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External genitalia of female rats born to mothers treated with very large doses of megestrol during pregnancy were virilized (Kawashima et al meldonium 500 mg line medications that cause tinnitus. Androgens Androgen use during pregnancy is strictly contraindicated purchase meldonium 250mg without a prescription symptoms yellow eyes, primarily due to the risk of masculinization of a female fetus generic meldonium 500mg with mastercard symptoms diabetes. Inadvertent use during early pregnancy results in virilization of 96 Endocrine disorders cheap meldonium 250mg amex treatment question, contraception, and hormone therapy during pregnancy female infants (Duck and Katayama, 1981; Kingsbury, 1985; Peress et al. A review of fetal exposure to danazol in 129 cases compiled from case reports revealed miscarriages in 12 cases and 23 elective abortions. There were 57 female fetuses whose mothers took dana- zol during the period of sensitivity to androgenic substances (8th week of embryogene- sis and thereafter), and 23 (40 percent) presented with virilization (clitoromegaly, par- tial fusion of labia majora) (Brunskill, 1992). The lowest daily dose that resulted in vir- ilization was 200 mg (Brunskill, 1992). Androgen influences on development of internal genitalia were present in only two cases (Quagliarello and Greco, 1985; Rosa, 1984). Therefore, the available data strongly indicate that virilization of the female fetus is a risk when there is exposure to danazol during the period of androgen receptor sensitiv- ity (beginning at the 8th week of embryogenesis and continuing through the fetal period). Virilization was not found among any infants exposed before the 8th week of embryogenesis (Rosa, 1984). A patient who becomes pregnant while taking the medication may not be diagnosed until a considerable fetal exposure has occurred because the drug is expected to cause amenorrhea. Therefore, physicians should be aware of the risk of female genital ambiguity occurring in the off- spring of women who are prescribed this drug. More than a dozen female infants were born to women treated with methyltestosterone during pregnancy, and they all had varying degrees of virilization of the external genitalia (clitoral enlargement and labioscrotal fusion) (Grumbach and Ducharme, 1960; Schardein, 1985). Paralleling other androgenic agents, clitoral enlargement may be induced by exposure to methyltestosterone throughout the postem- bryonic period, but labioscrotal fusion seems restricted to the period between the 8th and 13th weeks of gestation, and the degree of virilization appears dose related. Successful surgical correction of the defects associated with virilization is available. Sexual maturation seems normal, while menarche in virilized girls seems close to the median, following a healthy course. Female rats, dogs, and rabbits born to mothers treated with methyltestosterone in doses similar to those used medically had a dose-dependent increased frequency of vir- ilization (Jost, 1947; Kawashima et al, 1975; Neumann and Junkmann, 1963; Shane et al. Methyltestosterone and testosterone proprionate were associated with clitoromegaly with or without fusion of the labia minora. Hoffman and colleagues (1955) reported a masculinized fetus following administration to the mother of testosterone enanthate from the 4th to the 9th months. Grumbach and Ducharme (1960) summarized the human reports and concluded that masculinization of the female fetus was a significant risk with the use of these drugs. Illicitly, it is used to increase muscle mass and enhance athletic General hormonal therapy 97 Table 4. No studies have been published that have analyzed congenital anomalies among infants born to women treated with nandrolone during pregnancy. However, the strong androgenic action of this agent would be expected to cause virilization of the external genitalia in female fetuses. Intrauterine deaths were increased in frequency among rats born to mothers who were given up to twice the medically administered dose (Naqvi and Warren, 1971). As with other androgenic steroids, it is reasonable to expect virilization of the external genitalia of a female fetus with maternal use of stanozolol. Oxymethalone possesses significant androgenic action, and would be expected to cause virilization of the external genitalia of female fetuses. Embryonic loss occurred frequently after injection of about four times the usual human dose of oxymethalone in rats in early pregnancy (Naqvi and Warren, 1971). Significant virilization was found in female rats born to mothers given large doses of oxymethalone during preg- nancy (Naqvi and Warren, 1971), and embryonic death was increased in frequency in preg- nant rats given several times the medically administered dose (Kawashima et al. The effects of either of these drugs on a post- implantation pregnancy are unknown. Friedman and Polifka (2006) state that the risk of congenital anomalies is unknown following a failed attempt at abortion but ‘this risk may be substantial because the process of attempted abortion may disrupt normal embryogenesis or fetal development’. Breast cancer Aromatase inhibitors may be used to replace tamoxifen, because of fewer untoward effects, in the treatment of breast cancer. These agents include anastrozole (Arimidex), exemestane (Aromasin), and letrozole (Femara). Key references 99 Hyperprolactinemia Excess pituitary prolactin secretion can lead to symptoms of galactorrhea, menstrual irregularities, and infertility. Menstrual cycle abnormalities caused by hyperprolactine- mia include primary and secondary amenorrhea, oligomenorrhea, and luteal phase defects. Hyperprolactinemia may result from a variety of different causes (pituitary ade- noma, hypothyroidism, various pharmacologic agents). Primary therapy for idiopathic hyperprolactinemia, or a small pituitary adenoma, is an ergot alkaloid compound, such as bromocriptine. Many physicians prefer to use carbergone (Dostinex) to treat hyperprolactinoma instead of bromocriptine to avoid side effects. Surgical therapy is reserved for very large pituitary tumors or those unresponsive to medical treatment (see earlier sections on Prolactinoma and Bromocriptine). Endometriosis Endometriosis is the presence of endometrial implants (glands and stroma) outside the endometrial cavity. Various therapeutic regimens have been used to treat all stages of disease, including surgical ablation and extirpation, drug therapy, or both. Pregnancy usually resolves endometriosis; therefore, treatment during pregnancy is probably not an issue. Inadvertent oral contraceptive use during embryogenesis is not associated with an increased risk of con- genital anomalies. Diethylstilbestrol, high doses of progestins derived from testosterone, and all androgens are strictly contraindicated during pregnancy A summary of endocrinedrugs and their risk estimates appears in Table 4. The pharmacokinetics of oral and intramuscular administration of dexamethasone in late pregnancy. During an acute asthmatic attack, resistance of the airways is increased while forced expiratory flow and volume rates are decreased. Among more than 1000 patients reported in nine investigations, 48 percent of gravid asthmatics experienced no change in clinical severity of their symptoms, 29 percent improved, and in 23 percent the disease wors- ened in severity (Gluck and Gluck, 1976). Other data indicate that approximately one- third of women with asthma experienced worsened disease severity during pregnancy (Cunningham, 1994; Schatz et al. In contrast, no differences in the frequency of prematurity, low birth weight, and perinatal mortal- ity were found among 182 pregnancies complicated by asthma compared to 364 nonasthmatic controls. Importantly, complications were increased among gravidas with severe uncontrolled asthma (Jana et al. The objectives of asthma treatment are: (1) to decrease the frequency and number of asthmatic exacer- bations; (2) to prevent status asthmaticus – severe obstruction persisting for days or weeks; (3) to avoid respiratory failure; and (4) to prevent death (Greenberger and Patterson, 1983). These goals can be accomplished with available antiasthma agents at no added risk to either mother or fetus (Greenberger and Patterson, 1978; Turner et al. One medical authority has indicated that inhaled corticosteroids are the most efficacious of antiasthma agents (Dombrowski, 1997). Methylxanthines The xanthines and methylxanthines have a peculiar pharmacokinetic profile during pregnancy, and it important to note their unusual behavior. Xanthines tend to increase their steady-state concentration during pregnancy (Table 5. Consequently, achieving the desired plasma concentra- tions will require different doses throughout pregnancy, and physicians should antici- pate a decrease in doses required as the pregnancy advances (Table 5.

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IgG antibodies produced in response to periodontopathogens are increased in patients with clinical manifestations of periodontitis purchase 500 mg meldonium overnight delivery symptoms xanax overdose, and this reflects the subgingival colonization by the specific bacteria (Gunsolley et al buy 500 mg meldonium fast delivery medicine journal impact factor. Other reports indicate elevated levels of serum antibodies with disease progression possible indicating production of an ineffective class of antibody (Albandar et al discount meldonium 500mg free shipping moroccanoil oil treatment. Pathogenic strains of bacteria can be found in significant levels in the plaque of young children purchase meldonium 500mg with visa treatment junctional rhythm, eliciting a serum antibody response that increases with age, and may be related to incipient signs of periodontal disease (Bimstein et al. Differences in serum antibody response to periodontopathogens have been reported for different ethnic populations. The majority of studies examining IgG responses have focused on only a select few bacteria and no studies to date have reported the prevalence of serum IgG responses to a broad range of periodontopathogens in young children. More information on the acquisition of specific periodontal bacteria with concomitant immune responses in children could help to elucidate the development and pathogenesis of periodontitis. The aim of this cross sectional study is to measure the prevalence of serum IgG antibody responses against a broad range of oral and one non-oral bacteria for a population of 9-11 year-old-children. Briefly, 1,420 non-Hispanic African American or Caucasian participants were recruited from 34 schools that included a high proportion of minority students located in rural areas three regions (Eastern Coastal, Central Piedmont, and Western Mountain) in North Carolina. Demographic data were collected between January 2000 and February 2003 at participants’ respective schools by teams of trained and calibrated research assistants. The inclusion criteria consisted of ability to read and write English; and having at least one natural relative available to report family history. The exclusion criteria were 6 being physically handicapped as reported by parents, teachers, school nurses, or self; suffering from any serious illness such as type 1 diabetes requiring insulin, renal disease, or moderate to severe asthma as reported by parents, teachers, school, nurses, or self; having any major developmental disability as reported by parents. Seventy-five children in the cohort had elevated fasting glucose levels (≥100mg/dL). For each of these “prediabetic” children, three children matched for normal fasting glucose levels (≤100mg/dl), age, sex, and race were randomly selected. Analysis of serum IgG Responses Serum samples were obtained by sterile venipuncture from each participant early in the morning after an overnight fast. The blood samples (10ml) were allowed to clot for 2 hours at room temperature before centrifuging (20 minutes at approximately 2000 x g). Specific IgG responses for periodontal pathogens were measured using an immuno-checkerboard (Sakellari et al. Nitrocellulose membranes were prepared, and the Miniblotter apparatus was pre- chilled for 4 hours at 4°C. Each membrane was loaded with bacterial suspensions (in duplicate) at 125 µl and protein A at 10µg/ml as a positive control (Boehringer, Germany). Membranes were dried at 37°C, blocked, washed, incubated for one hour with 100 ml of a solution containing distilled water (105 ml), 100% methanol (30 ml) and 30% hydrogen peroxide (15 ml), and then washed and blocked again. Miniblotters were mounted and rotated 90°, and channels were loaded with 130 µl of the unknown serum samples (diluted at 1/50, 1/1000 and 1/2000) and standards (IgG at various concentrations). Images were scanned, and the IgG response to each of 18 bacteria, 17 periodontal pathogens (P. In addition to the individual bacteria responses, combinations of detectable bacteria were noted as present or absent for each subject. The combinations considered were: two or more red complex 8 bacteria; two or more of the orange complex bacteria; at least one orange complex bacteria plus A. Statistical Analysis Univariate statistics were used to summarize responses for the demographic and bacteria data. The Chi-square test was used to compare the detectable proportion of each bacteria between males and females and between African-American and Caucasian children. Fisher’s exact test was used to compare the presence of the combinations of bacteria between gender and ethnic subcohorts. Forty-five percent (n=135) were female and 58% (n=176) were African-American (Table 1). Prevalence of serum IgG response to individual bacteria The proportion of children with detectable bacterial threshold levels for all species examined ranged from 2. A higher proportion of girls had a positive IgG response to 14 of the individual pathogens (Table 2). Compared to the boys, girls had elevated proportions of detectable thresholds for all 3 10 red complex bacteria although this did not reach statistical significance. Within the other bacterial complexes statistically significant higher proportions of girls had IgG responses to two of the orange (P. For the red complex bacteria, significantly higher proportions of IgG responses to T. Statistically significant elevations in the proportions of detectable thresholds were also observed for five of the orange complex bacteria (C. Frequencies (n) of subjects with detectable levels of IgG BacteriaBacteria AllAll MalesMales FemalesFemales p-valuep-value CaucasianCaucasian AfricanAfrican p-valuep-value (n=303)(n=303) (n=168)(n=168) (n=135)(n=135) (n=127)(n=127) AmericanAmerican (n=176)(n=176) RedRed complexcomplex Pg 5. A higher proportion of females were IgG positive for 6 of the 7 combinations of bacteria, but girls and boys differed statistically only for all three of the red complex bacteria (p<0. Frequencies (n) of subjects with detectable levels of IgG to different combinations of bacteria Groups of Subject groups Bacteria All Males Females p-value Caucasian African p- (n=303) (n=168) (n=135) (n=127) American value (n=176) Red Complex At least 2 6. Again, a higher proportion of the African American children were positive for all seven of the combinations of bacteria with a statistically significant difference (P<0. This first paper documents the prevalence of positive IgG responses to a number of periodontal pathogens. The rationale is that IgG antibody response represents an estimate of the overall systemic burden induced by periodontal infection. When combined with clinical periodontal measurements, these immune and other inflammatory responses could provide better estimates of the overall systemic burden imposed by an oral infectious challenge in chronic diseases such as diabetes. The major finding of the present exploratory study is that the children in this cohort were exposed to and exhibited detectable immune responses to a broad range of known periodontal pathogens at an early age. This immune response against specific microorganisms can be used as evidence for exposure and impact of the microbial etiology on the pathogenesis of periodontitis (Kinane et al. Significantly more girls 9-11 years of age were likely to have IgG responses to one or more orange complex bacteria and A. In addition, significantly more African Americans had IgG responses to both red and orange complex bacteria as well as A. Early colonization of periodontal pathogens in the oral biofilm of children has been previously chronicled (Morinushi et al. Controversy still remains as to the percentages of children who harbor pathogenic bacteria, elicit an immune response and if 16 they are likely to develop periodontal disease. Significant numbers of children exhibited IgG responses to at least one of the orange complex bacteria (51. When combinations of bacteria were analyzed, it was apparent that over one-third of the children exhibted immune IgG responses to at least one orange complex bacteria in combination with A. The last bacterium is most closely associated with localized aggressive periodontitis (Van Winkelhoff et al. The prevalence of pathogenic bacteria colonizing the oral biofilm of young subjects shows wide variation. Other studies have found high levels of periodontopathgens in periodontally healthy subjects with no differences in levels among periodontal healthy and diseased subjects. Since periodontal examinations were not performed in this study, a positive IgG response is not indicative of a clinical diagnosis of periodontitis. The majority of studies have shown an association between IgG responses and presence of pathogens in the biofilm of children (Savitt et al. Periodontitis status in children has also been positively associated with IgG response especially with P.

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Multidrug resistance-related trans- port proteins in isolated human brain microvessels and in cells cultured from these isolates 250 mg meldonium with visa symptoms 2dpo. Transport of cyclosporin A across the brain capillary endothelial cell monolayer by P-glycoprotein 500 mg meldonium mastercard medicine 257. Restricted transport of cyclosporin A across the blood-brain barrier by a multidrug transporter cheap 500 mg meldonium fast delivery symptoms 2016 flu, P-glycoprotein meldonium 500mg mastercard medications 377. Novel experimental parameters to quantify the mod- ulation of absorptive and secretory transport of compounds by P-glycoprotein in cell culture models of intestinal epithelium. Rhodamine 123 requires carrier-mediated influx for its activity as a P-glycoprotein substrate in Caco-2 cells. Development, validation and utility of an in vitro technique for assessment of potential clinical drug-drug interactions involving P-glycoprotein. In vitro p-glycoprotein inhibition assays for assessment of clinical drug interaction potential of new drug candidates: a recommendation for probe substrates. Retention of vital dyes correlates inversely with the multidrug-resistant phenotype of adriamycin-selected murine fibrosarcoma variants. Relationship between cytotoxic drug response patterns and activity of drug efflux transporters mediating multidrug resistance. Reciprocal correlation between expression of P-glycoprotein and accumulation of rhodamine 123 in human tumors. Rhodamine efflux patterns predict P-glycoprotein substrates in the National Cancer Institute drug screen. Transport of rhodamine 123, a P-glycoprotein substrate, across rat intestine and Caco-2 cell monolayers in the presence of cytochrome P-450 3A-related compounds. Inhibitors of P-glycoprotein-mediated dauno- mycin transport in rat liver canalicular membrane vesicles. The function of Gp170, the multidrug-resistance gene product, in the brush border of rat intestinal mucosa. Characterization of the regional intestinal kinetics of drug efflux in rat and human intestine and in Caco-2 cells. Role of P-glycoprotein as a secretory mechanism in quinidine absorption from rat small intestine. Effects of intestinal and hepatic metabolism on the bioavailability of tacrolimus in rats. Possible involvement of multiple P-glycoprotein-mediated efflux systems in the transport of verapamil and other organic cations across rat intestine. Functional expression of mouse Mdr1 in an outer membrane permeability mutant of Escherichia coli. Functional complementation of yeast ste6 by a mammalian multidrug resistance mdr gene. Expression of human P-glycoprotein in yeast cells–effects of membrane component sterols on the activity of P-glyco- protein. Photometric microtiter assay of inorganic phos- phate in the presence of acid-labile organic phosphates. Human jejunal effective permeability and its correlation with pre- clinical drug absorption models. Hepatobiliary disposition of valproic acid and valproate glucuronide: use of a pharmacokinetic model to examine the rate-limiting steps and potential sites of drug interactions. Interactions between P-glycoprotein substrates and other cationic drugs at the hepatic excretory level. Hepatic sequestration and modulation of the canalicular transport of the organic cation, daunorubicin, in the Rat. Brain perfusion systems for studies of drug uptake and metabolism in the central nervous system. Kinetics of amino acid transport at the blood-brain barrier studied using an in situ brain perfusion technique. An in situ brain perfusion technique to study cerebrovascular transport in the rat. Facilitated transport of the neurotoxin, beta- N-methylamino-L-alanine, across the blood-brain barrier. Use of a physiologically based pharmacokinetic model to study the time to reach brain equilibrium: an experimental analysis of the role of blood-brain barrier permeability, plasma protein binding, and brain tissue binding. Development of a computational approach to predict blood-brain barrier permeability. Role of P-glycoprotein in the blood- brain transport of colchicine and vinblastine. New advances in the transport of doxorubicin through the blood-brain barrier by a peptide vector-mediated strategy. The effect of verapamil on the transport of peptides across the blood-brain barrier in rats: kinetic evidence for an apically polarized efflux mechanism. Regulation of protein secretion into bile: studies in mice with a disrupted mdr2 p-glycoprotein gene. Homozygous disruption of the murine mdr2 P-glycoprotein gene leads to a complete absence of phospholipid from bile and to liver disease. The three mouse multidrug resistance (mdr) genes are expressed in a tissue-specific manner in normal mouse tissues. The gene encoding multidrug resistance is induced and expressed at high levels during pregnancy in the secretory epithelium of the uterus. Cloning and characterization of a member of the rat multidrug resistance (mdr) gene family. Differential overexpression of three mdr gene family members in multidrug-resistant J774. Species differences in the pharmacokinetics and metabolism of indinavir, a potent human immunodeficiency virus protease inhibi- tor. Transgenic mice that express the human multidrug-resistance gene in bone marrow enable a rapid identification of agents that reverse drug resistance. Increased effectiveness of liposome- encapsulated doxorubicin in multidrug-resistant-transgenic mice compared with free doxorubicin. Hepatic canalicular membrane 1: the role of mdr2 P-glycoprotein in hepatobiliary lipid transport. Vermeulen Department of Pharmacochemistry, Vrije Universiteit, Amsterdam, The Netherlands I. The largest structural variations are found in the B0 helix and helices F and G and their connecting loop, which makes sense, since these regions are known to be involved in substrate access and recognition (8). Finally, a general summary and conclusions section is presented, and an outlook of expected developments in the field. Central in the struc- ture is the heme group with the iron as a space-filling sphere. The progression in fields of X-ray crystallography and homology model building, as well as their mutual complementarity, will be illus- trated and discussed in the following sections. However, the distance of the bound S-warfarin substrate to the heme iron is large (*10 A), which makes it unlikely that this crystal structure corresponds to a catalytically active state. In line with this suggestion, Arg105 and Arg108, implicated in the formation of putative anionic-binding sites by mutagenesis, pharmacophore and homology modeling studies both point away from the active site. It has been suggested that protein con- formational changes driven by electron transfer trigger the movement of these substrates into effective positions for hydroxylation (18). These effects probably are a result of ligand-induced conformational changes of the active site and the relatively large volume of the active site as compared with the volume occupied by the ligand. Although crystallographical protein structures are firmly based on exper- imental data, it must be borne in mind that for resolutions of around 2 A and worse, the electron density maps are not sufficiently detailed to resolve indi- vidual atoms.

When dry order meldonium 250 mg online symptoms 14 dpo, the pellets are filled in a vial purchase meldonium 250mg visa symptoms 3 days after conception, marked as to its contents buy meldonium 250 mg online medicine lookup, and well stoppered cheap meldonium 500mg fast delivery medications erectile dysfunction. All pellets moistened with the spirituous liquid have when dry a dull appearance; the crude, unmoistened pellets look whiter and more shining. To prepare the pellets to give to patients, one or a couple of such little pellets are put into the open end of a paper capsule containing two or three grains of powdered sugar of milk; this is then stroked with a spatula or the nail of the thumb with some degree of pressure until it is felt, that the pellet or pellets are crushed and broken, then the pellets will easily dissolve if put into water. Wherever I mention pellets in giving medicine, I always mean the finest, of the size of poppy-seeds, of which about 200 (more or less) weigh a grain. I say homoeopathic use, for it does not remain idem (the same); even if the prepared itch substance should be given to the same patient from whom it was taken, it would not remain idem (the same), as it could only be useful to him in a potentized state, since crude itch substance which he has already in his body as an idem is without effect on him. But the dynamization or potentizing changes it and modifies it; just as gold leaf after potentizing is no more crude gold leaf inert in the human body, but in every stage of dynamization it is more and more modified and changed. Thus potentized and modified also, the itch substance (Psorin) when taken is no more an idem (same) with the crude original itch substance, but only a simillimum (thing most similar). Isopathic and aequale are equivocal expressions, which if they should signify anything reliable can only signify simillimum, because they are not idem. A small pellet of one of the highest dynamizations of a medicine laid dry upon the tongue, or the moderate smelling of an opened vial wherein one or more such pellets are contained, proves itself the smallest and weakest dose with the shortest period of duration in its effects. Still there are numerous patients of so excitable a nature, that they are sufficiently affected by such a dose in slight acute ailments, to be cured by it if the remedy is homoeopathically selected. Nevertheless the incredible variety among patients as to their irritability, their age, their spiritual and bodily development, their vital power and especially as to the nature of their disease, necessitates a great variety in their treatment, and also in the administration to them of the doses of medicines. For their diseases may be of various kinds: either a natural and simple one but lately arisen, or it may be a natural and simple one but an old case, or it may be a complicated one (a combination of several miasmata), or again what is the most frequent and worst case, it may have been spoiled by a perverse medical treatment, and loaded down with medicinal diseases. I can here limit myself only to this latter case, as the other cases cannot be arranged in tabular form for the weak and negligent, but must be left to the accuracy, the industry and the intelligence of able men, who are masters of their art. Experience has shown me, as it has no doubt also shown to most of my followers, that it is most useful in diseases of any magnitude (not excepting even the most acute, and still more so in the half- acute, in the tedious and most tedious) to give to the patient the powerful homoeopathic pellet or pellets only in solution, and this solution in divided doses. In this way we give the medicine, dissolved in seven to twenty tablespoonfuls of water without any addition, in acute and very acute diseases every six, four or two hours; where the danger is urgent, even every hour or every half-hour, a tablespoonful at a time; with weak persons or children, only a small part of a tablespoonful (one or two teaspoonfuls or coffeespoonfuls) may be given as a dose. But since water (even distilled water) commences after a few days to be spoil, whereby the power of the small quantity of medicine contained is destroyed, the addition of a little alcohol is necessary, or where this is not practicable, or if the patient cannot bear it, I add a few small pieces of hard charcoal to the watery solution. This answers the purpose, except that in the latter case the fluid in a few days receives a blackish tint. This is caused by shaking the liquid, as is necessary every time before giving a dose of medicine, as may be seen below. Before proceeding, it is important to observe, that our vital principle cannot well bear that the same unchanged dose of medicine be given even twice in succession, much less more frequently to a patient. For by this the good effect of the former dose of medicine is either neutralized in part, or new symptoms proper to the medicine, symptoms which have not before been present in the disease, appear, impeding the cure. Thus even a well selected homoeopathic medicine produces ill effects and attains its purpose imperfectly or not at all. Thence come the many contradictions of homoeopathic physicians with respect to the repetition of doses. But in taking one and the same medicine repeatedly (which is indispensable to secure the cure of a serious, chronic disease), if the dose is in every case varied and modified only a little in its degree of dynamization, then the vital force of the patient will calmly, and as it were willingly receive the same medicine even at brief intervals very many times in succession with the best results, every time increasing the well-being of the patient. This slight change in the degree of dynamization is even effected, if the bottle which contains the solution of one or more pellets is merely well shaken five or six times, every time before taking it. This last solution may then be taken in the same manner, or at longer intervals, perhaps also less of the solution at a time; but every time the solution must be shaken up five or six times. This will be continued so long as the remedy still produces improvement and until new ailments (such as have never yet occurred with other patients in this disease), appear; for in such a case a new remedy will have to be used. On any day when the remedy has produced too strong an action, the dose should be omitted for a day. If the symptoms of the disease alone appear, but are considerably aggravated even during the more moderate use of the medicine, then the time has come to break off in the use of the medicine for one or two weeks, and to await a considerable improvement. He will dissolve one (two) pellet of the highly potentized, well selected medicine in seven, ten or fifteen tablespoonfuls of water (without addition) by shaking the bottle. He will then, according as the disease is more or less acute, and more or less dangerous, give the patient every half hour, or every hour, every two, three, four, six hours (after again well shaking the bottle) a whole or a half tablespoonful of the solution, or, in the case of a child, even less. If the physician sees no new symptoms develop, he will continue at these intervals, until the symptoms present at first begin to be aggravated; then he will give it at longer intervals and less at a time. As is well known, in cholera the suitable medicine has often to be given at far shorter intervals. Children are always given these solutions from their usual drinking vessels; a teaspoon for drinking is to them unusual and suspicious, and they will refuse the tasteless liquid at once on that account. But if the diseased organism is affected by the physician through this same appropriate remedy at the same time in sensitive spots other than the nerves of the mouth and the alimentary canal, i. The limbs which are thus rubbed with the solution may also be varied, first one, then another. Thus the physician will receive a greater action from the medicine homoeopathically suitable to the chronic patient, and can cure him more quickly, than by merely internally administering the remedy. This mode of procedure has been frequently proved by myself and found extraordinarily curative; yea, attended by the most startling good effects; the medicine taken internally being at the same time rubbed on the skin externally. This procedure will also explain the wonderful cures, of rare occurrence indeed, where chronic crippled patients with sound skin recovered quickly and permanently by a few baths in a mineral water, the medicinal constituents of which were to a great degree homoeopathic to their chronic disease. In order to introduce also here change and variation, when several of the limbs are free from cutaneous ailments, one limb after the other should be used, in alternation, on different days, (best on days when the medicine is not taken internally). A small quantity of the solution should be rubbed in with the hand, until the limb is dry. Convenient as the mode of administering the medicine above described may be, and much as it surely advances the cure of chronic diseases, nevertheless, the greater quantity of alcohol or whisky or the several lumps of charcoal which have to be added in warmer weather to preserve the watery solution were still objectionable to me with many patients. Therefore the homoeopathic remedy given internally must never be rubbed in on parts which suffer from external ailments. From a mixture of about five tablespoonfuls of pure water and five tablespoonfuls of French brandy - which is kept on hand in a bottle, 200, 300 or 400 drops (according as the solution is to be weaker or stronger) are dropped into a little vial, which may be half-filled with it, and in which the medicinal powder or the pellet or pellets of the medicine have been placed. From this solution one, two, three or several drops, according to the irritability and the vital force of the patient, are dropped into a cup, containing a spoonful of water; this is then well stirred and given to the patient, and where more especial care is necessary, only the half of it may be given; half a spoonful of this mixture may also well be used for the above mentioned external rubbing. On days, when only the latter is administered, as also when it is taken internally, the little vial containing the drops must every time be briskly shaken five or six times; so also the drop or drops of medicine with the tablespoonful of water must be well stirred in the cup. It would be still better if instead of the cup a vial should be used, into which a tablespoonful of water is put, which can then be shaken five or six times and their wholly or half emptied for a dose. Frequently it is useful in treating chronic diseases to take the medicine, or to rub it in in the evening, shortly before going to sleep, because we have then less disturbance to fear from without, than when it is done earlier. When I was still giving the medicines in undivided portions, each with some water at a time, I often found that the potentizing in the attenuating glasses effected by ten shakes was too strong (i. But during the last years, since I have been giving every dose of medicine in an incorruptible solution, divided over fifteen, twenty or thirty days and even more, no potentizing in an attenuating vial is found too strong, and I again use ten strokes with each. So I herewith take back what I wrote on this subject three years ago in the first volume of this book on page 149. In cases where a great irritability of the patient is combined with extreme debility, and the medicine can only be administered by allowing the patient to smell a few small pellets contained in a vial, when the medicine is to be used for several days, I allow the patient to smell daily of a different vial, containing the same medicine, indeed, but every time of a lower potency, once or twice with each nostril according as I wish him to be affected more or less. The author and publisher make no legal claims, express or implied, and the material is not intended to replace the services of a physician. The author, publisher, and/or copyright holder assume no responsibility for the loss or damage caused, or allegedly caused, directly or indirectly by the use of information contained in this book.

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