benzodiazepine or barbiturate (nembutal) adjunct. Such regimens are given in doses adjusted to the indi- vidual case to facilitate asymptomatic withdrawal, and the dose is gradually decreased over periods ranging from 10 days to 3–6 months. Substance addiction is a psychological phenomenon as well as a physical one, and both aspects must be addressed adequately in treatment protocols. Specialists in addic- tion psychology/psychiatry should be involved in the treatment plan early. We reported that in patient substance abuse treatment during pregnancy was associ- ated with increased birth weight and head circumference, and fewer perinatal complica- tions compared to untreated matched substance-abusing pregnant controls (Little et al. Obstetrical goals of substance abuse treatment Minimization of maternal and fetal/infant morbidity and mortality is the obstetrical goal of substance abuse treatment during pregnancy. In one study, prenatal care was the main determinant of pregnancy outcome among substance abusers, not attaining abstinence (MacGregor et al. Regardless of continued substance use, regular prenatal care was associated with better pregnancy outcomes than those who did not have prenatal care. This observation is important to obstetrical goals in the treatment of the gravid substance user (risks to both the mother and the fetus) because it implies that the single most important intervention in the pregnancy of a substance abuser is to provide prena- tal care early and regularly. When considering treatment for the pregnant substance abuser, the risks from contin- ued substance use (for example, maintenance) versus risk of withdrawal, and the benefits Alternatives to traditional treatment for substance dependence during pregnancy 303 of withdrawal, i. However, recent clinical experience does not support these increased risks with withdrawal (Luty et al. Currently, with- drawal of the gravid patient from substances of abuse is generally advocated, although no generally accepted regimen is recommended for use during pregnancy. As with nonpreg- nant adults, a benzodiazepine and antidepressant or a benzodiazepine and a low-dose alpha-blocker (e. The primary danger of the alpha-blockers is maternal hypotension, which may impede placental perfusion. In France, buprenorphine has been used, and the inci- dence of adverse pregnancy outcomes was no different from controls (Auriacombe et al. Blood pressure and fetal heart rate should be monitored closely with this regimen.
Examples include the inhibition of the renal tubular secretion of penicillins by probenecid order 20mg nifedipine visa arrhythmia potassium, which results in major increases in penicillin blood levels (6) or the increase in digoxin blood levels by the coadministration of quinidine purchase online nifedipine prehypertension vyvanse, presumably by the inhibition of digoxin renal tubular secretion through inhibition of the P-glycoprotein (P-gp) transporter (7) discount nifedipine 20mg mastercard pulse pressure of 10. Less commonly recognized than pharmacokinetic interactions—perhaps because fewer studies have been performed to detect them—are pharmacody- namic drug-drug interactions buy cheap nifedipine 20 mg online pulse pressure ejection fraction, changes in response to a drug caused by alteration in exposure/response relationships. This type of drug-drug interaction may arise when the substrate and interacting drug affect the same physiological system or An Integrated Approach to Assessing Drug-Drug Interactions 667 when one drug prevents an appropriate response to the other. As an example of the latter, marked hypotension was observed in patients switched from the calcium channel blocker mibefradil to a dihydropyridine calcium channel blocker, apparently because residual mibefradil inhibited the usual compensatory tachy- cardia caused by the dihydropyridine. Both pharmacokinetic and pharmaco- dynamic drug-drug interactions should be considered when two or more drugs are administered concurrently. The critical question in considering drug interactions is: Does the dose of a substrate drug need to be adjusted in the presence of the interacting drug? More specifically, is the pharmacokinetic and/or pharmacodynamic change in the substrate drug in the presence of the interacting drug of sufficient magnitude require adjustment of the substrate dose (or avoidance of the interacting drug)? Finally, how confident we need to be in the answer depends on the nature of interaction and the consequences of error. On the basis of this information, the potential importance of one or more routes of elimination in contributing to a clinically important drug- drug interaction can be estimated. Even when a metabolic route is important for the elimination of a substrate and is affected by an interacting drug, additional studies may be needed to understand whether a metabolic drug-drug interaction has clinical impact. Various methods may be used to develop the requisite information, including in vitro studies, in vivo pharmacokinetic and pharmaco- dynamic studies, population pharmacokinetic studies, clinical safety and efficacy studies, and postmarketing observational studies. All of these approaches can generate useful information about potentially important drug-drug interactions 668 Huang et al. Interactions in the liver may have only a small effect on single-dose Cmax, but may alter half-life and accumulation index. Interpretation of drug-drug interaction data is sometimes complicated when a substrate drug is actively transported from the serosal to the mucosal side of the gastrointestinal tract by transporters such as P-gp. The early elucidation of drug metabolism, for example, permits in vitro investigations of drug-drug interaction that in turn provide information useful in guiding the clinical program and possibly avoiding some clinical studies. Metabolism data can also provide information on the relevance of preclinical metabolism and toxicological data and permit early identification of drugs that are likely to have large interindividual pharmacokinetic variability due to genetically determined polymorphisms in drug-metabolizing enzymes or drug-drug interactions. An integrated approach is most useful, one in which evidence for and against a drug-drug interaction is examined at all stages of drug development, including (1) preclinical in vitro human tissue studies of drug metabolism and drug-drug interactions to determine which in vivo studies should be conducted, (2) early-phase in vivo studies to assess the most important potential drug-drug interactions suggested by in vitro data, (3) late-phase drug development population pharmacokinetic studies to expand the range of poten- tial interactions studied, including unexpected ones, and to allow examination of pharmacodynamic drug-drug interactions. The further sections of this chapter provide more specific information about these approaches. The utility of these studies has been enhanced by the availability of specific enzyme preparations, microsomal preparations, and liver cell preparations, together with An Integrated Approach to Assessing Drug-Drug Interactions 669 standard substrates and inhibitors/inducers. Information from in vitro metabolic studies can suggest not only that a substrate drug is or is not likely to be a candidate for certain metabolic drug-drug interactions but also whether a drug’s metabolism will be affected by genetic polymorphisms. This guidance emphasizes the value of in vitro studies in human bio- materials in ruling out important metabolic pathways in a drug’s metabolism or the possibility of the drug’s ability to affect certain enzyme systems. Previous chapters have detailed the relative advantages and disadvantages of various in vitro techniques in providing information pertinent to drug-drug interactions. Cellular-based in vitro models, such as isolated hepatocytes and precision- cut liver preparations 2. Expressed human drug-metabolizing enzymes These systems can be used to define a drug’s metabolic pathway, to assess its potential to inhibit the metabolism of other drugs, and to determine whether other drugs influence its metabolism. It is abundantly present in the intestinal epithelium and serves as an efflux pump for a variety of drugs and xenobiotics. In vitro models currently available allow investigation of transporter-mediated drug-drug interactions, including a human colon carcinoma cell line, Caco-2 (10). In Vitro–ln Vivo Correlation A complete understanding of the relationship between in vitro findings and in vivo results of metabolism/drug-drug interaction studies is still emerging. Quantitative prediction of the magnitude of clinical drug-drug interactions based on in vitro methodologies has been the topic of numerous publications and is described in earlier chapters (Chaps. Although excellent quantitative concordance of in vitro and in vivo results has been shown, in some cases in vitro data may also under- or overestimate the clinical effect (13), and at present an observed in vitro effect needs further elucidation in in vivo studies. The bases for in vitro/in vivo disassociations have been described and include (1) irrelevant substrate concentrations and inappropriate in vitro model systems, (2) mechanism-based inhibition, (3) activation/induction phenomena, (4) physical- chemical effects on absorption, (5) parallel elimination pathways that decrease the importance of the in vitro–assessed pathway, and (6) modulation of an important cellular transport mechanism. Specific Clinical Investigations If metabolism is an important mechanism of clearance and in vitro studies suggest that metabolic routes can be inhibited or that the drug may inhibit important clearance pathways of other drugs, in vivo studies are needed to evaluate the extent of these potential interactions. As with in vitro studies, in vivo studies can often use a screening approach involving probe drugs. Where interactions are found, the studies of probe drugs and other drugs will provide a basis for specific recommendations on product labeling as to what An Integrated Approach to Assessing Drug-Drug Interactions 671 concomitant uses should be avoided or what dosage adjustments to make. A critical determination for substrate effects is the size of the effect, measured in the in vivo interaction study, and the importance of the effect. Thus, a 50% increase in blood levels of a well-tolerated drug with little dose-related toxicity may require no dosage adjustment. The same degree of increase for a drug with a narrow therapeutic range might require careful adjustment in dose or avoidance of coadministration. The issues in the areas of study design and data analysis are discussed in more detail in the following section. If in vitro studies and other information suggest a need for in vivo meta- bolic drug-drug interaction studies, the following general issues and approaches should be considered. Depending on the study objectives, the substrate and interacting drug may be investigational agents or approved products. Study Design In general, interaction studies compare substrate levels with and without the interacting drug. Any may be suitable, depending on the specific objectives of the study and the desired outcome. The study may use a randomized crossover, a one-way (fixed sequence) crossover, or a parallel design. Depending on cir- cumstances, the studies can use various durations of exposure for substrate and interacting drug: single dose/single dose, single dose/multiple dose, multiple dose/single dose, and multiple dose/multiple dose. In general, the inhibiting/inducing drugs and the substrates should be dosed so that the exposure of both drugs is relevant to their clinical use. A substrate drug intended for chronic administration should generally be given until steady state is attained, with assessment of pharmacokinetics over one or more dosing intervals followed by administration of the interacting drug, which is also given until steady-state concentration is reached, again with collection of pharmacokinetic data on the substrate. The studies of erythromycin-terfenadine and ketoconazole-terfenadine interactions in healthy volunteers (14,15) are examples of this one-way, or fixed-sequence, crossover design. If the substrate drug has a long half-life and accumulates, the probability of seeing an effect may be enhanced by giving the substrate drug as a single dose and the interacting drug as multiple doses. Multiple-dose studies would generally be necessary to ensure that relevant metabolites can be assessed and that the relevant dose of the interacting drug is used, but special approaches may also be useful. For example, a loading dose of the potential inhibitor may allow relevant levels to be obtained more rapidly and selection of a one-way (fixed-sequence) crossover or a parallel design, rather than a randomized crossover study design, may also help. Using a one-way crossover design, a recent study (17) showed that multiple-dose administration of sertraline inhibited the clearance of desipramine to a considerably greater extent than did a single-dose administration.