In 2003 purchase rivastigimine 4.5mg free shipping treatment 4 burns, the Mashelkar Report raised concerns with Indian states’ uneven implementa- tion of drug regulations (Government of India proven rivastigimine 3mg treatment vaginitis, 2003) purchase rivastigimine discount medicine 2016. More recent testing and sampling confrms that drug quality is still more reliable in states with stricter regulations (Bate et al. Lack of Awareness and Action As Chapter 3 explains, there is a dearth of reliable estimates of the scope of the problem of falsifed and substandard medicines. Without a clear picture of the extent of the problem, which products are compro- mised, and where the products surface, it is diffcult to develop an appropri- ate prevention strategy and monitor progress. An insuffcient understanding of the scope of the problem also contributes to a lack of awareness about substandard and falsifed drugs among health workers and the general population. Increasing public awareness will not in and of itself decrease falsifed and substandard medicines, because consumers cannot distinguish safe and unsafe medicine in the marketplace. However, public awareness is a useful way to drive political will for correcting the problem and to edu- cate people on warning signs of compromised medicines. Uneven Awareness Starting in the early 2000s, medicines counterfeiting (as it was then called) has been the topic of some media attention. A 2010 Gallup poll in sub-Saharan African countries found that the majority of the public in 15 of the 17 countries surveyed were aware that fake medicines were a problem (see Table 4-8) (Ogisi, 2011). The leadership of drugs regulators in Nigeria, one of the largest and most infuential African countries, might have contributed to the public consciousness in Africa (see Box 4-7). More recently, Interpol launched an awareness campaign featuring South Africa’s Yvonne Chaka Chaka and Senegal’s Youssou N’Dour, two of the continent’s biggest ce- lebrities (Interpol, 2011). Other research suggests gaps in awareness, especially among the poor- est people in society. A qualitative study of Sudanese policy makers and pharmacists suggested that awareness of counterfeit products is lowest Copyright © National Academy of Sciences. By fake medicine, we mean a product that looks like the real one but doesn’t provide the same efect and could even have bad side efects. Participants at overseas site visits for this study mentioned similar patterns in many developing countries. Often, well-educated urban consumers un- derstand the threat of fake drugs and take precautions to avoid them. The poorest patients, and those living in areas with few to no reliable pharma- cies, are often the least aware. Moreover, as Chapter 5 will discuss, they often have no choice but to buy medicines in the open market or have no money to buy from a registered pharmacy. It is not clear how well informed populations in other parts of the Copyright © National Academy of Sciences. The success of this program may account for Nigerians’ high (83 percent) awareness of the problem (Ogisi, 2011). The agency broadcast short public service announcements on television and radio in English and local languages. The piece ends with the villain arrested at gunpoint to voiceover assurance of the agency’s commitment to protect the Nigerian public. Other pieces of the public awareness campaign intended to change consumer behavior (Akunyili, 2005). The regulators reasoned that if consumers were informed about falsifed medicines and empowered to make safe choices, they would. To this end, they published lists of known fake products and photos illustrating warning signs in daily newspapers (Akunyili, 2006; Raufu, 2006). Since 2002, the agency has sponsored an es- say contest on medicine safety for students, awarding cash prizes to the winners and computers to their schools (Akunyili, 2006). People in developed coun- tries, who have long taken medicines regulation for granted, are among the least knowledgeable. An Inter-Press Service story reported that 20 percent of Western Europeans did not consider it dangerous to circumvent traditional pharmacies to buy medicine (Stracansky, 2010). The same be- havior has long been normal in the United States, where pharmacy tourism to Canada and Mexico has been common since the 1970s (Rabinovitch, 2005). Chapter 5 will discuss the internet pharmacies that have largely replaced in-person cross-border shopping. Public Action Educating the public on the problems of falsifed and substandard medicines is important, but only insomuch as education empowers people to act. The reasons they gave included doubt that the regulator would act on their information and fear of litigation. Similar attitudes may underlie a lack of reporting of adverse drug reac- tions among health workers in developing countries. Their role in surveil- lance is important in low- and middle-income countries, where falsifed and substandard drugs are common, and less than 27 percent have func- tional pharmacovigilance systems (Pirmohamed et al. Few staff are trained in pharmacovigilance, a practice sometimes seen as adding to the responsibilities of already overworked health professionals (Olsson et al. The increasing awareness of falsifed and substandard medicines could drive improved pharmacovigilance in developing countries. Awareness cam- paigns and investigative reporting reach health workers as well as they reach the rest of the public. There is also a need for targeted health worker education on falsifed and substandard medicines, emphasizing the correct reporting channels health workers can use to confrm suspected cases of falsifed and substandard drugs. Much useful work has been done on the frst steps of this process; clinicians struggling to broach the topic with their patients can consult the World Health Professionals Alliance guidelines on how to inquire about suspicious medicines (see Box 4-8). Chapter 3 describes governments’ and drug companies’ reluctance to share information on substandard and falsifed drugs (Cockburn et al. Pharmaceutical companies fear damage to their branding from Copyright © National Academy of Sciences. Emphasis can be placed on the importance of buying medicine from a pharmacy or other known and reliable sources. It can be suggested that patients check the packaging, the product, and the patient leafet when they purchase medicine. For example: “Was the packaging of the product intact, properly sealed, clearly labeled with dosing, manufacturer, batch number, and expiry date? By explaining what should happen when patients take medicine, health professionals can help patients identify anything unusual. If a medicine is supposed to start relieving symptoms within 24 hours, for example, then patients should know, so that if the medicine does not take efect, then can notify their health professional. These concerns are well grounded, and an appropriate communication strategy will convey accurate information is a way that is sensitive to all stakehold- ers. Falsifed and substandard medicine is a sensitive and dynamic problem, and the public has a right to accurate information about it. This informa- tion can be presented in such a way as to empower the consumer to make safe choices and to build confdence in the regulatory system.
While performing the former order rivastigimine 4.5mg symptoms nausea fatigue, a normal gene is introduced into the cell type to replace activity of the defective gene (4) order rivastigimine pills in toronto medications peripheral neuropathy. Whether one performs ex vivo or in vivo gene therapy 6 mg rivastigimine sale treatment example, important focal points are duration of expression of the gene or therapeutic protein and speciﬁcity in deliv- ering the gene to the site of action with minimal adverse effects (1–3). Currently, genes packaged in viral vectors, such as retrovirus, adenovirus, adeno-associated virus, and herpes simplex virus, remain the leading therapeutic candidates for gene therapy, as they have produced functional improvements in several animal models of previously mentioned genetic diseased states. However, because of the risk fac- tors (pathogenicity, immunogenicity) associated with viral vectors, a major empha- sis has been placed on the formulation of nanoparticulate drug delivery vehicles for gene delivery (3). The term “nanometer” in the metric scale of linear measurement refers to one- billionth of a meter. According to National Nanotechnology Initiative, nanotechnol- ogy is deﬁned as research and technology resulting in “the controlled creation and usage” of unique small particles, varying from 1 to 100 nm in length. Looking at the biological systems, it is evident that they are composed of inherent “nanoblocks. This chapter focuses on the formulation of nanoparticulate drug delivery systems for gene delivery. The gene-loaded gold nanoparticles target the cells at a critical velocity that can puncture the cell membrane, and ultimately release the genes into the cell nucleus (9). This method, which involves physical transfer of genes, has the potential to replace the traditional transfection techniques characterized by dismal efﬁciency rates and immunotoxicity (9). It is to be noted, however, that original gene gun suffers from lack of precision and can crush the cells due to “sticking of gold par- ticles (pit damage)”. To overcome these pitfalls, Pui and Chen’s laboratory, at Uni- versity of Minnesota, devised a similar gene gun by using the patented technique called “continuous gene transfection” (9). As reported by Pui and Chen, the gold particle–coated gene composite is loaded into a capillary with the help of a syringe. The applied electric ﬁeld forces the gene suspension or spray out of the capillary at a constant velocity. The suspension is a complex mixture of “highly charged and dispersed gene-coated particles” (9). As mentioned before, the unusually high repelling velocity of similarly charged particles tear the cell membrane and “unload the genes into the cells” (9). Also, there is reduced or no risk of immunotoxicity and the cells can be transfected with plasmids as often as desired. Another added advantage is the possibility of incorporating multiple genes encoded by different plasmids (10). The potential problem of nons- electivity can be addressed by tagging the gold particles with speciﬁc antibodies. However, translat- ing this potential into reality is difﬁcult, as it is extremely tricky to deliver these short nucleotides to the site of action without degradation. Although, in nascent stage, polycation-based gene delivery shows promise in vitro and in vivo studies. However, these systems usually suffer from low sol- ubility and poor bioavailability (8). To circumvent these problems, scientists have developed a new class of nanoparticulate-based drug delivery systems known as nanocochleates (13). Originally developed by Papahadjopoulos in 1974 as an inter- mediate in the preparation of large unilamellar vesicles, the modiﬁed versions of nanocochleates (diameter range, 30–100 nm) are stable drug delivery vehicles for gene and drug delivery whose structure and properties differ enormously from those of liposomes (13). It comprises a puriﬁed calcium (or any other divalent cation, such as zinc, magnesium, or barium)–soy-based phospholipid, with lipids accounting for three- fourths of the weight. Different lipids that make up the nanocochleates include phosphotidyl serine, dioleoylphosphatidylserine, phosphatidic acid, phosphatidy- linositol, phosphatidyl glycerol, phosphatidyl choline, phosphatidylethanolamine, diphosphotidylglycerol, dioleoyl phosphatidic acid, distearoyl phosphatidylser- ine, and dimyristoyl phosphatidylserine, dipalmitoyl phosphatidylgycerol, or a mixture of one or more of these (13). Scanning electron microscopy reveals that nanocochleates have a unique solid lipid bilayer structure folded into a sheet and devoid of any aqueous internal space unlike a typical phospholipid (13). The divalent cations maintain the sheet structure by electrostatic interaction of its positive charge with the negatively charged lipid head groups in the bilayer (13). Nanocochleates can be formulated by any of the following techniques: hydrogel method, trapping method, liposomes before cochleates dialysis method, direct calcium dialysis method, or binary aqueous–aqueous emulsion system (13). The unique structure (which is extremely stable) protects the associated or encochleated drug or nucleotides from harsh conditions, enzymes, and digestion in the stomach (13). This feature also makes them an ideal vehicle for the oral and systemic delivery of drugs and polynucleotides, with the possibility of increasing oral bioavailibity of the delivered species such as drugs or genes (13). However, a major impediment in using them in vivo stems from their tendency to agglomerate or dissociate when challenged with salt and serum (14). Using biocompatible and biodegradable polymeric micelles as drug or gene deliv- ery vehicles can solve this problem. Amphiphilic block copolymers organize into “micelles of mesogenic size in aqueous milieu owing to differences in solubility between hydrophobic and hydrophilic segments” (15). These copolymer micelles can be differentiated from surfactant micelles in that they have low critical micelle concentration and low dissociation constants (15). These features enhance the reten- tion time of drugs or genes in polymeric micelles, ultimately “loading a higher concentration of genes into the target sites” (15). The polymeric entity is a copolymer containing two hydrophilic groups, one neutral and other charged. Block ionomer complex between poly(ethylene oxide)-[b]-polymethacrylate anions and cetylpyridinium cations produce nanoparticles in the size range from 30 to 40 nm (8). Despite neutralization of the charges of the polyion and the surfactant, this complex is soluble and stable, unlike the regular polyelectrolyte– surfactant complexes that are usually water insoluble. Researchers have demonstrated increased stability, transport, and efﬁciency of antisense oligonucleotides both in vitro and vivo, using cationic copolymers as gene-delivering vehicles (8). For example, Professor Sayon Roy (Boston University) demonstrated the reduction of ﬁbronectin expres- sion by intravitreal administration of antisense oligonucleotides, using block ionomer complexes (8). Nanogels represent miniature hydrogel particles that were formulated by using an emulsiﬁcation/solvent evaporation technique by chemically cross- linking polyethyleneimine with double-end–activated poly(ethylene oxide) (7,8,16). Polynuceotides can be easily entrapped in this system by mixing with nanogel sus- pensions. Oligonucleotide-loaded nanogel particles are small (<100 nm in diam- eter), stable in aqueous dispersions, show no agglomeration with time, cross the intestinal cell layers, and affect gene transcription in a sequence-speciﬁc manner (8,16). The nanogels form a protective coating around the oligonucleotides and pre- vent their degradation. They are composed of three func- tional units: the inner core, the internal shell containing the repetitive units, and the terminal functional groups (18). They can be synthesized by divergent approach (starting from the central core and proceeding toward the outermost periphery), a reverse convergent approach, or by covalent attachment or self-assembly of dendrons (18,19). Apparent similarities of dendrimer architecture with “rigidiﬁed micelles” make them attractive candidates for drug and gene delivery. Smaller drug moieties can be encapsulated in the inner core, whereas oligonucleotides can form complex with cationic surface groups (19). The drug is dissolved or encapsulated or attached to the nanoparticles and, depending on the methods used for preparation, one can get nanospheres, nanocapsules, or aquasomes (16).
Many effective cationic lipids contain protonatable polyamines linked to dialkyl or cholesterol anchors order rivastigimine 1.5 mg on-line treatment zona. To increase the biodegradability of cationic lipids purchase cheap rivastigimine on line medicine interactions, a series of cationic lipids have been synthesized in which the ether bonds were replaced with ester bonds order 6mg rivastigimine with mastercard treatment brachioradial pruritus. Cationic lipid-based gene delivery systems lack target specificity, which results in low transfection efficiency in certain tissues due to the interference from cationic lipid-binding macromolecules either in the circulation or in the extracellular matrix. To circumvent this problem, neutral plasmid/lipospermine complexes containing a trigalactolipid have been prepared and shown to efficiently transfect hepatoma HepG2 cells bearing asialoglycoprotein receptor. Addition of 25% (mol mol−1) of the triantennary galactolipid increased the transfection efficiency by a thousand fold, compared to the lipid-based system with no targeting ligand. An efficient transfection of β-galactosidase into HeLa cells has been shown with the combination of transferrin and cationic liposome Lipofectin, whereas Lipofectin alone had low transfection efficiency. Asialofetuin is an asialoglycoprotein containing terminal galactosyl residues that have been used to target liposomes to the liver. The resulting complexes retain their ability to interact specifically with target cell receptors, leading to receptor-mediated internalization of the complex into the cells. It is known that the active sites of enzymes, receptor ligands and antibodies usually involve about 5 to 20 amino acids. One example of such a gene delivery system comprises: 343 • a galactosylated peptide that both condenses the plasmid into monodisperse nanoparticles of about 100 nm in diameter and enables specific recognition and binding to asialoglycoprotein receptors; • an amphipathic, pH-selective peptide that enables the plasmid to leave the endosomes prior to their fusion with lysosomes and entry into the cytoplasm. Two general classes of lipopeptide analogs of Tyr-Lys-Ala-Lys -n Trp-Lys peptides have been prepared by including a hydrophobic anchor. The general structures are N, N- dialkyl-Gly-Tyr-Lys-Ala-Lys -Trp-Lys and N ,N -diacyl-Lys-Lys -Trp-Lys. These peptides differ from theα n n parent structures in that they self-associate to form micelles in aqueous solutions. The lytic characteristics are revealed as the carboxyl groups of the aspartyl and glutamyl side chains are protonated, which allows the peptides to assume a a-helical conformation that can be inserted into the membrane bilayer. The hydrophobic face contains only strongly apolar amino acids, while negatively charged glutamic acid residues dominate the hydrophilic face at physiological pH. At a given charge ratio of condensing peptide to plasmid, the transfection efficiency has been shown to be proportional to the concentration of the endosomolytic peptide added to the complex. The increased hydrophobicity of the complex may enhance interaction with cell membranes and facilitate cell uptake. However, these polymers cannot be used for in vivo application due to their poor transfection efficiency and high cytotoxicity. The effect of colloidal and surface characteristics of plasmid/ dendrimer complexes on gene transfer has been examined. These complexes were monodisperse, with a mean hydrodynamic diameter of about 200 nm. The particle size, surface charge and gene transfer efficiency of plasmid/dendrimer complexes prepared with the 5th generation of dendrimers has been shown to be influenced by dendrimer concentration in the complexes. The colloidal and surface properties of plasmid/chitosan complexes have been shown to depend on the molecular weight of chitosan, the ratio of plasmid to chitosan and the preparation medium. Smaller nanoparticles have been observed with low molecular weight chitosan (2 kDa) as compared to high molecular weight chitosan (540 kDa). Interestingly, the transfection efficiency of the complexes was not affected by the presence of serum proteins, even though the presence of serum is known to adversely affect the transfection efficiency. The blood capillary walls are comprised of four layers, namely plasma-endothelial interface, endothelium, basal lamina, and adventia. Macromolecules can cross the endothelial barrier: • through the cytoplasm of endothelial cells themselves; • across the endothelial cell membrane vesicles; • through inter-endothelial cell junctions; • through endothelial cell fenestrae. Based on the morphology and continuity of the endothelial layer, capillary endothelium can be divided into three categories: continuous, fenestrated, and discontinuous endothelium (see Section 5. The continuous capillaries are found in skeletal, cardiac, and smooth muscles, as well as in lung, skin, subcutaneous and mucous membranes. The endothelial layer of brain microvasculature is the tightest endothelium, with no fenestrations. Capillaries with fenestrated endothelia and a continuous basement membrane are generally found in the kidney, small intestine and salivary glands. Most of these capillaries have diaphragmed fenestrae, which are circular openings of 40–60 nm in diameter. The discontinuous capillaries, also known as sinusoidal capillaries, are common in the liver, spleen, and bone marrow. These capillaries show large interendothelial junctions (fenestrations up to 150 nm). Highly phagocytic Kupffer cells line the sinusoids of the liver, and those of the bone marrow by flattened, phagocytic reticuloendothelial cells. In the spleen, the endothelial cells contain a large number of pinocytic vesicles (up to 100 nm in diameter). Due to their large molecular weight (> 1,000 kDa) and hydrodynamic diameter in aqueous suspension of 100 nm, plasmids extravasate poorly via continuous capillaries because of tight junctions between the cells. However, plasmids can easily extravasate to sinusoidal capillaries of liver and spleen. Formulating plasmids into unimeric particles of 20–40 nm in diameter may enhance extravasation of plasmids across continuous and fenestrated capillaries. The (patho)physiology and microanatomy of tumors is significantly different from normal tissues (see Section 5. A tumor contains vessels recruited from the pre-existing network and vessels resulting from angiogenic response induced by cancer cells. There is a considerable variation in the cellular composition, basement membranes and in the size of the interendothelial cell fenestrations. Tumor interstitium is characterized by large interstitial volume and high diffusion rate. Sven Frøkjaer, Lona Christrup and Povl Krogsgaard-Larsen; Munksgaard, Copenhagen, 1998, pp. Tumor accumulation of plasmid could result from the enhanced permeability of the tumor vasculature, combined with their reduced clearance from the tumor due to the absence of the lymphatic system. Pharmacokinetic analysis of in vivo disposition profiles of radiolabeled plasmid provides useful information on the overall distribution characteristics of systemically administered plasmids, with one critical limitation. The plasma half-life of plasmid is less than 10 min, and hence tissue distribution and pharmacokinetic parameters of plasmid calculated on the basis of total radioactivity are not valid at longer time points. Thus, polymerase chain reaction and Southern-blot analysis are required to establish the time at which the radiolabel is no longer an index of plasmid distribution. The deposition of plasmids after systemic administration is restricted to the intravascular space due to its low microvascular permeability in most organs with continuous capillary bed. Some organs with fenestrated capillaries, such as liver, spleen, and bone marrow, provide some opportunities for extravasation of plasmids. Intravenously injected plasmids initially perfuse the pulmonary vascular beds, maximizing the 347 Figure 14. Reproduced with permission from: Biodistribution and gene expression of plasmid/lipid complexes after systemic administeration, Mahato R.
When emer- mometers shall be tested for accuracy gency procedures are used discount rivastigimine 3 mg overnight delivery medicine prescription, no con- against a known accurate standard tainers may enter the retort and the thermometer upon installation and at process and procedures used shall be least once a year thereafter purchase 3mg rivastigimine with mastercard georges marvellous medicine, or more noted on the production records buy rivastigimine 4.5 mg free shipping treatment 02. Records of thermometer ac- specified in the scheduled process shall curacy checks which specify date, be measured and recorded on the proc- standard used, method used, and person essing record at intervals of sufficient performing the test should be main- frequency to ensure that the factors tained. Each thermometer should have are within the limits specified in the a tag, seal, or other means of identity scheduled process. The minimum that includes the date on which it was headspace of containers, if specified in last tested for accuracy. A thermom- the scheduled process, shall be meas- eter that has a divided mercury column ured and recorded at intervals of suffi- or that cannot be adjusted to the cient frequency to ensure that the standard shall be repaired or replaced headspace is as specified in the sched- before further use of the retort. The headspace of solder- mometers shall be installed where they tipped, lapseam (vent hole) cans may can be accurately and easily read. The headspace of double seamed be installed either within the retort cans may also be measured by net shell or in external wells attached to weight determinations for homogenous the retort. External wells or pipes shall liquids, taking into account the spe- be connected to the retort through at cific can end profile and other factors least a 3⁄4-inch-diameter opening, and which affect the headspace, if proof of equipped with a 1⁄16-inch or larger the accuracy of such measurements is bleeder opening so located as to pro- maintained and the procedure and re- vide a full flow of steam past the sultant headspace is in accordance length of the thermometer bulb. When the bleeder for external wells shall emit product consistency is specified in the steam continuously during the entire scheduled process, the consistency of processing period. I (4–1–10 Edition) shall be the reference instrument for additional bleeders shall be located not indicating the processing temperature. Each Bleeders may be installed at positions retort shall have an accurate tempera- other than those specified above, as ture-recording device. Graduations on long as there is evidence in the form of the temperature-recording devices heat distribution data that they ac- shall not exceed 2 °F within a range of complish adequate removal of air and 10 °F of the processing temperature. Each chart shall have a working scale In retorts having top steam inlet and of not more than 55 °F per inch within bottom venting, a bleeder shall be in- a range of 20 °F of the processing tem- stalled in the bottom of the retort to perature. All bleeders shall be adjusted to agree as nearly as pos- be arranged in a way that enables the sible with, but to be in no event higher operator to observe that they are func- than, the known accurate mercury-in- tioning properly. A means of preventing unauthor- The air in each retort shall be removed ized changes in adjustment shall be before processing is started. A lock, or a notice from man- tribution data or documentary proof agement posted at or near the record- from the manufacturer or from a com- ing device that provides a warning that petent processing authority, dem- only authorized persons are permitted onstrating that adequate venting is to make adjustments, is a satisfactory achieved, shall be kept on file. At the means for preventing unauthorized time steam is turned on, the drain changes. The recorder may be com- should be opened for a time sufficient bined with the steam controller and to remove steam condensate from the may be a recording-controlling instru- retort and provision should be made for ment. The temperature-recorder bulb containing drainage of condensate dur- shall be installed either within the re- ing the retort operation. Each temperature-recorder bulb speed of the retort shall be specified in well shall have a 1⁄16-inch or larger the schedules process. The speed shall bleeder opening emitting steam con- be adjusted, as necessary, to ensure tinuously during the processing period. The rotational speed should have adequate filter systems to as well as the process time shall be re- ensure a supply of clean, dry air. Each retort should Alternatively, a recording tachometer be equipped with a pressure gage, may be used to provide a continuous which should be graduated in divisions record of the speed. A lock, or a be equipped with an automatic steam notice from management posted at or controller to maintain the retort tem- near the speed-adjustment device that perature. This may be a recording-con- provides a warning that only author- trolling instrument when combined ized persons are permitted to make ad- with a recording thermometer. A justments, is a satisfactory means of steam controller activated by the preventing unauthorized changes. Critical factors able if it is mechanically maintained specified in the schedules process shall so that it operates satisfactorily. Bleeders, except those for essing record at intervals of sufficient thermometer wells, shall be one-eighth frequency to ensure that the factors inch or larger and shall be wide open are within the limits specified in the during the entire process, including the scheduled process. Graduations on seam (vent hole) cans may be measured the temperature-recording devices by net weight determinations. When shall not exceed 2 °F within a range of the product consistency is specified in 10 °F of the processing temperature. The temperature chart shall and recorded at intervals of sufficient be adjusted to agree as nearly as pos- frequency to ensure that the consist- sible with, but to be in no event higher ency is as specified in the scheduled than, the known accurate mercury-in- process. Minimum closing machine glass thermometer during the process vacuum in vacuum-packed products, time. A means of preventing unauthor- maximum fill-in or drained weight, ized changes in adjustment shall be minimum net weight, and percent sol- provided. A lock, or a notice from man- ids shall be as specified in the sched- agement posted at or near the record- uled process for all products for which ing device that provides a warning that deviations from such specifications only authorized persons are permitted may affect the scheduled process. All to make adjustment, is a satisfactory measurements and recordings of crit- means for preventing unauthorized ical factors should be made at intervals changes. The temperature-recorder bulb agitating retorts—(1) Indicating mercury- shall be installed either within the re- in-glass thermometer. Each retort shall tort shell or in a well attached to the be equipped with at least one mercury- shell. Air-operated temperature con- in-glass thermometer whose divisions trollers should have adequate filter are easily readable to 1 °F and whose systems to ensure a supply of clean dry temperature range does not exceed 17 air. Each retort should against a known accurate standard be equipped with a pressure gage which thermometer upon installation and at should be graduated in divisions of 2 least once a year thereafter, or more pounds or less. Records of thermometer ac- be equipped with an automatic steam curacy checks which specify date, controller to maintain the retort tem- standard use, method used, and person perature. This may be a recording-con- performing the test should be main- trolling instrument when combined tained. The rotational that includes the date on which it was speed of the retort shall be specified in last tested for accuracy. The speed shall eter that has a divided mercury column be adjusted, as necessary, to ensure or that cannot be adjusted to the that the speed is as specified in the standard shall be repaired or replaced scheduled process. Ther- as well as the process time shall be re- mometers shall be installed where they corded for each retort load processed. Alternatively, a recording tachometer Bulbs of indicating thermometers shall may be used to provide a continuous be installed either within the retort record of the speed. A means of pre- shell or in external wells attached to venting unauthorized speed changes the retort. A lock, or a notice eter—not the recorder chart—shall be from management posted at or near the reference instrument for indicating the speed adjustment device that pro- the processing temperature. Records of thermometer ac- ment, is a satisfactory means of pre- curacy checks which specify date, venting unauthorized changes.
Mechanistic and Other Afer 1 year order 3 mg rivastigimine with amex medicine kit for babies, mean body weights for the Relevant Data control and treated rats in the frst experiment were similar buy rivastigimine online now medicine plus. Te metabolic scheme for sulfasalazine in Te incidence of transitional cell papilloma of humans is shown in Fig buy cheap rivastigimine on line medicine song. Slow absorption of small amounts (~10– transitional cell papilloma of the urinary bladder 30%) via the small intestine has been reported also had grossly visible concretions in the kidney before enterohepatic recycling, and with the and/or urinary bladder. In the third experiment, majority of unchanged drug reaching the colon no signifcant increase in the incidence of transi- (Das & Dubin, 1976; Azad Khan et al. Tis cleavage is the A group of 12 male Wistar rats was given rate-limiting step for clearance of sulfasala- 1,2-dimethylhydrazine at a dose of 40 mg/kg bw zine (Das & Dubin, 1976). In of “colon tumours” (mainly adenocarcinomas) the liver, sulfapyridine undergoes hydroxylation was assessed histologically at week 21. All rats and/or N-acetylation to 5′-hydroxysulfapyri- developed tumours of the intestine. In the dine, N4-acetylsulfapyridine, and N4-acetyl-5′- control group receiving 1,2-dimethylhydrazine hydroxysulfapyridine subsequently forming only, there were 70 tumours of the intestine glucuronic acid conjugates, before excretion with a tumour multiplicity of 6. Metabolites (sulfapyridine, and acetylated disease) were similar to those in four healthy and glucuronidated derivatives) were detected in subjects, each given a single oral dose of sulfasala- the serum at 3–5 hours afer dosing (Schröder zine (3 or 4 g). Te metabolism been studied in three healthy male Japanese of sulfasalazine was markedly reduced in patients volunteers (Tokui et al. Maximum plasma concentration (Cmax) of rheumatoid arthritis had a signifcantly higher the metabolite N-acetyl-5-aminosalicylic acid (and more sustained) plasma concentration was 0. It was estimated that an infant would able to cross the placenta (Azad Khan & Truelove, receive sulfapyridine at dose of 3–4 mg/kg bw, 1979; Järnerot et al. In fve patients with afer a maternal dose of 2 g of sulfasalazine per day ulcerative colitis treated with sulfasalazine (0. Sulfapyridine four times per day) throughout and afer preg- and its acetylated and glucuronidated metabo- nancy, sulfasalazine was detected in the umbilical lites have been shown to be excreted by babies, cord blood (mean concentration, 50% of that in 1–2. Analyses of metabolites showed that total concentrations of sulfapyridine were equal in (i) N-Acetyltransferases maternal and cord sera, but concentrations Te sulfasalazine molecule may be consid- of free sulfapyridine were signifcantly lower ered as a slow-release carrier for sulfapyridine, (P < 0. Total concentrations of but there is large inter-individual variation in the acetylated sulfapyridine were signifcantly higher rate of metabolism of sulfapyridine, which can (P < 0. Patients with a “slow” acetylator Small quantities of sulfasalazine and phenotype generally show signifcantly higher, sulfapyridine have also been detected in breast and more sustained plasma concentrations of milk (Azad Khan & Truelove, 1979; Järnerot & sulfapyridine and its non-acetylated metabo- Into-Malmberg, 1979). Te elimination half-life of sulfasalazine in sulfasalazine and total sulfapyridine in milk, patients with a slow-acetylator phenotype may compared with concentrations in maternal be approximately 50–100% longer than in those serum, were approximately 30% and 50%, respec- with a fast-acetylator phenotype (Taggart et al. Studies in 21 Japanese pharmacokinetics of various drugs, including subjects (8 healthy subjects and 13 patients with sulfasalazine. Te rate of elimination of that is 19 times higher than apical-to-basolateral sulfasalazine was similar in rats and mice; plasma permeability, indicative of net mucosal secre- elimination rate constants were 1. In Caco-2 cells and rat jejunum), specifc inhibitors F344/N rats given a low oral dose of 67. Inhibitors of P-glycoprotein had no efect on the movement (b) Role of transporter proteins of sulfasalazine. Te reported, but confounding factors were apparent results indicated that sulfasalazine is a substrate in the study (Erskine et al. Additionally, an indomethacin-in- in mutations conferring 6-thioguanine resist- duced increase in sulfasalazine permeability ance in mouse lymphoma L5178Y cells, with or through the gut wall was also shown in the rat without metabolic activation (Iatropoulos et al. Tus the results of tests greater systemic exposure than rats to sulfapyri- for chromosomal damage in vitro afer treat- dine, the active moiety, afer administration of ment with sulfasalazine were generally negative, similar doses (Zheng et al. In one study, no evidence for genotoxicity In vivo, consistent with results reported in was obtained for sulfasalazine when tested for assays in vitro, no increases in the frequency the induction of micronuclei in mouse bone of chromosomal aberration were observed marrow, with or without pretreatment with folate. N4-acetylsulfapyridine was capable Chinese hamster ovary cells in vitro (Mackay of inducing both sister chromatid exchange and et al. In vivo, no increase micronucleus formation, while N4-acetyl-5′- in the frequency of micronucleated polychro- hydroxysulfapyridine only induced sister chro- matic erythrocytes was observed in the bone matid exchange. Reactions to sulfasalazine may result of metabolic activation, at concentrations that from an idiosyncratic delayed-type hypersensi- reached 400 µg/mL. Sulfapyridine induced a tivity reaction that may afect internal organs in strong, dose-related increase in the frequency variable ways (Jobanputra et al. As with sulfasalazine, the therapy; the pattern of liver injury can be hepa- majority of micronucleated erythrocytes induced tocellular or cholestatic, and may lead to liver by sulfapyridine in mice were shown to contain failure. Te incidence of Te role of metabolites in sulfasalazine-me- clinically restrictive renal impairment has been diated toxicity was investigated in vitro, using estimated at < 1 per 500 patients (World et al. Te mechanism is unclear, although both cytes as target cells in the presence of human liver a delayed cell-mediated response, and a dose-de- microsomes; methaemoglobin formation and pendent efect have been considered (Corrigan cytotoxicity were selected as toxicity end-points. Chromatographic analysis demonstrated documented nephrotoxic potential (Corrigan & that sulfapyridine was converted to a short- Stevens, 2000). Treatment-related alterations hydroxylamine (10–500 µM) caused a concen- in the levels of biomarkers of oxidative stress tration-dependent increase in both methae- were detected in kidney and liver tissues of male moglobinaemia (2. At sulfasalazine nor any of the other test metabolites the highest dose, there were signifcant decreases had such efects. When the microsomal incuba- in the activities of renal and hepatic superoxide tions were conducted in the presence of micro- dismutase, and signifcant increases in catalase molar concentrations of reducing agents (e. In a group of 50 patients where it may undergo redox cycling to nitroso- receiving sulfasalazine at 2. Reduced levels of in sulfasalazine-induced carcinogenesis of the S-adenosylmethionine or 5,10-methylenetet- bladder in male rats. In the rat, Te adverse efects of sulfasalazine have been colonic bacterial folate is incorporated in the linked to sulfapyridine (Das et al. Environmental increased incidences of transitional cell papil- contamination with sulfasalazine in ground- loma of the urinary bladder, and clear evidence water has been noted, but exposure is likely to for carcinogenic activity in male and female be predominantly through use as a medication. B6C3F1 mice on the basis of increased incidences of hepatocellular adenoma and hepatocellular 5. Te data on mutagenicity of sulfasalazine and Te available studies of exposure to sulfasala- its metabolite, sulfapyridine, suggested that the zine included a surveillance study, two cohort parent drug and the metabolite are predomi- studies, three nested case–control studies, and nantly aneugens (Bishop et al. Increased frequencies of micronucleus colorectum among patients with infammatory bowel disease or ulcerative colitis. However, were also concerns about selection bias in some patients reported to have an elevated frequency studies based on clinical populations. Most of these relative risks infammation associated with urolithiasis may were not statistically signifcant. In the studies be a factor in sulfasalazine-induced carcinogen- that evaluated dose–response relationships, no esis of the bladder in male rats. Cleavage of carcinoma (combined) in both sexes; there was the azo bond by bacterial azoreductases in the also an increase in the incidence of hepatocellular colon releases two pharmacologically active carcinoma in females.
For nasal drug delivery purchase rivastigimine toronto medications and mothers milk 2014, it has been suggested that two mechanisms of absorption exist effective 4.5mg rivastigimine symptoms zinc deficiency adults, based on the physicochemical properties of the drug: • a fast rate generic rivastigimine 1.5 mg visa medications known to cause hair loss, which is dependent on the lipophilicity of the drug; • a slower rate, which is dependent on molecular weight. Thus, lipophilic drugs such as propanolol, progesterone, 17β-œstradiol, naloxone and testosterone are absorbed rapidly and completely from the nasal cavity. In contrast, their oral bioavailabilities range from 25% for propranolol to less than 1% for progesterone. As such, the rate of absorption will be affected by the concentration of drug in solution at the absorbing membrane. The higher the drug concentration, the steeper the concentration gradient driving the absorption process and the faster the drug will be absorbed. Therefore if the drug is formulated as a solution, the highest concentration possible should be chosen that is compatible with an accurate and reproducible dosing volume. However, care must be taken, as high local drug concentrations over extended periods of time may also cause severe local irritation or adverse tissue reactions. For absorption of aerosol formulations, deposition of the aerosol must occur followed by dissolution of solid particles if applicable. The extent and site of deposition of an aerosol from a nasal spray will depend upon: • the aerodynamic diameter of the particle (which is also a function of droplet size, shape and density); • the particle charge (which might also depend on the drug, formulation excipients and method of aerosolization); • the velocity at which the particle is moving (which depends on respiratory patterns). In general, particles or droplets in the size range 5–10 μm tend to deposit in the nasal passages. Although the extent and site of particle deposition can be estimated from a knowledge of the aerodynamic size distribution of the aerosol, the situation can be complicated by the fact that the size of the particle can increase (and possibly its density decrease) as a result of water condensation, due to the humidity change upon entering the nasal cavity. Deposition mechanisms in the nose include inertial impaction, sedimentation, diffusion, interception and electrostatic attraction. The structure and physiology of the nasal cavity, with the small cross-section for airflow and sharp curves, suggests that inertial impaction is the most significant mechanism for drug deposition in the nasal cavity. The implications to nasal bioavailability of these deposition patterns from the different delivery devices is discussed further below (see Section 9. In contrast to the oral route, this route avoids degradation in the intestinal wall or the liver, prior to the drug reaching the systemic circulation. Accessibility The nasal cavity offers a readily accessible surface for drug delivery, obviating the need for complex delivery devices to enable the drug to reach its absorption site. Thus devices for nasal delivery are simpler in design than those intended to deliver drugs to, for instance, the alveolar region of the lung and are non- invasive, requiring the simple instillation of drops or sprays. Ease of administration Nasal devices, such as metered-dose nasal sprays, are simple for the patient to use and might be expected to be more acceptable to the patient than the use of pessaries or suppositories for the intravaginal and rectal delivery routes respectively. Intestinal alternative The nasal route may become a useful alternative to the intestinal route for drug absorption in situations where use of the gastrointestinal route is unfeasible. Examples include: • patients with nausea and vomiting; 234 • patients with swallowing difficulties and/or children; • drugs that are unstable in the gastrointestinal fluids; • drugs that undergo extensive first-pass effects in the gut wall or liver. For drugs which are rapidly absorbed, mucociliary clearance is likely to be of little consequence, but for those compounds with physicochemical properties dictating slow absorption the effect of mucociliary clearance is likely to be profound. Mucus barrier Drug diffusion may be limited by the physical barrier of the mucus layer and the binding of drugs to mucins. Limited to potent molecules For drugs of a high molecular weight (which are thus poorly absorbed), the route is limited only to potent drug molecules; typically those with effective plasma concentrations in the ng mL−1 (or lower) range. Lack of reproducibility The major problem associated with intranasal delivery is the question of whether it can provide reliable absorption. Diseases such as the common cold and hayfever are recognized to alter the condition of the nose, either increasing or decreasing mucociliary clearance, or altering the permeability of the absorbing mucosa. The frequency with which these diseases occur means that patients requiring chronic drug therapy will undergo periods when drug absorption might be expected to be higher or lower than “normal”. Adverse reactions Locally irritating or sensitizing drugs must be used with caution in this route. This contrasts with, for example, the buccal epithelium which is much more robust and less prone to irritation. The fragility of the tissue also means that this route is particularly sensitive to the adverse effects of penetration enhancers. Damage to the epithelium could result in compromised mucocilary clearance which is associated with respiratory disease. Some intranasally delivered drugs showing systemic absorption are given in Table 9. They are also available as metered-dose devices, which would be expected to give more reproducible dosing, as a mechanical actuation delivers a pre-determined volume to the patient. Thus the dose of drug received by the patient will be dependent on the concentration of drug in the formulation. Commercial examples of metered-dose sprays include Syntaris, Beconase and Rhinocort which deliver flunisolide, beclomethasone and budesonide respectively. As discussed above, nasal sprays tend to deposit at their impaction site, in the anterior, unciliated regions of the nasal cavity, where airflow associated with inspiration is high and mucociliary clearance is slow or erratic. Thus a drug moiety depositing in this region is cleared slowly and is transported over a large area en route to the pharynx. As described above, nasal drops, if administered correctly, deposit drug throughout the nasal cavity (Figure 9. However this also means that: • some drug is inevitably deposited on ciliated regions of the mucosa and is therefore immediately available for clearance; • a proportion of the dose actually deposits at the nasopharynx where it may be immediately swallowed and is therefore not available for nasal absorption. To ensure a complete coating of the nasal mucosa from the atrium to the nasopharynx, the method depicted in Figure 9. Since this is either unknown or inconvenient to most patients, variable drug absorption is likely to result, which would be unacceptable for drugs with a narrow therapeutic window. In this second slower phase, clearance of the drops is much faster than clearance of the spray, probably because most of the spray deposits on non-ciliated regions. Due to this faster clearance, nasal drops are more suitable for drug moieties which are rapidly absorbed. Drug molecules which diffuse across the nasal epithelium relatively slowly will need a longer contact time and may therefore be better administered as sprays. The bioavailability of the peptide drug desmopressin is greater from a metered-dose nasal spray than from drops. The success of this dosage form in promoting nasal absorption is evidenced by the commercial availability of nasal sprays for the systemic delivery of various peptide drugs, including buserelin, desmopressin, oxytocin and calcitonin. However, peptides and proteins generally have a molecular weight in excess of 1,000 Da and are therefore unlikely to be absorbed across the nasal mucosa in any appreciable amounts without pharmaceutical intervention. Strategies under development to promote drug absorption via the nasal cavity are detailed below. The mechanisms of absorption promotion proposed for the different compounds are numerous and it is likely that more than one mechanism is involved: Alteration of mucus layer Agents that decrease the viscoelasticity of mucus, for example anionic and cationic surfactants and bile salts, have been shown to increase absorption. Thus, the paracellular route becomes leakier, permitting increased absorption of substances that use this route. Reversed micelle formation The differing adjuvant activities of various bile salt species relate to their differing capacities to penetrate and self-associate as reverse micelles within the membrane. In reverse micelles, the hydrophilic surfaces of the molecules face inward and the hydrophobic surfaces face outward from the lipid environment. The formation of reverse micelles within the cell membranes may create an aqueous pore, through which drug moieties can pass.
Medical professionals are ideally placed to encourage a refocusing of debate on these important issues and to influence national and global drug policy cheap rivastigimine 3 mg amex medicine 831. Their role in relation to illicit drug use cheap rivastigimine 3 mg online medications prescribed for migraines, both as individuals and as a profession buy rivastigimine paypal treatment 2 stroke, is examined in the closing chapter of this report (Chapter 11). Such use is associated with a range of harms for some people, while for others there are few negative consequences. The addictiveness (dependence potential – see Glossary) of different psychoactive drugs is presented in Appendix 2. Attitudes towards the acceptability of substance use vary widely, with particular debate regarding the concept of pathological substance use and a disease model for addiction. This section examines the evidence for considering harmful/dependent substance use as a medical disorder. Internationally, different countries have either accepted a disease model and treated harmful/dependent users as patients, and/or used the judicial system as a means to define substance use primarily as a criminal activity. Often, particularly nowadays, national systems combine both disease and crime models. Sir Humphrey Rolleston, then President of the Royal College of Physicians, chaired the Departmental Commission on Morphine and Heroin Addiction (commonly known as the Rolleston Committee), whose recommendations were accepted as Government policy. This committee described addiction as a disease and that those suffering with addiction should receive medical treatment rather than legal sanction. Recreational use Many people are able to use psychoactive substances in a recreational manner (see Glossary) that causes no problems to the individual or those around them. This pattern of use is usually characterised by moderate levels of consumption and periods when the person stops using the substance without difficulty. Harmful, dependent and hazardous use There are clear, internationally agreed frameworks for describing harmful and dependent patterns of substance use. These frameworks define a hierarchy of physical, psychological and social harm to the individual. Within the chapter on mental and behavioural disorders, a subchapter defines mental and behavioural disorders due to psychoactive substance use. It defines a number of categories including acute intoxication (see Glossary), harmful use, dependence and withdrawal. The level of harm caused by a particular pattern of substance use is defined by the categories ‘harmful’ and ‘dependent’. Psychological dependence involves a need (craving – see Glossary) for repeated doses of the drug to feel good, or avoid feeling bad. Physiological (physical) dependence is associated with tolerance (see Glossary), where increased doses of the drug are required to produce the effects originally produced by lower doses, and development of withdrawal syndrome (see Glossary) when the drug is withdrawn. Withdrawal syndrome is characterised by physiological and psychological symptoms that are specific to a particular drug. The term ‘dependence’ is often used interchangeably with ‘addiction’ (see Glossary). In contrast to harmful use, hazardous use also refers to patterns of use that are of public health significance, despite the absence of any current disorder in the individual user. These terms, and many others that are used throughout the report, are discussed in more detail in the Glossary. Substances have been clearly shown to affect the brain in the short and longer term. Some substances (eg heroin, cannabis) mimic endogenous neurotransmitters, while others (eg cocaine, amphetamine) increase the availability of endogenous neurotransmitter to the brain, by either increasing neurotransmitter release or inhibiting its breakdown. If a person uses substances over a longer period of time, the brain’s structure and function begin to change, prompting behavioural changes in that individual. The prefrontal cortex area of the brain is particularly vulnerable to the effect of substances. This brain area is crucial for decision making, such as weighing up the pros and cons of a certain activity. Research suggests that the prefrontal cortex is one of the last brain areas to mature. It is a naturally occurring, ‘feel good’ neurotransmitter that is important in rewarding positive behaviours (eg eating, drinking). Some psychoactive substances cause dopamine to be released rapidly and in huge quantities when compared to usual brain levels. Raised levels of dopamine in the mesolimbic system lead to intense feelings of pleasure, known to users as a ‘high’ (see Glossary). If substance use persists, the brain responds to the dopamine overstimulation by decreasing the amount of dopamine produced and reducing the number of dopamine receptors (see Glossary) available. This, in turn, can lead to the user feeling emotionally flat and exhausted once the immediate effect of the drug has subsided. The user will often try to stimulate further additional dopamine release by using larger quantities of the substance. The role of dopamine in the effect of psychoactive drugs is considered further in Section 4. Genetics There is strong evidence for a genetic component to dependence, provided by family, twin and adoption studies (see Chapter 4). Although research suggests many genes may be involved,18 there is evidence that a single genetic variant in the aldehyde dehydrogenase 2 gene impacts on patterns of drinking and the risk of dependence. The genetics of dependence is a rapidly developing area but, apart from the studies on the aldehyde dehydrogenase 2 gene, there is little immediate prospect of a breakthrough in genetics leading to improved patient care. As described above, dependence can be considered primarily a brain disorder, but one that interacts with a range of predisposing, precipitating, perpetuating and protective factors. These factors can best be described in a framework in which the biological, psychological and social components are identified. Psychological factors include comorbid mental health problems such as depression, psychosis and personality disorder. Traumatic events, such as childhood sexual abuse, may also increase a person’s vulnerability to subsequent use of psychoactive substances. Social factors include the availability of a particular substance; the nature of, and support provided by, a person’s social network; peer pressure; and environmental factors such as housing and employment. A range of evidence-based treatments are available to help people with harmful/ dependent substance use, and some of these are discussed in Chapters 8 to 10. Each individual is unique, and treatment of harmful/dependent use should be planned with a clear understanding of the predisposing and protective factors. Appendix 2 gives further details about the nature and addictiveness of these drugs, and Appendix 3 gives details of health-related harms associated with illicit drug use. These recommendations are non-binding, and have, on occasion, been ignored or rejected. Mephedrone and related cathinone derivatives, as well as naphthylpyrovalerone analogues, were classified as Class B drugs in 2010. The Drugs Act 2005 amended the Misuse of Drugs Act 1971 and the Police and Criminal Evidence Act 1984, to increase the powers of the police and courts in relation to drug control (see Glossary). It includes stronger measures to allow police to test drug offenders on arrest rather than at the time of charging, and requires those testing positive to undergo treatment.