By J. Koraz. State University of New York College of Agriculture and Technology, Cobleskill.
House of Commons Home Affairs Select Committee The government’s drugs policy: is it working? Jaffe J & O’Keeffe C (2003) From morphine clinics to buprenorphine; regulating opioid antagonist treatment of addiction in the United States proven 160 mg kamagra super impotence what does it mean. Haasen C cost of kamagra super erectile dysfunction gif, Verthein U & Degkwitz P (2007) Heroin-assisted treatment for opioid dependence: randomised controlled trial purchase generic kamagra super from india diabetes erectile dysfunction wiki. National Institute for Health and Clinical Excellence (2007) Methadone and buprenorphine for the management of opioid dependence buy kamagra super from india erectile dysfunction treatment with viagra. Her Majesty’s Government (2010) Drug strategy 2010: reducing demand, restricting supply, building recovery: supporting people to live a drug free life. Robins L (1993) Vietnam veterans rapid recovery from heroin addiction: a fluke, or normal expectation? Recovery Orientated Drug Treatment Group, National Treatment Agency for Substance Misuse (2012) Medications in recovery. Hubbard R, Marsden M, Rachel J et al (1989) Drug abuse treatment: a national study of effectiveness. Bell J, Dru A, Fischer B et al (2002) Substitution therapy for heroin addiction Substance Use and Misuse 37: 1145-74. Romelsjö A, Engdahl B, Stenbacka M et al (2010) Were the changes to Sweden’s maintenance treatment policy 2000-06 related to changes in opiate-related mortality and morbidity? De Maeyer J, Vanderplasschen W & Broekaert E (2010) Quality of life among opiate-dependent individuals: a review of the literature. Moffatt S, Weatherburn D & Donnelly N (2005) What caused the recent drop in property crime? Rosenbaum M (1985) A matter of style: variation among methadone clinics in the control of clients. General Accounting Office (1990) Methadone maintenance: some treatment programs are not effective; greater federal oversight needed. Report to the chairman, Select Committee on Narcotic Abuse and Control, House of Representatives. De Maeyer J, Vanderplasschen W, Camfield L et al (2011) A good quality of life under the influence of methadone: a qualitative study among opiate-dependent individuals. Bell J, Chan J & Kuk A (1995) Investigating the effect of treatment philosophy on outcome of methadone maintenance. Bell J, Butler B, Lawrance A et al (2009) Comparing overdose mortality associated with methadone and buprenorphine treatment. Bell J, Shanahan M, Mutch C et al (2007) A randomised trial of effectiveness and cost effectiveness of observed versus unobserved administration of buprenorphine-naloxone for heroin dependence. Barau K, Thirion X, Micallef J et al (2001) Comparison of methadone and high dosage buprenorphine users in French care centres. Auriacombe M, Fatséas M, Dubernet J et al (2004) French field experience with buprenorphine. Amato L, Minozzi S, Davoli M et al (2011) Psychosocial combined with agonist maintenance treatments versus agonist maintenance treatments alone for treatment of opioid dependence. Gossop M, Stewart D, Browne N et al (2003) Methadone treatment for opiate dependent patients in general practice and specialist clinic settings: outcomes at 2-year follow-up. Taylor D, Paton C & Kapur S (2009) The Maudsley prescribing guidelines in psychiatry (10e). National Institute for Health and Clinical Excellence (2011) Alcohol dependence and harmful alcohol use. Minozzi S, Amato L, Vecchi S et al (2011) Oral naltrexone maintenance treatment for opioid dependence. Volume 1: A study of effectiveness and financing of public and private drug treatment systems. Strang J, Manning V, Mayet S et al (2007) Does prescribing for opiate addiction change after national guidelines? Methadone and buprenorphine prescribing to opiate addicts by general practitioners and hospital doctors in England 1995-2005. Marsden J, Eastwood B, Bradbury C et al (2009) Effectiveness of community treatments for heroin and crack cocaine addiction in England: a prospective, in-treatment cohort study. Bell J, Trinh L, Butler B et al (2009) Comparing retention in treatment and mortality in people after initial entry to methadone and buprenorphine treatment. Bell J, Butler B, Lawrance A et al (2009) Comparing overdose mortality associated with methadone and buprenorphine treatment. Strang J, Griffiths P, Powis B et al (1999) Which drugs cause overdose among opiate misusers? Zador D & Sunjic S (2000) Deaths in methadone maintenance treatment in New South Wales, Australia 1990-1995. Williams A, Reed K, Groshkova T et al (2010) Training family members and carers of opiate users in overdose management and naloxone administration: a randomised trial. Strang J, Darke S, Hall W et al (1996) Heroin overdose: the case for take-home naloxone? Neale J, Tompkins C & Sheard L (2008) Barriers to accessing generic health and social care services: a qualitative study of injecting drug users. Barnaby B, Drummond C, McCloud A et al (2003) Substance misuse in psychiatric inpatients: comparison of a screening questionnaire survey with case notes. Kouimtsidis C, Reynolds M, Hunt M et al (2003) Substance use in the general hospital. Ryrie I & Ford C (2001) The primary care treatment of drug users: is shared care really the best approach? McCambridge J & Strang J (2004) The efficacy of single-session motivational interviewing in reducing drug consumption and perceptions of drug-related risk and harm among young people: results from a multi-site cluster randomized trial. Marijuana Treatment Project Research Group (2004) Brief treatments for cannabis dependence: findings from a randomized multisite trial. National Institute for Health and Clinical Excellence (2007) Drug misuse: opioid detoxification. Bell J (2010) The global diversion of pharmaceutical drugs: opiate treatment and the diversion of pharmaceutical opiates: a clinician’s perspective. Blackwell J (1988) The saboteurs of Britain’s opiate policy: overprescribing physicians or American-style ‘junkies’? National Institute for Health and Clinical Excellence (2011) Anxiety: management of anxiety (panic disorder, with or without agoraphobia, and generalised anxiety disorder) in adults in primary, secondary and community care. Sikdar S (1998) Physical dependence on zopiclone: prescribing this drug to addicts may give rise to iatrogenic drug misuse. Reed K, Bond A, Witton J et al (2011) The changing use of prescribed benzodiazepines and z-drugs and of over-the-counter codeine-containing products in England: a structured review of published English and international evidence and available data to inform consideration of the extent of dependence and harm. Schweitzer E & Rickels K (1998) Benzodiazepine dependence and withdrawal: a review of the syndrome and its clinical management. Royal College of Psychiatrists (1997) Benzodiazepines: risks, benefits or dependence: a re-evaluation. American Psychiatric Association (1994) Diagnostic and statistical manual of mental disorders (4e). Vandrey R & Haney M (2009) Pharmacotherapy for cannabis dependence: how close are we? Darke S & Hall W (2003) Heroin overdose: research and evidence-based intervention. Strang J, McCambridge J, Best D et al (2003) Loss of tolerance and overdose mortality after inpatient opiate detoxification: follow-up study. Williams A, Reed K, Groshkova T et al (2010) Training family members and carers of opiate users in overdose management and naloxone administration: a randomised trial. Australasian Professional Society on Alcohol and Other Drugs Conference 2010 Paper 122. Minozzi S, Amato L, Vecchi S et al (2011) Oral naltrexone maintenance treatment for opioid dependence. Castells X, Casas M, Pérez-Mañá C et al (2010) Efficacy of psychostimulant drugs for cocaine dependence. Lussier J, Heil S, Mongeon J et al (2006) A meta-analysis of voucher-based reinforcement therapy for substance use disorders. Prendergast M, Podus D, Finney J et al (2006) Contingency management for treatment of substance use disorders: a meta-analysis. Stulza N, Gallop R, Lutzc W et al (2010) Examining differential effects of psychosocial treatments for cocaine dependence: an application of latent trajectory analyses. Gossop M, Stewart D & Marsden J (2008) Attendance at narcotics anonymous and alcoholics anonymous meetings, frequency of attendance and substance use outcomes after residential treatment for drug dependence: a 5-year follow-up study. National Institute for Health and Clinical Excellence (2010) Pregnancy and complex social factors. Archie C (1998) Methadone in the management of narcotic addiction in pregnancy (editorial). National Institute for Health and Clinical Excellence (2007) Methadone and buprenorphine for the management of opioid dependence. Royal College of General Practitioners, Royal Pharmaceutical Society & The Secure Environment Pharmacist Group (2011) Safer prescribing in prisons. Stewart D (2010) Drug use and perceived treatment need among newly sentenced prisoners in and. Singleton N, Meltzer H, Gatward R et al (1998) Psychiatric morbidity among prisoners in England and Wales.
Of course cheap kamagra super 160mg fast delivery male erectile dysfunction pills review, most elimination processes are capable of being saturated if enough drug is administered quality kamagra super 160 mg erectile dysfunction treatment nyc. However 160mg kamagra super with visa best erectile dysfunction drug review, for most drugs buy cheap kamagra super 160mg impotence 21 year old, the doses administered do not cause the elimination processes to approach their limitations. Clinical Correlate Many drugs exhibit mixed-order pharmacokinetics, displaying first-order pharmacokinetics at low drug concentrations and zero-order pharmacokinetics at high concentrations. It is important to know the drug concentration at which a drug "order" switches from first to zero. Phenytoin is an example of a drug that switches order at therapeutic concentrations, whereas theophylline does not switch until concentrations reach the toxic range. For a typical drug having dose-dependent pharmacokinetics, with saturable elimination, the plasma drug concentration versus time plot after a dose may appear as shown in Figure 10-3. After a large dose is administered, an initial slow elimination phase (clearance decreases with higher plasma concentration) is followed by a much more rapid elimination at lower concentrations (curve A). However, when a small dose is administered (curve B), the capacity of the elimination process is not reached, and the elimination rate remains constant. At high concentrations, the elimination rate approaches that of a zero-order process (i. At low concentrations, the elimination rate approaches that of a first-order process (i. A model that has been used extensively in biochemistry to describe the kinetics of saturable enzyme systems is known as Michaelis-Menten kinetics (for its developers). This system describes the relationship of an enzyme to the substrate (in this case, the drug molecule). In clinical pharmacokinetics, it allows prediction of plasma drug concentrations resulting from administration of drugs with saturable elimination (e. The equation used to describe Michaelis-Menten pharmacokinetics is: where -dC/dt is the rate of drug concentration decline at time t and is determined by Vmax, the theoretical maximum rate of the elimination process. Km is the drug concentration when the rate of elimination is half the maximum rate, and C is the total plasma drug concentration. For drugs metabolized by the liver, Vmax can be determined by the quantity or efficiency of metabolizing enzymes. In simplified terms, Km is the concentration above which saturation of drug metabolism is likely. Vmax and Km are related to the plasma drug concentration and the rate of drug elimination as shown in Figure 10-4. When the plasma drug concentration is less than Km, the rate of drug elimination follows first-order pharmacokinetics. In other words, the amount of drug eliminated per hour directly increases with the plasma drug concentration. When the plasma drug concentration is much less than Km, the first-order elimination rate constant (K) for drugs with nonlinear pharmacokinetics is approximated by Vmax; therefore, as Vmax increases (e. With drugs having saturable elimination, as plasma drug concentrations increase, drug elimination approaches its maximum rate. When the plasma concentration is much greater than Km, the rate of drug elimination is approximated by Vmax, and elimination proceeds at close to a zero-order process. Next, we consider how Vmax and Km can be calculated and how these determinations may be used to predict plasma drug concentrations in patients. Relationship of drug elimination rate to plasma drug concentration with saturable elimination. Therefore, we must apply the Michaelis-Menten equation presented earlier in this lesson: The change in drug concentration over time is related to the Michaelis-Menten parameters Vmax, Km, and the plasma drug concentration (C). We know that at steady state (after multiple drug doses) the rate of drug loss from the body (milligrams removed per day) is equal to the amount of drug being administered (daily dose). In the Michaelis-Menten equation, -dC/dt indicates the rate of drug loss from the body; therefore, at steady state: Now we have an equation that relates Vmax, Km, plasma drug concentration, and daily dose (at steady state). To use this relationship, it is first helpful to transform the equation to a straight-line form: 10-1 Then: daily dose = -Km(daily dose/C) + Vmax Y (slope) = mX + b(intercept) So the relationship of the Michaelis-Menten parameters, C, and dose can be expressed as a straight line (Figure 10-5). If the straight line can be defined, then Vmax and Km can be determined; if Vmax and Km are known, then the plasma concentrations at steady state resulting from any given dose can be estimated. To define the line, it is necessary to know the steady-state concentrations achieved at a minimum of two different doses. For example, a patient receiving 300 mg of phenytoin per day achieved a steady-state concentration (trough) of 9 mg/L; when the daily dose was increased to 400 mg/day, a steady-state concentration of 16 mg/L was achieved. The y- intercept equals Vmax (observed to be 700 mg/day), and the slope of the line equals -Km. Plot of patient data using two steady-state plasma phenytoin concentrations at two dose levels. Calculating Dose Knowing Vmax and Km, we can then predict the dose necessary to achieve a given steady-state concentration or the concentration resulting from a given dose. If we wish to increase the steady- state plasma concentration to 20 mg/L, we can use the Michaelis-Menten equation to predict the necessary dose: Note how units cancel out to yield mg/day. Calculating Steady-State Concentration from This Km and Dose If we wish to predict the steady-state plasma concentration that would result if the dose is increased to 500 mg/day, we can rearrange the Michaelis-Menten equation and solve for C: 10-3 See Lesson 15 for examples of how these calculations are applied. Clinical Correlate When performing this calculation using sodium phenytoin or fosphenytoin, be sure to convert doses to their phenytoin free-acid equivalent before substituting these values into the equation. The preceding example demonstrates how plasma drug concentrations and drug dose can be predicted. However, it also shows that for drugs like phenytoin, with saturable elimination, when plasma concentrations are above Km, small dose increases can result in large increases in the steady- state plasma concentration. When clearance changes with plasma concentration, there is no true half-life as with first-order elimination. As clearance changes, the elimination rate changes, as does the time to reach steady state. With high doses and high plasma concentrations (and resulting lower clearance), the time to reach steady state is much longer than with low doses and low plasma concentrations (Figure 10-7). Theoretically, if the dose is greater than Vmax, steady state will never be reached. The Michaelis-Menten equation can be rearranged to provide an equation that estimates the time required (in days) for 90% of the steady-state concentration to be reached (t90%), as shown below (where the dose equals the daily dose): 10-4 From the previous example, when dose = 300 mg/day, Vmax = 700 mg/day, Km = 12 mg/L, and the volume of distribution (V) is estimated to be 50 L: When the dose is increased to 400 mg/day: We can see that as the dose is increased, it takes a longer time to reach steady state, drug continues to accumulate, and the plasma drug concentration continues to rise. Clinical Correlate The t90% equation will only provide a rough estimate of when 90% of steady state has been reached, and its accuracy is dependent on the Km value used. Other ways to check to see if a patient is at steady state are to examine two levels drawn approximately a week apart. Additionally, it is safe to wait at least 2 weeks (and preferably 4 weeks) after beginning or changing a dose before obtaining new steady-state levels. Linear pharmacokinetics means that the plot of plasma drug concentration versus time after a dose is a straight line. When hepatic metabolism becomes saturated, any increase in drug dose will lead to a proportionate increase in the plasma concentration achieved. When the rate of drug elimination proceeds at half the maximum rate, the drug concentration is known as: A. Which of the equations below describes the form of the Michaelis-Menten equation that relates daily drug dose to Vmax, Km, and the steady-state plasma drug concentration? The phenytoin dose is then changed to 400 mg/ day, and 2 months after the dose change the plasma concentration determined just before a dose is 18 mg/L. After the dose of 400 mg/day is begun, how long will it take to reach 90% of the steady-state plasma concentration? Drugs with linear pharmacokinetics may exhibit plasma concentrations versus time plots that are not straight lines, as with multiple-compartment drugs. There will be a disproportionate increase in the plasma concentration achieved because the amount of drug that can be eliminated over time cannot increase. At very low concentrations, drugs are more likely to exhibit first-order kinetics because hepatic enzymes are usually not yet saturated, whereas at higher concentrations, enzymes saturate, making zero-order kinetics more likely. Use dose pairs of 300 and 400 and concentration pairs of 10 and 18 to calculate Km. The steady-state plasma concentration resulting from a daily dose of 500 mg would be estimated from the line equation as follows: Rearranging gives: C, D. When using the t90% equation, examine what happens to t90% when dose greatly exceeds Vmax. Discuss several practical methods to determine when a nonlinear drug has reached steady state. Examine the "time to 90% equation" and note the value of Km that is used in this equation. Substitute several different phenytoin Km values based on a range of population values (i. Based on this observation, what value of Km would you use when trying to approximate the t90% for a newly begun dose of phenytoin? Discuss the patient variables that can affect the pharmacokinetic calculation of a nonlinear drug when using two plasma drug concentrations obtained from two different doses. Write a pharmacy protocol describing an appropriate phenytoin dosing and monitoring service. Explain how the various sources of pharmacokinetic variation affect pharmacokinetic parameters. Describe ways to avoid or minimize errors in the collection and assay of drug samples. These differences in drug effect are sometimes related to differences in pharmacokinetics.
Studies of the exposure of 58 Handbook of Pharmaceutical Manufacturing Formulations: Semisolid Products the drug substance or drug product to extreme conditions This takes into account that degradation of biotechnolog- may help reveal patterns of degradation; if so 160mg kamagra super with visa trazodone causes erectile dysfunction, such ical and biological products may not be governed by the changes should be monitored under proposed storage con- same factors during different intervals of a long storage ditions generic 160 mg kamagra super amex erectile dysfunction vegan. Conditions should be carefully selected on a For products with proposed shelf lives of greater than case-by-case basis purchase kamagra super 160 mg with visa erectile dysfunction vitamin shoppe. Container and Closure where data are available that demonstrate adequate stabil- Changes in the quality of the product may occur as a result ity buy discount kamagra super on-line cheap erectile dysfunction pills online uk. Where data exist that indicate that the stability of a of the interactions between the formulated biotechnolog- product is not compromised, the applicant is encouraged ical or biological product and the container and closure. Data should be supplied for Although biotechnological and biological products may all different container and closure combinations that will be subject to signiﬁcant losses of activity, physicochem- be marketed. Recommendations for maximum accept- of withstanding the conditions of repeated insertions and able losses of activity, limits for physicochemical withdrawals so that the product retains its full potency, changes, or degradation during the proposed shelf life purity, and quality for the maximum period speciﬁed in have not been developed for individual types or groups the instructions for use on containers, packages, or pack- of biotechnological or biological products but are con- age inserts. These speciﬁcations and limits should be derived Product from all available information, using the appropriate sta- The stability of freeze-dried products after their reconsti- tistical methods. The use of different speciﬁcations for tution should be demonstrated for the conditions and the release and expiration should be supported by sufﬁcient maximum storage period speciﬁed on containers, pack- data to demonstrate that the clinical performance is not ages, or package inserts. Thus, it is and drug products, precisely deﬁned storage temperatures difﬁcult to draft uniform guidances regarding the stability are recommended. Speciﬁc recommendations should be study duration and testing frequency that would be appli- stated, particularly for drug substances and drug products cable to all types of biotechnological and biological prod- that cannot tolerate freezing. With only a few exceptions, however, the shelf lives appropriate, recommendations for protection against light for existing products and potential future products will or humidity should appear on containers, packages, or be within the range of 0. Such labeling should be in accordance guidance is based on expected shelf lives in that range. In general, appearance, assay, and deg- radation products should be evaluated for all dosage forms. Metered-dose inhalations and nasal aerosols should be The list of tests presented for each dosage form is not evaluated for appearance (including content, container, intended to be exhaustive, nor is it expected that every and the valve and its components), color, taste, assay, listed test be included in the design of a stability protocol degradation products, assay for cosolvent (if applicable), for a particular drug product (e. Furthermore, it is not expected that aerodynamic particle size distribution, microscopic eval- every listed test be performed at each time point. Tablets should be evaluated for appearance, color, odor, For suspension-type aerosols, the appearance of the assay, degradation products, dissolution, moisture, and valve components and container’s contents should be eval- friability. These particles lead to clogged valves or nonrepro- Hard gelatin capsules should be evaluated for appearance (including brittleness), color, odor of contents, assay, deg- ducible delivery of a dose. Corrosion of the inside of the radation products, dissolution, moisture, and microbial container or deterioration of the gaskets may adversely affect the performance of the drug product. Testing of soft gelatin capsules should include appearance, color, odor of contents, assay, degradation A stress temperature-cycling study should be per- formed under the extremes of high and low temperatures products, dissolution, microbial limits, pH, leakage, and expected to be encountered during shipping and handling pellicle formation. In addition, the ﬁll medium should be to evaluate the effects of temperature changes on the qual- examined for precipitation and cloudiness. After storage, samples of suspen- inhalation should include appearance, color, assay, degra- sions should be prepared for assay according to the rec- dation products, pH, sterility, particulate matter, preserva- ommended labeling (e. D, after particle size distribution of the emitted dose, microscopic 60 Handbook of Pharmaceutical Manufacturing Formulations: Semisolid Products evaluation, microbial limit, moisture content, foreign par- microbial limit and sterility, peel and adhesive forces, and ticulates, content uniformity of the emitted dose, and num- drug release rate. The stability lotions, pastes, gels, solutions, and nonmetered aerosols of drug for injection products should also be evaluated for application to the skin. Speciﬁc parameters to be examined at appropriate ance, clarity, color, homogeneity, odor, pH, resuspendabil- intervals throughout the maximum intended use period of ity (for lotions), consistency, viscosity, particle size dis- the reconstituted drug product, stored under conditions tribution (for suspensions, when feasible), assay, recommended in labeling, should include appearance, degradation products, preservative and antioxidant content clarity, odor, color, pH, assay (potency), preservative (if (if present), microbial limits and sterility, and weight loss present), degradation products and aggregates, sterility, (when appropriate). Appropriate stability data should be provided for The stability studies for drug injectable suspension products supplied in closed-end tubes to support the max- and drug for injectable suspension products should also imum anticipated use period—during patient use—once include particle size distribution, redispersibility, and the tube seal is punctured, allowing product contact with rheological properties in addition to the parameters cited the cap and cap liner. Ointments, pastes, gels, and creams above for drug injection and drug for injection products. Evaluation of nonmetered topical aerosols should Continued assurance of sterility for all sterile products include appearance, assay, degradation products, pressure, can be assessed by a variety of means, including evalua- weight loss, net weight dispensed, delivery rate, microbial tion of the container and closure integrity by an appropri- limits, spray pattern, water content, and particle size dis- ate challenge test or tests, or sterility testing as described tribution (for suspensions). Stability studies should evaluate product stability following exposure to at least the maximum spec- iﬁed process lethality (e. Stability Testing of Drug Substances and Drug Products 61 Interaction of administration sets and dispensing diluents or other drug products for admixture are refor- devices with parenteral drug products, where warranted, mulated. Continued assurance of sterility for all sterile products may be assessed by a variety of means, including evalu- ation of the container and closure integrity by an appro- O. The stability protocol should considered through appropriate-use test protocols to include studies at 37° or 40°C over a sufﬁcient period of ensure that absorption and adsorption during dwell time time to simulate the in vivo use of the drug delivery do not occur. Tests should include appearance, color, clarity, impossible to address stability requirements for all assay, degradation products, pH, particulate matter, inter- changes in an exhaustive manner in this guidance. Some action with the container and closure and device, and more common examples of changes to an approved drug sterility. Appropriate supporting data may be provided in application for which supportive stability data should be lieu of an evaluation of photodegradation. All changes should be accom- bility and the stability of the drug products should be panied by the standard stability commitment to conduct conﬁrmed in all diluents and containers and closures as or complete long-term stability studies on the ﬁrst one or well as in the presence of all other drug products indicated three batches of the drug substance or drug product and for admixture in the labeling. Compatibility studies annual batches thereafter, in accordance with the approved should be conducted on at least the lowest and highest stability protocol. The accumulated stability data should concentrations of the drug product in each diluent as be submitted in the subsequent annual reports. The stability and compatibility otherwise noted, if the data give no reason to believe that studies should be performed on at least three batches of the proposed change will alter the stability of the drug the drug product. Compatibility studies should be product, the previously approved expiration dating period repeated if the drug product or any of the recommended can be used. Ordinarily, the approved expiration A change in the manufacturing process of the drug sub- dating period for the drug product may be retained if the stance at the approved manufacturing site should be sup- drug substance is shown to be of comparable quality (e. If the drug sub- stability of the drug substance and the resulting drug prod- stance is not of comparable quality, then more extensive uct. Because chemical stability of a substance is an intrinsic stability data on the drug product manufactured from the property, changes made in the preparation of that substance drug substance will be needed. Special con- will be addressed in a separate forthcoming guidance on cerns for biological products may exist if changes are made postapproval changes for the drug substance. Site Change for the Drug Product Speciﬁc submission and stability issues will be addressed in detail in a separate forthcoming guidance For a move of the manufacturing site within an existing dealing with postapproval changes for drug substances. Site changes consist of changes in the location of the site For a move to a different campus using similar equip- of manufacture, packaging operations, or analytical test- ment and manufacturing processes, stability data on the ing laboratory both of company-owned as well as contract drug product in the new facility should be submitted in manufacturing facilities. Three months of accelerated ﬁling mechanisms indicated below apply to site changes and available long-term stability data on one to three only. If other changes occur concurrently, the most exten- batches of drug product manufactured in the new site is sive data package associated with the individual changes recommended, depending on the complexity of the dos- should be submitted. A commitment should be made to conduct long- ing site for any portion of the manufacturing process of a term stability studies on the ﬁrst or ﬁrst three production drug substance or drug product is made, sufﬁcient data to batch or batches of the drug product, depending on the show that such a change does not alter the characteristics dosage form and the existence of a signiﬁcant body of or compromise the quality, purity, or stability of the drug information, manufactured at the new site in accordance substance or drug product may be necessary. If the stability data should include a side-by-side comparison of all attributes are satisfactory, the existing expiration dating period may to demonstrate comparability and equivalency of the drug be used. Site Change for the Drug Substance A stand-alone packaging operation site change for solid For a change limited to an alternate manufacturing site for oral dosage–form drug products using containers and clo- the drug substance using similar equipment and manufac- sures in the approved application should be submitted as turing process, stability data on the drug substance may a Changes Being Effected Supplement. No up-front sta- not always be necessary because, for essentially pure drug bility data are necessary. The facility should have a current substances, stability is an intrinsic property of the material. The standard annual batches thereafter on long-term stability studies stability commitment should be made to conduct long-term using the approved protocol in the application and to sub- stability studies in accordance with the approved stability mit the resulting data in annual reports. Stability Testing of Drug Substances and Drug Products 63 A packaging site change for other than solid oral dos- G. The stability data packages for changes in container and closure of a drug product vary. Change in Testing Laboratory determining the stability data package recommendation is whether the protective properties of the container and clo- An analytical testing laboratory site change may be sub- sure system are affected by the proposed change. Protective mitted as a Changes Being Effected Supplement under properties of the container and closure system include, but certain circumstances. Changes that may affect these properties should be supported by a greater amount D. A solid dosage form will A change limited to the manufacturing process of the drug generally be less affected by a container change than a product, such as a change in the type of equipment used, liquid dosage form. Because considerably more informa- can be supported by the submission of sufﬁcient data to tion will be needed to document a container and closure show that such a change does not alter the characteristics change than just stability data, applicants are encouraged or compromise the stability of the drug product. Such a modiﬁcation to the approved stability protocol nature of the reprocessing procedure and any speciﬁc should be submitted as a Prior Approval Supplement. The effect it might have on the existing stability proﬁle of the justiﬁcation may include a demonstrated history of satis- drug. The expiration dating period for a reprocessed batch factory product stability, which may in turn include, but should not exceed that of the parent batch, and the expi- not be limited to, full long-term stability data from at least ration date should be calculated from the original date of three production batches. For example, drug products with an expiration procedure, which can range from repackaging a batch when dating period of less than 18 months should be tested at packing equipment malfunctions to regrinding and recom- quarterly intervals, products with an expiration dating pressing tablets. The appropriate chemistry review team period of 18 but not more than 30 months should be tested should be contacted to determine whether the reprocessing semiannually, and products with an expiration dating procedure is acceptable. Any batch of the drug product that period of 36 months or longer should be tested annually. Quinine actinometry as a method for calibrat- ing ultraviolet radiation intensity in light-stability testing of pharmaceuticals, Drug Dev. The design assumes that the stability of the inter- technological and biological products, some degradation mediate condition samples is represented by those at the products may be active. Examples of complex dosage forms Active ingredient that is intended to furnish pharmacolog- include modiﬁed-release dosage forms, metered-dose ical activity or other direct effect in the diagnosis, cure, inhalers, transdermal patches, and liposome preparations. Impurity — Any entity of the drug substance (bulk mate- Date of Production — Date that the ﬁrst step of manu- rial) or drug product (ﬁnal container product) that is not facture is performed that involves the combining of an the chemical entity deﬁned as the drug substance, an active ingredient, antioxidant, or preservative with other excipient, or other additives to the drug product. For a biological product subject to but for which manufacture is critical to the successful pro- licensure, see the deﬁnition of date of manufacture in duction of the drug substance or the drug product.
Repeated adminis- tration of phenolphthalein-containing laxatives to children has led to serious illness and multiple hospitalizations (Sugar et al discount kamagra super 160 mg fast delivery erectile dysfunction trials. Phenolphthalein did not appear to be toxic in rats order kamagra super without a prescription erectile dysfunction meds list, and no laxative effect was observed best purchase for kamagra super erectile dysfunction protocol foods. Treated rats showed increased relative (to body weight) kidney weights (males only) and elevated absolute and relative liver weights at concentrations of 12 000–50 000 ppm order kamagra super 160mg online erectile dysfunction young male. Female rats showed no effect on body-weight gain, but those receiving concentrations of 6000–50 000 mg/kg had elevated liver weights. The primary treatment-related findings in mice involved the reproductive and haematopoietic systems. The haematopoietic changes included bone-marrow hypo- plasia (at 12 000–50 000 mg/kg) and increased splenic haematopoiesis (males only; 25 000 and 50 000 mg/kg) (National Toxicology Program, 1996). In female mice [strain not specified] fed 5, 25 or 50 mg/kg bw phenolphthalein per day orally for 135 days, no toxic manifestations or evidence of histopathological changes were found in the liver, kidney or gastrointestinal tract (Visek et al. Phenolphthalein at doses of 25 and 50 μg/mL was cytotoxic in cultured Chang liver cells, causing decreased cell growth and increased anaerobic glycolysis, i. Doses of 1–10 mg given subcutaneously twice daily for two days to female Wistar rats weighing 35–40 g induced a dose-related increase in uterine weight, but the maximum increase was only about half of that induced by oestradiol. Phenolphthalein was shown to bind to the oestrogen receptor and was a competitive antagonist to oestradiol (Nieto et al. In a study reported in an abstract, exposure of female B6C3F1 mice to 1895 mg/kg bw phenolphthalein orally [method not stated] daily for 30 or 60 days caused no changes in weight gain, oestrous cycles or the numbers of oocyte-containing follicles of any class (primordial, primary, growing or antral), or any detectable pathological change in ovarian cells (Hoyer et al. Pairs of 40 control and 20 treated mice were housed together and allowed to produce up to five litters, the last of which was reared and their reproductive performance measured. Significant reproductive toxicity was observed at the intermediate and high doses. At the intermediate dose, the proportions of pairs producing one to five litters were 100, 89, 84, 68 and 36%, the percentages producing second to fifth litters being significantly smaller than in controls. The decrease at the high dose was more severe, only 5% of pairs producing a fifth litter. Overall, the mean number of litters per pair was reduced by 24 and 50% at the inter- mediate and high doses, and the number of pups per litter decreased by 58–59%. Cross-over breeding of animals at the inter- mediate dose with controls showed that the fertility of the females was affected, the litter sizes being reduced to half. Breeding of the F1 offspring at the intermediate dose with controls showed that treatment halved the number of litters and the litter size. Examination of F0 males at the intermediate dose showed a reduction in testis weight by 36% and in the epididymal sperm count by 30%, and seminiferous tubular degeneration was seen in 9 of 10 treated males. The oestrous cycles and ovarian histology of females at this dose were not affected. After 13 weeks of exposure to the same doses as used in the studies of toxicity, there was no evidence of reproductive toxicity in female B6C3F1 mice or male or female Fischer 344/N rats. Lower epididymal weights and lower sperm density (number of sperm/g of crude epididymal tissue) were observed in male mice at 12 000, 25 000 and 50 000 mg/kg (National Toxicology Program, 1996). Phenolphthalein did not induce sister chromatid exchange in Chinese hamster ovary cells in the presence or absence of exogenous metabolic activation, but it induced a dose-related response in chromosomal aberrations in these cells only in the presence of exogenous metabolic activation. In experiments in which a number of end-points were studied in Syrian hamster embryo cells (a mixed population of cell types that retain some endogenous metabo- lizing enzymic activity, including oxidation and peroxidation), phenolphthalein induced chromosomal aberrations and Hprt mutations, but not ouabain mutations or aneuploidy. Phenolphthalein caused cellular transformation in the same cell line, indicating that it is metabolized appropriately in this system. They found significant increases in the frequency of micronucleated ery- throcytes, most of which appeared to arise from whole chromosomes rather than chromosomal damage; these were observed at doses comparable to those to which humans are exposed. In phenolphthalein-induced thymic lymphomas in B6C3F1 mice, p53 protein accumulated in most tumour cell nuclei, but detectable p53 protein was not seen in control thymuses in this model (Dunnick et al. Other studies have shown that accumulation of p53 protein results from p53 gene alterations (Hegi et al. In p53+/– heterozygous mice, phenolphthalein induced atypical hyperplasia and malignant lymphomas of thymic origin within six months in 0% of controls, 5% of animals at 200 mg/kg, 5% at 375 mg/kg, 25% at 750 mg/kg, 100% at 3000 mg/kg and Table 5. Two of two thymic lymphomas examined from animals at 750 mg/kg, 13/13 from those at 3000 mg/kg and 6/6 from those at 12 000 mg/kg had lost the remaining p53 wild-type allele (Dunnick et al. No spontaneous thymic lymphomas were found in control mice in these studies, but in other studies in p53+/– mice of spontaneous tumours (which may occur in mice after one year of age), only 55% showed loss of the remaining functional p53 allele (Harvey et al. When this protein is absent, as is the case in phenolphthalein-induced thymic lym- phomas, regulation of cell cycle electrophoresis is lost and malignant progression may be enhanced. Generally available without prescription, it is now being withdrawn from the market in many countries because of recent toxicological concern. Phenolphthalein has also long been used in the laboratory as an indicator in acid–base titrations. In one experiment in mice, it induced histiocytic sarcomas and lymphomas in both males and females and benign ovarian tumours in females. In an experiment in mice lacking one allele of the p53 tumour suppressor gene, it increased the incidence of lymphomas. It induced benign renal tumours in male rats and benign phaeochromocytomas in males and females. As it passes through the small intestine, it is partially deconjugated and reabsorbed. Phenolphthalein and its glucuronide enhance oxygen radical production and cause oxidative damage in vitro. Phenolphthalein has also been shown to have low oestrogenic activity in some model systems. Phenolphthalein induced micronucleated erythrocytes in mice given multiple but not single treatments by gavage or in feed. Abnormal spermatozoa were induced in male mice but not male rats treated with phenolphthalein in the feed for 13 weeks. The malignant thymic lymphomas induced by phenolphthalein in female heterozygous p53-deficient mice showed loss of the normal p53 allele. Phenolphthalein induced chromosomal aberrations, Hprt gene mutations and morphological transformation but not aneuploidy or ouabain-resistant mutations or sister chromatid exchange in cultured mammalian cells. There is sufficient evidence in experimental animals for the carcinogenicity of phenolphthalein. Biphenyl, stilboestrol and phenolphthalein in the rat: Molecular weight, polarity and meta- bolism as factors in biliary excretion. The Metabolism and Detoxication of Drugs, Toxic Substances and Other Organic Compounds, 2nd Ed. The K vitamins all contain the 2-methyl-1,4-naphthoquinone (menadione) moiety, and the various naturally occurring forms differ in the alkyl substituent at the 3-position. Phylloquinone (vitamin K1) is 2-methyl-3-phytyl-1,4-naphthoquinone and is widely found in higher plants, including green leafy vegetables, and in green and blue algae. The menaquinones (formerly vitamin K2) have polyisoprenyl substituents at the 3-position and are produced by bacteria. The compound menadione (formerly vitamin K3) lacks an alkyl group at the 3-position but can be alkylated in vivo in some species. Several synthetic water-soluble derivatives, such as the sodium diphosphate ester of menadiol and the addition product of menadione with sodium bisulfite, also have commercial applications (National Research Council, 1989; Gennaro, 1995; Weber & Rüttimann, 1996). The United States Pharmaco- peia uses the name ‘phytonadione’; The European Pharmacopoeia uses the name ‘phytomenadione’, which is a synonym occasionally found in the pharmaceutical and pharmacological literature. In the biolo- gical literature, vitamin K2 is frequently referred to as menaquinone and is further designated by the number of isoprene units in the side-chain. For example, vitamin K2(20) is also called menaquinone-4 for the four isoprene units in the side-chain. The compound originally isolated from rotting fish meal and named vitamin K2 was later identified as menaquinone-7 (2-methyl-3-farnesylgeranyl-geranyl-1,4-naphthoquinone). In the older literature, the designation vitamin K2(35) is used for menaquinone-7, but this is no longer used. Menaquinones found in nature have side-chains of 4–13 isoprenoid residues and are usually in the all-trans configuration; however, menaquinones with the cis confi- guration and partially saturated side-chains also exist (Suttie, 1985, 1991; Weber & Rüttimann, 1996; Van Arnum, 1998). Phylloquinone occurs in nature only as the 2′,3′-trans-phylloquinone stereoisomer (Weber & Rüttimann, 1996; American Hospital Formulary Service, 1997; Council of Europe, 1997). Phylloquinone is available as a 5- and 10-mg tablet (chewable), a 2- and 10 mg/mL injection solution, a 10- and 20-mg/mL oral solution and a 20-mg/mL emulsion. The tablet may also contain carmellose, carob bean flour, carob gum, cocoa butter, cocoa powder, ethyl cellulose, ethyl vanillin, glucose, glycerol, gum arabic, hard and viscous paraffin, lactose, rice starch, sugar, silicic acid, silicon dioxide, skim- milk powder, sodium cyclamate, talc and titanium dioxide. The injection solution may also contain benzyl alcohol, dextrose, glacial acetic acid, glucose, glycocholic acid, hydrochloric acid, macrogol ricinoleate, phenol, phosphatidylcholine from soya beans, polyethoxylated fatty acid derivative (castor oil), polysorbate 80, propylene glycol, sodium acetate, sodium hydroxide and water. The oral solution may also contain benzoic acid, glycocholic acid, hydrochloric acid, lecithin, macrogol ricino- leate, methyl 4-hydroxybenzoate, propyl 4-hydroxybenzoate, sodium hydroxide and water. Menaquinone-4 is available in Japan as 5- and 15-mg capsules and as a 2-mg/mL syrup. The syrup may also contain polyoxyethylene hydrogenated castor oil 60, propylene glycol, ethyl parahydroxybenzoate, sodium benzoate and flavouring (Japan Medical Products Trade Association, 1996). Trade names for menaquinone-4 include Glakay and Kaytwo (Japan Medical Products Trade Association, 1996). Menadione is available as a 2-, 5- and 10-mg tablet and as a 2- and 10-mg/mL injection (in oil). Menadione sodium bisulfite is available as a 10-mg tablet and as a 5- and 10-mg/mL and 72-mg/10 mL injection (Gennaro, 1985). Trade names for menadione sodium bisulfite include Austrovit-K, Golagen K, Hemoklot, Hetrogen K, Hetrogen K Premix, Hykinone, Ido-K, K-Thrombin, K- Trombina, Kalzon, Kareon, Kavitamin, Kavitan, Kavitol, Kawitan, Klotogen, Libavit K, Nuvit K, Vikaman, Vikasol, Vitaminum K and Zimema K (Swiss Pharmaceutical Society, 1999). Trade names for menadiol sodium phosphate hexahydrate include Kappadione, Kativ (injection), Kipca water soluble, Naphthidone, Procoagulo, Synkavit, Synka- Vit, Synkavite, Synkayvite and Thylokay (Swiss Pharmaceutical Society, 1999). Trade names for acetomenaphthone include Adaprin, Davitamon-K, Davitamon-K- oral, Kapathrom, Kapilin, Kapilon, Kappaxan, Kativ powder, Kayvite, Pafavit, Pro- kayvit Oral and Vitavel K.
Five of 53 evaluable patients (9%) had clonal cytogenetic abnormalities involving chromosomes 1 160mg kamagra super amex erectile dysfunction jackson ms, 9 purchase kamagra super 160mg fast delivery erectile dysfunction age 32, 20 and 21 before treatment discount 160 mg kamagra super protocol for erectile dysfunction, and 15% had these abnormalities at follow-up purchase generic kamagra super line erectile dysfunction in diabetes type 1, during or after hydro- xyurea treatment. Acute leukaemia developed in nine patients and myelo- dysplastic syndrome in one; seven of the leukaemia patients had been treated with hydroxyurea alone. The duration of therapy for patients who developed leukaemia or myelodysplastic syndrome was 5–111 months. Seven of 19 previously untreated patients with initially normal karyotypes treated with hydroxyurea alone developed clonal chro- mosomal abnormalities during therapy (37%). The t(1;20) affected the same region of chromosome 20 as the 20q– abnormality; it could not be determined whether the translocation was related to the treatment. The karyotype was normal at the time of diagnosis of essential thrombocythaemia but revealed del(5)(q23), del(7)(q31), inv(16)(p13;q22),+8 when acute myeloid leukaemia emerged. Reviews on the mutagenicity of anticancer drugs in general, including hydroxy- urea, were provided by Ferguson (1995) and Jackson et al. Ferguson and Denny (1995) commented on some practical issues in testing antimetabolites, which may limit the usefulness (and meaning) of some types of in-vitro assays. In various Saccharomyces cerevisiae strains, hydroxyurea induced mitotic crossing over, mitotic gene conversion, intra- chromosomal recombination and aneuploidy, but not ‘petite’ mutations. In meiotic yeast cells, hydroxyurea increased the frequency of meiotic recombination. Hydroxyurea caused chromosomal aberrations in cultured Chinese hamster cells, in mouse cells and in various human cell lines. Karon and Benedict (1972) found that hydroxyurea induced chromosomal aberrations when given during S phase but not when given during G2 phase. It did not induce micronuclei in human peripheral blood lymphocytes but increased the frequency of sister chromatid exchange and of gene Table 3. Hydroxyurea induced sister chro- matid exchange in various Chinese hamster cell lines in vitro. Although hydroxyurea alone did not induce morpho- logical transformation in Syrian hamster embryo cells, the cell cycle arrest caused by the drug led to enhancement of cell transformation by bromodeoxyuridine (Tsutsui et al. Hydroxyurea did not enhance metabolic cooperation between V79 cells (Toraason et al. These effects may indicate an enhanced effect on chromosomal damage in certain situations in vivo. Although hydroxyurea is a mutagen in somatic cells, there is no evidence that it mutates germ cells. It did not induce chromosomal damage in spermatogonial cells of male Swiss mice, although it enhanced damage induced by X-rays. Hydroxy- urea had a synergistic effect on ultraviolet-induced sister chromatid exchange (Ishii & Bender, 1980) and enhanced X-radiation-induced damage in spermatogonial cells of Swiss mice (van Buul & Bootsma, 1994). The differences in the results of various studies may depend on the exact cell culture conditions, especially in regard to the amounts of deoxyribonucleotides available. In a number of experiments, hydroxyurea appeared to enhance the susceptibility of cells to mutagenesis by other agents (e. It halts the progression of cells in the late G1 phase of the cycle, allowing synchronization of the culture (e. Thus, if cells are sensi- tive to a certain agent in a particular phase of the cell cycle, hydroxyurea may reveal this effect. Prempree and Merz (1969) suggested that hydroxyurea could inhibit the repair of chromosomal breaks without itself inducing breaks. Hydroxyurea is sometimes used for the treatment of psoriasis and various solid tumours. Overall, 5–6% of patients developed either acute leukaemia or myelodysplastic syndrome subsequent to the start of hydroxyurea treatment. Large variation in the length of active follow-up was not taken into account in the analyses. The risk for leukaemia in patients with chronic myeloproliferative disorders who were not treated with hydroxyurea or other agents (e. The available data do not allow a conclusion about whether the occurrence of acute leukaemia and myelodysplastic syndrome in the hydroxyurea-treated patients represents progression of the myeloproliferative process or an effect of the treatment. In one study, 35% of an administered dose was excreted unchanged in the urine of humans. Hydroxyurea is teratogenic and causes postnatal behavioural deficits after prenatal exposure in all species of animals in which it has been tested. It has commonly been used as positive control substance in studies of developmental toxicity. In one study of patients treated with hydroxyurea for essential thrombocythaemia who developed leukaemia, a statistically non-significant association was found with a 17p chromosomal deletion in leukaemic cells. Hydroxyurea does not induce gene mutation in bacteria and does not cause mutation at the Hprt locus in mammalian cells. It causes chromosomal mutations and mutagenic effects at the Tk locus in mouse lymphoma cells. It is an effective recombinogen in yeast and induces sister chromatid exchange in mammalian cells. It also causes gene amplification in mammalian cells and may lead to transformation of some but not all cell lines. Although it has been reported to be ineffective in causing germ-cell mutation, it has not been extensively tested for that end-point. There is inadequate evidence in experimental animals for the carcinogenicity of hydroxyurea. Comparison of the embryotoxic and teratogenic effects following single intraperitoneal or repeated oral administrations to pregnant rats. Modification of hydroxyurea-induced teratogenesis by the antioxidant propyl gallate. An analysis of three new cases of leukaemic transformation and review of the literature. The tablets may also contain aloin, aspartame, bile salts, butylparaben, cascara sagrada, cascara sagrada extract, corn starch, cocoa butter, cocoa paste from cocoa seeds, colourants (D&C Yellow No. The capsule may also contain dehydrocholic acid, docusate calcium, ethanol, parabens, povidone and sorbitol. In the manufacture of phenolphthalein, a stage is reached in which certain by- products formed in the synthesis have not yet been removed, resulting in a product called yellow phenolphthalein. Compounds isolated from one sample of yellow phenolphthalein were: white phenolphthalein, 93%; fluoran, 0. Trade names for phenolphthalein include Alophen Pills, Ap-La-Day, Bonomint, Brooklax, Caolax N. Trade names for phenolphthalein that have been discontinued include Alophen, Bom-Bon, Confetto, Euchessina, Fructine-Vichy, Koprol, Laxatone, Laxogen, Neo- purghes, Phthalin, Prunetta, Purgen, Purgestol, Spulmako-lax and Trilax. Trade names for multi-ingredient preparations of phenolphthalein include Abfuhr- dragees, Agarol, Agoral, Aid-Lax, Alofedina, Alophen, Alsiline, Bicholate, Calcium Docuphen, Caroid, Carter Petites Pilules, Carters, Carters Little Pills, Cholasyn, Colax, Damalax, Dialose Plus, Disolan, Docucal-P, Doulax, Doxidan, Emuliquen Laxante, Evac-Q-Kwik, Ex-Lax Extra Gentle Pills, Ex-Lax Light, Falqui, Fam-Lax, Feen-a-mint Pills, Femilax, Ford Pills, Grains de Vals, Herbalax Forte, Juno Junipah, Kest, Kondremul with Phenolphthalein, Laxa, Laxante Bescansa, Laxante Bescansa Aloico, Laxante Olan, Laxante Salud, Laxarol, Laxo Vian, Le 100 B, Lipograsil, Mackenzies Menthoids, Mahiou, Modane Plus, Mucinum, Nylax, Obstinol, Paragar, Paragol, Petrolagar No. Trade names for preparations containing phenolphthalein which have been dis- continued include Agarbil, Amaro Lassativo, Bilagar, Boldolaxine, Boldolaxine Aloes, Confetti Lassativi, Confetto Complex, Correctol, Crisolax, Dietaid, Dragées 19, Emulsione Lassativa, Flamlax, Lactolaxine, Lax-Lorenz, Laxante Geve, Laxante Richelet, Laxativum, Laxicaps, Medimonth, Ormobyl, Pillole Lassative Aicardi, Pillole Schias, Pluribase, Reolina, Rim and Verecolene Complesso. Several methods for the analysis of phenolphthalein in various matrices have been reported, which include spectrophotometric, titrimetric, polarographic and chromato- graphic methods. The chromatographic methods include paper, gas, thin-layer and high-performance liquid chromatography (Al-Shammary et al. The laxative effect of phenolphthalein was discovered in 1902, and it has been widely used since that time (Mvros et al. It usually has an effect within 4–8 h after oral administration, generally in tablets or capsules; it is also available as an emulsion with liquid paraffin. The usual oral laxative dose of phenolphthalein (white or yellow) is 30–200 mg daily taken at bedtime for adults and children aged ≥ 12 years (270 mg should not be exceeded); 30–60 mg daily for children aged 6–11 years; and 15–30 mg daily for children aged 2–5 years, given as a single or divided doses. A dose of 260 mg has been used in regimens for bowel evacuation (American Hospital Formulary Service, 1997; Royal Pharmaceutical Society of Great Britain, 1999). The use of laxatives to relieve constipation and to maintain regularity in bowel habits is common in western cultures. The two groups in North Carolina comprised subjects aged 30–89 years, 58% and 53% of whom were female; the group in California comprised subjects aged 50–74 years of whom 34% were female. In the two studies in North Carolina, 18% of case subjects and 25% of controls reported ever having used phenolphthalein laxatives, and 10% of cases and 7% of controls had used them at least once a month (Longnecker et al. Phenolphthalein in a 1% alcoholic solution is also used as a visual indicator in titrations of mineral and organic acids and most alkalis. After the publication in 1996 of the results of studies in rodents indicating that phenolphthalein was carcinogenic and genotoxic in several test systems, with damage (loss) of the p53 tumour suppressor gene (Food & Drug Administration, 1999), many countries moved to restrict over-the-counter sales of phenolphthalein-containing laxa- tives. Canada has suspended the sale of all products containing phenolphthalein (Canadian Pharmacists Association, 1999). The German Federal Institute for Drugs and Medical Devices recommended that holders of authorizations to market phenol- phthalein-containing laxative products withdraw their products from the market because of the potential toxicological risks. The Food and Drug Administration (1999) issued a final rule establishing that phenolphthalein is not generally recognized as safe and effective. Studies of Cancer in Humans Studies of the association between colorectal neoplasia and use of phenol- phthalein-containing laxatives are summarized in Table 1. Poten- tially eligible controls were selected by stratified random sampling of subjects in house- holds identified by random-digit dialling, to approximate the distribution by age, sex and county of residence of the case subjects. Data on laxative use were obtained by telephone interview, and subjects were also asked to complete a mailed food frequency questionnaire. The relative risk for colon cancer associated with up to 349 lifetime uses of phenolphthalein-containing laxatives compared with no regular use was 1. Frequent constipation during the 10 years before the reference date (two years before diagnosis) was associated with an increased risk for colon cancer (4. When constipation and commercial laxative use were adjusted for mutually, the association with commercial laxative use was no longer apparent, whereas the association with constipation persisted (2.
Proper design of package and labelling of drugs is one of the ways to eliminate most of the risks associated with medication errors occurring on all stages of drug turnover: in pharmacies buy generic kamagra super line can erectile dysfunction cause low sperm count, warehouses kamagra super 160mg visa erectile dysfunction treatment following radical prostatectomy, hospitals order kamagra super 160 mg online erectile dysfunction books download free, patient‘s home purchase kamagra super discount erectile dysfunction treatment spray. Most of the abovementioned recommendations are not mandatory yet, but in future they should be guidance for designers, manufacturers and authorized bodies to establish standardized rules to the package design that can strongly influence on the safe use of drugs. Medicinal immunobiological preparations and, in particular, vaccines, serums, anatoxin, antigens, etc. Great range of different equipment and system types has been developed for their transportation and storage. There are a lot of manuals and guidelines concerning their proper use, because it‘s very responsible process. Transporting, storage and handling errors can cost thousands of dollars in wasted vaccine and need for revaccination. Errors can also result in the loss of patient confidence when repeat doses are required Aim. The objective of the present article is study of conditions for transportation of immunobiological preparations, in particular vaccines, in cold chain system. In the present study different information data sources including normative documentation concerning principles and methods of transportation of immunobiological preparations have been analyzed. To maintain appropriate storage and transportation conditions for vaccines from manufacturer to medical or pharmaceutical institutions there should be used cold chain system consisting of: - personnel providing medical aid and refrigerating machinery services; - procedures used to control distribution and use of vaccines; - equipment itself which should conform the requirements for safe storage eliminating dependence on environment and various surrounding factors. To protect vaccines one should use thermocontainers and portable transferring bags where special cards-indicators & freeze indicators are placed into, providing necessary control over regimens of transportation. Thermocontainers as well as transferring bags have a cover tightly closing them, and also they have heat-insulating properties, the difference is only in that transferring bag is much less in its sizes. Charging of thermocontainers with preparations is carried out in fridge storage rooms (premises for vaccine storage) or under exceptional situations at ambient temperature if duration of charging does not exceed 10 minutes. Onto 306 a box for vaccines, anatoxins, tubercular allergen which do not allow freezing a label with inscriptions ―Vaccine! On the 1st and 2nd levels of transportation of immunobiological preparations from a manufacturer to a wholesale storage warehouse on large distances during 1–3 days it‘s necessary to use refrigerator transport vehicles with temperature from +2 to +8°С. On the 2nd level an authorized person should have coordinated supply schedule of immunobiological preparations to the 3rd level and should supervise their remaining shelf-life which should be not less than 1 month at the moment of shipment. Transporting from the 3rd to the 4th level (to treatment-prophylactic establishments) is carried out in thermocontainers. At obtaining of vaccines, anatoxins, tubercular allergen they should be immediately placed into refrigerating machinery and indications of control means should be checked. Important parameter during transportation and storage of immunobiological preparations is duration of cold preservation inside equipment which is defined by time during which this equipment preserves temperature not above +10 °С. There are some factors which this time depends on: - type of a portable transferring bag, materials of which it is produced, thickness of its walls; - temperature under which a cooling element has been placed into a container, and also weight of a vaccine; - exposure time when a container was kept opened; - environment, namely air temperature. The complete set of the equipment for transportation of immunobiological preparations includes refrigerating elements (packets). For temperature maintenance within range from 0 to +8 ºС also such frozen cooling packets are used. During transportation in deep-freezer it‘s necessary to keep the second complete set of refrigerating elements and while the first complete set is used, the second one should be kept in frozen state. Vaccines must be transported and stored properly under cold chain from the time they are manufactured until they are administered. Rapid development of pharmaceutical industry during recent years undoubtedly influenced package-producing industry. Today the latter is highly automated manufacturing of modern, attractively designed original packages. Development and introduction of new kinds of materials and technologies allow to implement advanced types of packages which design provides necessary consumer properties: to be convenient in transporting and use, to contain information about medical product, to have attractive appearance, etc. The objective of the given paper is study of consumer properties of pediatric oral drugs. As materials of the research we use information taken from normative documents, scientific and educational literature, and also Internet sources. For packages of medical products applied in pediatrics there should be more strict requirements as well as for materials used in production of containers especially for primary packages and their design because children should get only the best. Hence, to reduce danger of child self-poisoning there is a challenge for elaboration of such package types which would complicate availability of a drug to a child. So, in number of European countries there are new requirements for packages of medical products according to which they should have protective devices preventing their opening by children. Review of patent materials shows that leading countries of the world pay great attention to this question: more than 37 % of overall quantity of patents directed to creation of new containers and packages which prevent their opening by children. Child poisonings by overdosing of medical products after their administration at home when they are dispensed with tea or table spoon are observed. Therefore creation of special portioning devices and their wide introduction in practice is an important task. So, auxiliary means (special measuring spoon, measuring reservoir, piston dispenser, etc. Conveniently and simply is always important when it concerns administration 308 of a drug by a child. And it means that dosage form of a medical product should be adapted for children as much as possible. Abovementioned requirements can be considered on an example of Nurofen drug for children which is very popular among parents. The drug quickly reduces fever, eliminates pains of various origin and simultaneously it is standard of simplicity in use. Not a treatment but true delicacy as the syrup is manufactured with taste of orange and strawberry. One more advantage – convenient measuring syringe is attached to the package that allows to calculate necessary quantity of the drug precisely. As though it would be desirable, that all manufacturers of drugs for children in such manner will care of comfort for both child and adult. Dosing devices should have attractive, not frightening appearance, and an instruction for application (leaflet) of a given medical product should contain all necessary information about calibration and usage of a dispenser that young patients will necessarily appreciate. One of the most important requirements shown to closure means for pharmaceuticals of pediatric group is control of their dosing and protection against casual opening. Namely this should be a priority direction in development and creation of closure means and new kinds of packages. It has been developed the device with passive resistance to flow of liquid pediatric dosage forms and also the package of such dosage forms containing single dose. Proceeding from the aforementioned, it is possible to make a conclusion that, speaking about new tendencies in development of package- producing industry, it is impossible to skip a problem of drugs applied in pediatrics. The given medical products require more serious and attentive approach for proper dispensing, high-quality package and rationally designed marking, because children are the most trustful but also the most exacting patients. The structure the lip skin differs from the rest of the skin: due to the large amount of nerve endings they are more sensitive, lips have lack of oil glands and melanin and thin epidermis. That is why the lips are sensitive to external climatic factors (cold, dry air, wind, etc. The aim of the study was to streamline the classification and study the pharmacy range of lip care products that are on the market of Ukraine. During our study analysis of the current literature concerning existing classification and characteristics of lip care products was conducted. Also, during the study methods of semantic analysis and hierarchical classification were used. The range of modern lip care products that are sold through drugstores are hygienic lipsticks, lip balms and creams. Тайсс Натурварен Гмбх» (Germany), «Nature House» (Italy), «Laino», «La Roche», «Vichy», «Uriage Bariederm» , «Сaudalie» (France), Apivita (Greece), etc. Lip creams are presented by «Сaudalie», «Bioderma», «Vichy» (France), Apivita (Greece). Into a separate group can be identified child lip care products («Біокон», «Красота и здоровье», «Моя Прелесть» (Ukraine), Apivita (Greece)), and also lip care for men («Биокон», «Фармаком», «Красота и здоровье» (Ukraine)). The main active ingredient in the composition of lipcare products are mineral and vegetable oils (castor, coconut, almond, sea buckthorn, avocado, jojoba, shea), natural and synthetic waxes. As the bioactive components added vitamins A, E, F and B group, that have regenerating effect, prevent cracking, inflammation. Due to information above, we can conclude that Ukraine market has a wide range lipcare products of hygienic and preventive action. At present, the range of cosmetic products is actively expanding and adding new manufacturers and products. Studying of consumer properties of certain skincare products in the form of sponges from the Asian plant roots. The object of the study was konjac sponge for washing, made of the root of the Asian plant Amorphophallus konjac. Amorphophallus konjac is considered a dietary product and is a vegetarian substitute for gelatin, from it in Asia cook desserts and jellies. Konjac is 97% of water, filled with minerals, thus having an ideal environment pH, which has a positive effect on the skin. That is why in Japan, China and Korea for many years, it is used in the beauty industry and medicine. In the analysis of the range it has been found that this type of sponges is available in different shapes and colors. The color depends on the sponge‘s components that manufacturers add to provide certain cosmetic effect. This plant contains a lot of minerals, vitamins and amino acids, which have a positive effect on the condition of the skin, smoothing out its defects and nourishing with necessary substances.