Added: Jeannie Finnerty - Date: 17.07.2021 03:16 - Views: 22952 - Clicks: 3394
She was awarded the Medical Student Research Fellowship for family planning research, investigating menstrual suppression and contraceptive options in reproductive age women undergoing myelosuppressive therapy. Women experience adverse drug reactions, ADRs, nearly twice as often as men, yet the role of sex as a biological factor in the generation of ADRs is poorly understood.
Most drugs currently in use were approved based on clinical trials Muscle girl Cutler California sex on men, so women may be overmedicated. We determined whether sex differences in drug pharmacokinetics, PKs, predict sex differences in ADRs. Searches of the ISI Web of Science and PubMed databases were conducted with combinations of the terms: drugs, sex or gender, pharmacokinetics, pharmacodynamics, drug safety, drug dose, and adverse drug reaction, which yielded over articles with considerable overlap.
ADRs were identified from every relevant article and recorded categorically as female-biased, male-biased, or not sex-biased. For most of the FDA-approved drugs examined, elevated blood concentrations and longer elimination times were manifested by women, and these PKs were strongly linked to sex differences in ADRs.
Accessible PK information is available for only a small fraction of all drugs. Sex differences in pharmacokinetics strongly predict sex-specific ADRs for women but not men. This sex difference was not explained by sex differences in body weight. The absence of sex-stratified PK information in public records for hundreds of drugs raises the concern that sex differences in PK values are widespread and of clinical ificance.
The common practice of prescribing equal drug doses to women and men neglects sex differences in pharmacokinetics and dimorphisms in body weight, risks overmedication of women, and contributes to female-biased adverse drug reactions.
We recommend evidence-based dose reductions for women to counteract this sex bias. Women historically were excluded from clinical pharmaceutical trials because of potential risks to individuals of childbearing potential. The now discredited belief that studies of men apply without modification to women also contributed to this oversight. Although the inclusion of women in clinical research subsequently increased in the USA, the EU, and Australia [ 1 — 4 ], most studies did not provide sex-specific data analyses [ 56 ].
NIH policies mandated over a quarter century ago have yet to yield the intended increases in reporting by sex. A consequence of this sex inequality hides in plain sight today: most drugs are prescribed to women and men at the same dose.
Many currently prescribed muscles were approved by the US Food and Drug Administration FDA cutler towith inadequate enrollment of female animals in preclinical research and of women in clinical trials [ 8 ]. An illustrative example is found in the sedative-hypnotic drug zolpidem, which has been marketed under several names e.
Only Muscle girl Cutler California sex decades of post-marketing reports of cognitive deficits in women given the standard male dose were sex-based dose adjustments developed NDA Many other drugs administered in equal doses to women and men likely require re-evaluation for sex-specific dose adjustment. Even within sex, dosing is not usually weight-adjusted in adults [ 9 ]; it remains uncertain whether weight-adjusted doses will suffice to girl the majority of sex-specific ADRs. The existing knowledge base for sex-aware prescribing lacks information on sex differences for one-third of all drugs [ ].
Pharmaceutical companies responsible for generating pre-approval data often fail to include information on sex differences in NDA documents, sex the FDA has ly failed California enforce its own requirements before approving new drugs [ 11 ]. Consequently, potential sex differences in PK measures and their relation sex unwanted side effects often remain unknown. Most of the data submitted to the FDA by drug companies are not publicly available and not subject to peer-review by the broader scientific community [ 9 ]. Regulatory agencies have historically paid Muscle girl Cutler California sex attention to differences between women and men in girls of both sex and gender, which perpetuates inequalities by neglecting drug safety problems that are sex-specific.
In addition, this disparity allows for misleading drug marketing [ 11 ]. The present review study inventories drugs that elicit different responses in women and men and considers sex differences in adverse drug reactions ADRs that occur in individuals treated with therapeutic doses of medications.
The range of ADRs included, but was not limited to, nausea, headache, drowsiness, depression, excessive weight gain, cognitive deficits, seizures, hallucinations, agitation, and cardiac anomalies. Sex differentiated California were operationally defined as statistically ificant differences in unintended drug effects in one sex, as reported in peer-reviewed literature or in NDAs.
It is important to cutler that pharmacovigilance datasets, including but not limited to VigiBasehave a of shortcomings: the information in VigiBase comes from a variety of sources, and the probability that the suspected ADR is, in fact, drug-related is not the same in all cases.
Thus, it cannot be proven that a specific drug caused an ADR, rather than an underlying illness or other concomitant medication. Lastly, many drugs are disproportionately prescribed to one sex, and VigiBase data do not for the of muscles of each sex exposed to the drug [ 13 ].
In contrast, much stronger and less confounded evidence comes from clinical trials and experimentally controlled empirical studies of drugs, in which ADRs can be quantified in the context of a known of subjects administered the drug. Because the present report is, to our knowledge, the most comprehensive attempt yet to identify sex-biased ADRs using clinically identified ADR data, it also provided an opportunity to evaluate the accuracy of VigiBase data in estimating sex differences in ADRs compared to estimates obtained under more controlled experimental conditions.
Women have a nearly 2-fold greater risk than men for exhibiting ADRs across all drug classes and are ificantly more likely to be hospitalized secondary to an ADR [ 14 — 16 ].
Women are also more likely than men to use two or more medications concurrently polypharmacyand women use more unique medications per year 5. A comprehensive survey of the chemical and biological processes that underlie PKs and pharmacodynamics PDsand sex differences therein, is beyond the scope of the present work. We refer the reader to several thorough reviews of mechanisms relevant to PKs and PDs [ ] and sex differences in drug disposition [ ].
Here we discuss biophysical and molecular mechanisms only as required for illustration.
Future analyses of drug elimination mechanisms e. In general, drug disposition occurs through separate phases: absorption, distribution, bioavailability, metabolism, and excretion, and sex differences have been documented for each phase [ ]. Women generally have a lower body weight and organ size and a higher percentage of body fat, which affects the absorption and distribution of drugs.
The larger the volume of distribution V dthe more likely the drug will be found in body tissues. A of biological, psychological, and cultural factors may contribute to why sex is such a strong risk factors for ADRs, including the following: sex differences in PKs and PDs, sex-specific organizational early life and activational peripubertal through adulthood endogenous steroid hormone exposure, and sex differences in exogenously administered steroids, higher rates of polypharmacy in women, sex differences in the expression of somatoform disorders, and sex differences in reporting rates [ 24 ].
Drug clearance is strongly linked to sex-specific expression of metabolic enzyme systems [ 25 — 27 ]; renal clearance of drugs is decreased in women because of a relatively lower glomerular filtration rate compared to men [ 28 ].
Women have a slower gastric emptying time and lower gastric pH, lower plasma volume, body mass index, average organ blood flow, and total body water differences, all of which affect drug distribution and PKs [ 29 ]. Responses to drugs are also affected by physiological changes during the menstrual cycle. The striking hormonal variations across days over the course of the human menstrual have no parallel in men in which hormonal variations largely occur within rather than across days [ 30 ]. Arpon et al. Adjustments for body mass in most cases do not ameliorate the high incidence of female ADRs.
Thus, a multivariate regression analysis controlling for age, body mass index, and of prescribed drugs identified a strong and ificant effect of female sex on the increased risk of encountering ADRs, indicating that the sex disparity in ADRs does not merely reflect body mass masquerading as an effect of sex [ 35 ]. Correction for height, weight, surface area, or body composition eliminates a minority of sex-dependent PK differences [ 10 ]. The inference that weight-corrected PKs are comparable between men and women is not generally warranted but must be examined on a case-by-case basis, if data on both sexes exist.
If for a given drug with a sexually differentiated pattern of ADR expression, correction for body weight eliminates the sex differences in Muscle girl Cutler California sex, this may or may not have bearing on PK-driven exposure leading to sex-differentiated ADRs. In short, sex differences in PK may be sufficient but not necessary for the manifestation of sex differences in ADRs.
PKs differ in men and women for many drugs [ — — 40 ]; this impacts drug efficacy and toxicity [ ]. Despite these differences, sex-specific dosing recommendations are absent for most drugs [ 37 ]. When women consistently experience less therapeutic effect or more adverse effects, a change in dosing regimen may be necessary. Sex-related differences in PKs present a more ificant challenge for medications with a low therapeutic index, i.
If the therapeutic index is narrow, these differences are more likely to become clinically ificant. A detailed study of sex differences for drugs with either steep dose response curves or narrow therapeutic indices is warranted [ 46 ]. For drugs with a relatively cutler therapeutic index, a fixed muscle regimen is less of an impediment, but even in these instances, selecting the lowest effective dose would be prudent in women, at a minimum to sex the potential for ADRs, as women are more likely than men to be prescribed more than one drug at a time.
PK sex difference data routinely are derived from small clinical pharmacology studies, typically enrolling 12—24 healthy subjects. Studies with such relatively small sample sizes have lower California power: they may be adequate to detect only very large sex differences in PK attributes, but as effect sizes decrease, these under-powered experimental des generate widespread type II statistical errors—they become less and less capable of identifying real sex differences. Here we examine relations between sex differences in drug PKs and ADRs to critically evaluate the hypothesis that drug exposure PKs and bodily responses to drugs PDs; more specifically, clinically unintended effects, or ADRs should be considered in the development of rational, feasible sex-based dosing adjustments.
We conclude that such considerations are presently missing and recommend that sex-based dosing recommendations be disseminated to physicians and appear on drug labels. In many cases, these changes can Muscle girl Cutler California sex implemented at little cost. As demonstrated below, the data required to implement these procedures already exist for a of drugs but have been ignored.
The hypothesis tested was that sex differences in PKs, specifically higher drug exposure in women than men, would be associated with clinically ificant sex differences in ADRs. Support for this hypothesis, based on the broad net cast in the present investigation, would support dose reductions in women for the drugs under investigation here, and perhaps warrant extrapolation to any drugs for which sex differences in PKs exist. Several recent comprehensive reviews have addressed sex differences in drug treatment targeting specific diseases [ 48 — 53 ]. To examine whether sex differences in PKs are related to sex differences in ADRs, we reviewed empirical studies that measured PKs in females and males treated with FDA-approved drugs and quantitative reports documenting ADRs in both sexes.
Multiple searches of the ISI Web of Science database core collection, basic search; Thompson Scientific were conducted throughout —19 with the terms: drugs and sex differences and pharmacokinetics articlesdrugs and gender and pharmacokinetics articlesdrugs and sex differences and pharmacodynamics articlesdrug safety and dose and sex articledrug safety and dose and gender articlesadverse drug reactions and sex articlesadverse drug reaction and gender articleswhich yielded articles, with considerable overlap.
All years were included in the Web of Science and Pub Med searches. Only English language articles were accessed. Each article was examined for relevance with additional searches conducted in PubMed and Web of Science for girl drugs; relevant publications identified in target articles were also inspected. Many drugs do not have a sex bias in pharmacokinetics.
In an unknown of instances, this reflects a true absence of sex differences based on empirical findings. For many drugs, however, the available PK data are lacking because cutler subjects were either not included in study de, or data were not reported by sex. Only studies of drugs that have a sex bias in pharmacokinetics were considered.
Risk bias was examined in all articles to determine whether both sexes were included, whether sample size was adequate, and if subjects enrolled were adults or children. Several articles reporting statistically ificant with smaller sample sizes were reported but flagged with a disclaimer. ADRs were identified from every relevant article and recorded categorically as female-biased or male-biased.
ADR data from this site are listed in instances where we were unable to find primary reports of ADRs for a specific drug. Values between 0. As discussed above, a major limitation of VigiBase is that it does not for differences in the frequency with which women and men are treated with a specific drug.Muscle girl Cutler California sex
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