By W. Keldron. Urbana University.

Dose Oral Moton sickness Adult: 30 mg 2 hr before travel and 15 mg every 8 hr during travel if needed midamor 45 mg amex blood pressure medication name brands. Precautons Hypotension order midamor 45 mg with visa blood pressure numbers for seniors, patents should not drive or operate machinery, pregnancy (Appendix 7c), lactaton, elderly, children and neonates, interactions (Appendix 6c). Precautons Increased susceptbility to and severity of infecton; actvaton or exacerbaton of tuberculosis, amoebiasis, strongyloidiasis;risk of severe chickenpox in non-immune patent (varicella-zoster immunoglobulin required if exposed to chickenpox); avoid exposure to measles (normal immunoglobulin possibly required if exposed); diabetes mellitus; peptc ulcer; hypertension; precautons relatng to long-term use of cortcosteroids; glaucoma, epilepsy; drug should not be abruptly withdrawn; interactons (Appendix 6c), lactaton (Appendix 7b). Adverse Efects Nausea, dyspepsia, malaise, hiccups; hypersensitvity reactons including anaphylaxis; perineal irritaton afer intravenous administraton; adverse efects associated with long-term cortcosteroid treatment; hyperglycaemia, abdominal distension, angioedema, bradycardia, acne, erythema, Cushing’s syndrome, oropharangeal candidiasis, hypothalamic pituitary adrenal axis suppression. Fexofenadine Pregnancy Category-C Schedule H Indicatons Allergic rhinits, urtcaria. Child- (6 month to 2 years): 15 mg twice daily, more than 2 years: 30 mg twice daily. Adverse Efects Dizziness, stomach discomfort, pain in extremity, back pain, vomitng, diarrhoea, upper respiratory tract infecton, headache, dysmenorrhoea. Dose Intramuscular injecton or slow intravenous injecton or intravenous infusion Adult-100 mg to 500 mg, 3 to 4 tmes in 24 h or as required. Contraindicatons Not relevant to emergency use but for contra-indicatons relatng to long-term use; ulcers. Precautons Not relevant to emergency use but for precautons relatng to long-term use, interactons (Appendix 6d), lactaton (Appendix 7b), pregnancy (Appendix 7c). Adverse Efects Adverse efects associated with long-term cortcosteroid treatment; opportunistc infectons. Levocetrizine Pregnancy Category-B Schedule H Indicatons Allergic rhinits, chronic urtcaria. Dose Oral Rhinits, chronic urtcaria: Adult & children (>12 years) - 5 mg once daily in the evening. Contraindicatons Hypersensitvity, end-stage renal disease with creatnine clearance < 10 ml/min. Adverse Efects Somnolence, fatgue, dry mouth, nasopharyngits have been reported in adults. Storage Store protected from heat, light and moisture at a temperature not exceeding 30⁰C. Noradrenaline Pregnancy Category-C Indicatons Acute hypotension, adjunct in cardiac arrest, upper gastrointestnal haemorrhage. Reconsttuton Dilute with 5% glucose injecton, with or without sodium chloride; diluton with sodium chloride injecton alone is not recommended. Contraindicatons Hypertension, pregnancy (Appendix 7c), patents with peripheral or mesenteric vascular thrombosis unless necessary as a life-saving procedure. Adverse Efects Elevaton of blood pressure, bradycardia, peripheral ischemia, arrhythmias, anxiety, transient headache, respiratory difculty, extravasaton necrosis at injecton site. Pheniramine* Pregnancy Category-C Schedule H Indicatons Symptomatc relief of allergy; allergic rhinits; urtcaria. Contraindicatons Epilepsy; pregnancy (Appendix 7c); acute asthma; acute porphyria; symptomatc prostatc hypertrophy; neonates and premature infants. Precautons Glaucoma; driving or operatng machinery; asthma or severe cardiovascular disease, pregnancy (Appendix 7c), lactaton. Dose Oral Adult and Child- Initally up to 10 to 20 mg daily in divided doses (severe diseases up to 60 mg), preferably afer breakfast. Contraindicatons Untreated systemic infecton; administraton of live virus vaccines; hypersensitvity. Adverse Efects Nausea, dyspepsia, malaise, hiccups; hyper- sensitvity reactons including anaphylaxis; supraclavicular lump, fragile skin. The disease mainly afects the older populaton and is the most common cause of dementa (early stage). As the disease advances behavioural changes such as confusion, irritability and aggression, mood swings, language break- down, long term loss of memory etc. The biochemical mechanisms involved in its pathogenesis are suggested to be the accumulaton of abnormally folded amyloid β and τ proteins in the brain, involvement of infammatory cytokines, alteraton in distributon of diferent neurotrophic factors and expression of their receptors etc.

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This dilemma means that actors in the feld buy midamor 45mg online arrhythmia in pregnancy, producers buy midamor 45mg visa blood pressure ranges for young adults, regulators, prescribers and users, wish that the introduction of useful drugs is not delayed while at the same time being concerned about the licensing of drugs which later will shown detrimental side effects. The double bind in this context as the Halcion case shows is an essential ingredient of a regulatory system of checks and balances to account for a cultural 41 J. Bury, ‚Tranquillisers as a Social Problem‘, The Sociological Review 36 (1988): 320-352; J. Bury, ‘Halcion Nights: A Sociological Account of a Medical Controversy’ Sociology 30 (1996): 447-469. Our study suggests that consumers by interfering with the process of drug evaluation through trial at the bar have learned to use the double bind to their own advantage. Hence, the double bind is an important factor in shaping and surviving the Seige cycle. Drugs can be understood as tools for the management of disease, industrial products, commercial goods, or research objects: in short, they experience multiple “modes of existence”. Given this observation, one might ask how specifc compounds cut through commercial, medical, legal, and experimental regimes in the course of their existence. This seemingly unproblematic question erroneously views drugs as well-defned substances that maintain their chemical identity during their trajectory through different drug-making and drug-using practices. Borrowing from Andrew Barry’s discussion of chemical substances as “informed material” , we believe that it is possible to go beyond this uneasy mix of (soft) social constructivism and realism, and to track the circulation and testing of therapeutic substances as a process of “progressive informational enrichment”. In Barry’s original formulation, informed molecules, rather than discrete objects, are “constituted in their relations to informational and material environments”: such entities, in other words, are constituted by a space defned, on the one hand, by the distance between the properties of a molecule and the properties of the models used in deriving those properties, and, on the other hand, by the distance between a molecule and its competitors in the legal and economic environment in which it operates and to whose defnition it contributes. Barry notes that the notion of a chemical space is a native category, routinely used by chemists and pharmacologists. And indeed, recent contributions to the novel area of analysis that lies at the interface of pharmacology and computational biology commonly resort to this notion, in both a metaphorical and literal sense. We would like to thank the participants in the Drug Trajectories V Workshop, and in particular Harry Marks, for their comments and suggestions, and to further extend our thanks to the clinicians who kindly accepted to be interviewed for this project. Cancer clinical trials: a device for the informational enrichment of anti-cancer drugs As noted by several authors, randomized clinical trials have become the obligatory passage point for the translation of a given substance into a legitimate prescription drug. Our claim refers both to the production of new nosological categories (as when a given kind of cancer is shown to consist, in fact, of two different kinds of neoplasms, i. For instance, one of the early chemotherapy protocols in the treatment of leukemia was Protocol No. Chapel Hill: University of North Carolina Press, 2004; Harry M Marks, The Progress of Experiments: Science and Therapeutic Reform in the United States, 1900-1990. The innovation consisted of treating different phases of the disease, which were the direct creation of the protocol itself, as separate kinds of disease. For instance, remission and relapse were treated as independent events occurring in the same person with ostensibly the same disease. By replacing the natural history of a disease with its treated history, protocols incorporate an evolving understanding of the biology of the disease. They thus reveal new targets for therapeutic substances, modifying, in the process, the socio-technical space of these substances. Of special interest, in this respect, is the fact that contemporary protocols often defne their target population (or target disease) on the basis of prior treatment with other substances as, for instance, in the case of “Tamoxifen-treated, node-negative breast cancer”11 or “Desatinib in Imatinib-resistant, Philadelphia Chromosome-positive leukemias”. For each substance we see, with the exception of the last few years, a constant growth in the number of papers over a period of approximately 40 years. This is obviously not due to an increase in the number of clinical trials devoted exclusively to that substance but, 11 S. The latter vary according not only to the quantities administered and the modes and schedules of administration, but also to the type and number of substances they mobilize. Two different regimens may deploy the same substance with different routes of admission (e. The protocol specifed that the two regimens would be tested on patients suffering from “metastatic breast carcinoma”. In other words, protocols further diversify the space of therapeutic experimentation by adding such qualifcations as the stage of a patient’s disease trajectory as well as a growing set of parameters 13 G. These strictures integrate the results of previous interventions, insofar as the comparison of two different regimens can be performed as part of a protocol that aims at developing a frst-line (standard) chemotherapy, or an adjuvant chemotherapy (i.

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Chlorhexidine is incompatble with soaps and other anionic materials discount midamor 45mg free shipping blood pressure medication zestoretic, such as bicarbonates order midamor 45 mg fast delivery blood pressure medication and gout, chlorides, and phosphates, forming salts of low solubility which may precipitate out of soluton. Ethanol has bacteri- cidal actvity and is used to disinfect skin prior to injecton, venepuncture or surgical procedures. Precautons Avoid contact with eyes; avoid use in body cavites; meninges and middle ear. Chlorhexidine* Pregnancy Category-B Indicatons Antseptc; disinfecton of clean instruments; gingivits. Dose Antseptc (pre-operatve skin disinfecton and hand washing): use soluton in alcohol (70%). Adverse Efects Occasional skin sensitvity and irritaton; Upper respiratory tract infecton. Ethyl Alcohol* Indicatons Disinfecton of skin prior to injecton, venepuncture or surgical procedures. Precautons Flammable; avoid broken skin; patents have sufered severe burns when diathermy has been preceded by applicaton of alcoholic skin disinfectants; lactaton (Appendix 7b). Storage Store in a tghtly closed container at a temperature not exceeding 30⁰C, away from fre and protected from moisture. Contraindicatons Avoid regular or prolonged use in patents with thyroid disorders or those taking lithium; avoid regular use in neonates; avoid in very low birthweight infants; burn covering large surface area; hypersensitvity to iodine. Precautons Pregnancy (Appendix 7c); lactaton (Appendix 7b); broken skin (see below); renal impairment; avoid contact with eyes; neonates. The applicaton of povidone iodine to large wounds or severe burns may produce systemic adverse efects such as metabolic acidosis; hypernatraemia; and impairment of renal functon. Adverse Efects Irritaton of skin and mucous membranes; may interfere with thyroid functon tests; systemic efects (see under Precautons). Disinfectants do not necessarily kill all organ- isms but reduce them to a level, which does not harm health or the quality of perishable goods. Disinfectants are applied to inanimate objects and materials such as instruments and surfaces to control and prevent infecton. They may also be used to disinfect skin and other tssues prior to surgery (see also Antseptcs, above). Where water is not disinfected at source it may be disin- fected by boiling or by chemical means for drinking, cleaning teeth and food preparaton. It is highly corrosive in concentrated soluton and splashes can cause burns and damage the eyes. Appropriate precautons must be taken when concentrated chlorine solutons or powders are handled. The chlorinated phenolic compound, chloroxylenol, is efec- tve against a wide range of Gram-positve bacteria. It is less efectve against staphylococci and Gram-negatve bacteria; it is ofen inefectve against Pseudomonas spp. The aldehyde bactericidal disinfectant, glutaraldehyde, is strongly actve against both Gram-positve and Gram-negatve bacteria. A 2% w/v aqueous alkaline (bufered to pH 8) glutaral soluton can be used to sterilize heat-sensitve pre-cleansed instruments and other equipments. Dose Surface disinfecton (minor contaminaton): apply solutons containing 1000 parts per million. Instrument disinfecton: soak in soluton containing 1000 parts per million for a minimum of 15 min; to avoid corrosion do not soak for more than 30 min; rinse with sterile water. Chloroxylenol Pregnancy Category-C Indicatons Antseptc; disinfecton of instruments and surfaces. Dose Antseptc (wounds and other skin damage): apply a 1 in 20 diluton of 5% concentrate in water. Disinfecton of instruments: use a 1 in 20 diluton of 5% concentrate in alcohol (70%). Precautons Aqueous solutons should be freshly prepared; appropriate measures required to prevent contaminaton during storage or diluton; pregnancy (Appendix 7c); lactaton. Precautons Signifcant peripheral neuropathy; patents with diabetes at risk of neuropathic ulcers; protect surrounding skin and avoid broken skin; not suitable for applicaton to face; anogenital region; or large areas; increased levels of serum aminotransferase. Glutaraldehyde* Indicatons Disinfecton and sterilizaton of instruments and surfaces; conditons like warts and hyperhidrosis of palms and soles. Dose Disinfecton of clean instruments - immerse in undiluted soluton for 10 to 20 min; up to 2 h may be required for certain instruments (for example bronchoscopes with possible mycobacterial contaminaton); rinse with sterile water or alcohol afer disinfecton.

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Intravenous infusion makes for delivery challenges with the possibility of supply interruption and venous line derived infections such as sepsis purchase 45mg midamor with amex heart attack exo lyrics. The advent of alternative therapies means that epoprostenol is now oen reserved for severe cases that fail to respond well to oral or inhaled treatment options generic midamor 45 mg on line prehypertension causes and treatment. This new formulation, Veletri, is more stable at room temperature, allowing for greater convenience in respect of preparation with stability of up to 7 days at refrigerator temperature and 2 days at room temperature. The agent is chemically stable with a half-life of 2–4 hours and can be delivered subcutaneously in addition to intravenously (Remodulin). The major adverse event is discomfort at the infusion site, with approximately 80% of patients experiencing pain or erythema. Treprostinil is not approved for use in chil- dren although there is a small amount of supporting data showing benet with paediatrics. Intravenous tre- prostinil has shown clinically signicant improvements in exercise walking capacity and pulmonary haemodynamics in clinical trials23 and benets from a longer 48 hour infusion reservoir change time relative to epoprostenol as a result of the increased chemical stability. One potential drawback is a higher incidence of Gram-negative infections possibly as a result of a neutral saline diluent, although this can be minimised with use of an alkaline system. A monotherapy trial displayed a clear improvement in the 6 minute walk distance of approxi- mately 23 metres, while combination studies with either Revatio or Tracleer failed to achieve clinical signicance. The agent has a human half-life of 20–25 minutes resulting in therapy of 6 to 9 deliveries per day. Regulatory approval was based on one key clinical trial that demonstrated a signicant improvement in 6 minute walking distance (36 metres overall) together with improved pulmonary haemodynamics. Iloprost is not approved for use in children although the limited data available suggests benecial acute effects and a possible role in the short-term treatment of paediatrics. The chemical structures of the three approved prostacyclin-based agents are shown in Figure 13. View Online 376 Chapter 13 forms, endothelin-1, -2 and -3 were discovered and important biological roles established. Endothelin-1 is the major isoform in the human cardiovascular system and is a highly potent vasoconstrictor involved in important processes that include the regulation of vascular tone, cell proliferation and endothelial dysfunction. With increasing knowledge of the functional role of the endothelin system, the belief arose that endothelin receptor antagonists could play an important role in mediating disease states, such as hypertension-based diseases wherein the endothelins played a key role. Additionally, the endothelin system is implicated in foetal development, appearing to play a crucial role in craniofacial and cardiovascular develop- ment. Hence all endothelin receptor antagonists are likely to be teratogenic and contraindicated in pregnancy. In particular, maintaining good physicochemical properties consistent with the necessary human pharmacokinetics for oral delivery while achieving sufficient efficacy and therapeutic index has proven difficult. Achieving an appropriate balance was crucial to success in the bosentan programme. Approval was based on two key clinical trials wherein 6 minute walk distance, functional class status and time to clinical worsening were signif- icantly improved. Headache was the most common adverse event observed and pregnancy testing is required for women of child-bearing potential. View Online 378 Chapter 13 Subsequent clinical trials underpinned the label extensions. Bosentan was well tolerated and key haemodynamic parameters were signicantly improved. This structural series is characterised by low molecular weight and good physicochemical properties relative to endothelin antagonists as a whole. Key data were that 6 minute walking distance improved by up to 51 metres for the higher 10 mg dose and a signicant improvement in the time to clinical worsening when data from both trials were combined. Elevated liver serum transaminase levels were seen but none greater than three times normal levels. The cause of endothelin receptor antagonist induced liver toxicity is unclear, however preclinical data points to a possible inhibition of bile salt excretion mechanism, based on comparison of bosentan and ambrisentan effects. Thus ambrisentan does not interact with either of the phosphodiesterase-5 inhibitors, sildenal or tadalal and combination studies are ongoing.

The problems associated with retroviruses as vectors 45 mg midamor overnight delivery prehypertension blood pressure symptoms, which illustrate some of the problems associated with the use of viruses as a whole purchase midamor 45mg online blood pressure bulb replacement, include: • Most retroviruses can only integrate into actively replicating cells, which clearly restricts their use. As the identity of most retroviral receptors remains unknown, it is difficult to predict the range of cell types the virus will infect during treatment. Physiological complications may arise if integration and transfection occur in non-target cells. The alternative approach is to use non-viral vectors, such lipid-based, peptide-based and polymer-based delivery systems, as described in detail in Chapter 14. Liposomes are relatively easy to manufacture, are generally non-toxic and are devoid of the capability to cause an infection (see Section 5. The various initial studies that have been carried out using gene therapy have highlighted the technical innovations required to achieve successful gene transfer and expression. These, in turn, should render future (“second-generation”) gene therapy protocols more successful. It should now be apparent that conventional drug delivery systems are associated with a number of limitations which can reduce drug efficacy. These limitations include an inability to: • facilitate adequate absorption of the drug; • facilitate adequate access to the target site; • prevent non-specific distribution throughout the body (resulting in possible toxic side-effects and drug wastage); • prevent premature metabolism; • prevent premature excretion; • match drug input with the required timing (zero-order or variable input) requirements Limitations of conventional drug delivery systems are particularly acute for the new biotherapeutics, such as peptide and protein drugs and nucleic acid therapies. Advanced drug delivery and targeting systems are thus being developed in order to optimize drug therapy and overcome these limitations. Further chapters will describe these new and emerging technologies, with reference to the various routes of delivery under investigation. Define the term bioavailability and describe the differences between (a) relative bioavailability and (b) absolute bioavailability. Describe the most likely pathway of drug absorption for (i) a large therapeutic peptide, (ii) a small hydrophilic molecule and (iii) a small hydrophobic molecule. The rationale for developing novel drug delivery systems therefore lies primarily in the potential commercial benefits of developing more effective means of delivering the new biotherapeutic agents. This chapter gives a market perspective to the rationale for the development of novel drug delivery systems. As introduced in the previous chapter, drug delivery technology, as a separate sector within the pharmaceutical sphere, is of quite recent origin. It had its origins in the 1950s and 1960s, when the first 44 sustained-release oral forms appeared; the best known was probably the Spansule capsule formulation developed by Smith Kline & French Laboratories. That company merged with Beecham early in the 1990s to form SmithKline Beecham and, more recently, with Glaxo-Wellcome to form “GlaxoSmithKline”. At first, drug delivery technology was relatively crude by today’s standards and its main objective was to prolong the effect of oral doses of medication in order, for example, to provide usefully prolonged relief of symptoms. Because the technology was simplistic, it could not be relied on to address any more difficult clinical needs, such as improving the absorption of insoluble drugs. It was not until the late 1970s that advanced drug delivery technology began to evolve into a serious branch of pharmaceutical science, capable of being used to tackle more fundamental problems associated with pharmacotherapy. By the mid-1990s, it was possible to identify at least six commercial reasons for the continued research and development of advanced drug delivery and targeting systems. Convenience meant that patients would find the medicine easier to take; they would therefore be more likely to purchase it in preference to rival products with less convenient dosage regimes. Thus a sustained-release dosage form gave the product an additional benefit, or in contemporary marketing jargon it conferred “added value”. Although the consumers of medicines primarily perceived convenience as a benefit, it soon became a clinical issue as well, because it was linked with improved compliance; that is, better adherence to prescribed dosage regimes. Poor compliance has always been a major problem in drug therapy, especially when the treatment is for an asymptomatic condition such as essential hypertension. For an active working man or woman to have to remember to take a tablet three or four times a day is a nuisance; it can also be embarrassing. Good compliance is also a problem for the elderly, for whom forgetfulness is often the main problem.

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Pharmacist informaton and advice can be a valuable reinforcement order 45mg midamor visa arrhythmia ekg, as long as it agrees with the doctor’s advice purchase 45mg midamor with visa heart attack under 30. The Healthcare System The healthcare system may be the biggest hindrance to adherence. Long waitng tmes, uncaring staf, uncomfortable environment, exhausted medicine supplies and so on, are all common problems in developing countries, and have a major impact on adherence. An important problem is the distance and accessibility of the clinic from the patent. Some studies have confrmed the obvious, that patents farthest from the clinic are least likely to adhere to treatment in the long term. They difer from accidental to deliberate excessive dosage or medicine maladministraton. Thalidomide marked the frst recognized public health disaster related to the introducton of a new medicine. It is now recognized that clinical trials, however thorough, cannot be guaranteed to detect all adverse efects likely to be caused by a medicine and hence necessitatng post-marketng surveillance. Health workers are thus encour- aged to record and report to the Natonal Pharmacovigilance Centre for any unexpected adverse efects with any medicine to achieve faster recogniton of serious related problems. Major Factors Predisposing to Adverse Efects It is well known that diferent patents ofen respond difer- ently to a given treatment regimen. For example, in a sample of 2422 patents who had been taking combinatons of drugs known to interact, only 7 (0. Drugs which commonly cause problems in the elderly include hypnotcs, diuretcs, non-steroidal ant-infamma- tory drugs, anthypertensives, psychotropics, digoxin etc. All children, and partcularly neonates, difer from adult in their response to drugs. Some drugs are likely to cause problems in neonates (for example morphine ), but are generally toler- ated in children. Other drugs associated with problems in children include chloramphenicol (grey baby syndrome), antarrhythmics (worsening of arrhythmias), acetylsalicylic acid (Reye’s syndrome etc). Drug Interactons Interactons (see Appendix 6) may occur between drugs which compete for the same receptor or act on the same physiolog- ical system. They may also occur indirectly when a medicine- induced disease or a change in fuid or electrolyte balance alters the response to another medicine. Interactons may occur when one medicine alters the absorpton, distributon, metabolism or eliminaton of another medicine, such that the amount which reaches the site of acton is increased or decreased. When two drugs are administered to a patent, they may either act independent of each other, or interact with each other. Interactons may increase or decrease the efects of the drugs concerned and may cause unexpected toxicity. As newer and more potent drugs become available, the number of serious medicine inter- actons is likely to increase. Remember that interactons which modify the efects of a medicine may involve non-prescripton drugs, non-medicinal chemical agents, and social drugs such as alcohol, marijuana, tobacco and traditonal remedies, as well as certain types of food. Pharmaceutcal Interactons Certain drugs, when added to intravenous fuids, may be inactvated by pH changes, by precipitaton or by chemical reacton. Benzylpenicillin and ampicillin lose potency afer 6-8 hours if added to dextrose solutons, due to the acidity of these solutons. Some drugs bind to plastc containers and tubing, for example diazepam and insulin. The Efect of Food on Medicine Absorpton Food delays gastric emptying and reduces the rate of absorp- ton of many drugs; the total amount of medicine absorbed may or may not be reduced. However, some drugs are pref- erably taken with food, either to increase absorpton or to decrease the irritant efect on the stomach. Pharmacist plays and important role as a connectng link between the physician and patent. Analgesics, Antpyretcs, Non-Steroidal Ant-Infammatory Drugs Analgesics are used to relieve/reduce body pain and antpy- retcs are used to reduce elevated body temperature. Non- opioid analgesics are partcularly suitable for relieveing or management of pain in musculoskeletal conditons whereas the opioid analgesics are more suitable for moderate to severe visceral pain. Neuro- genic pain generally responds poorly to conventonal anal- gesics; treatment can be difcult and includes the use of carbamazepine for trigeminal neuralgia and amitriptyline for diabetc neuropathy and post-therapeutc neuralgia.

Up to eight Gliadel wafers are implanted in the cavity created when a neurosurgeon removes the brain tumor generic midamor 45 mg overnight delivery pulse pressure quizlet. The wafers gradually degrade in the cavity and allows the delivery of high discount 45mg midamor with amex arteria bologna, localized doses of the anticancer agent for a long period, thereby minimizing systemic side-effects. The thin- disk type morphology of the wafer confers a high surface-to-volume ratio on the implant, so that the total surface area of the implant is kept almost constant over the time of polymer degradation, which facilitates a constant release of carmustine with time. This results in polymer degradation proceeding purely by surface erosion, which results in zero-order drug release from disk-shaped devices. Degradable block copolymers with polyethylene glycol, diglycolide, substituted caprolactones and l-valerolactone can also be synthesized. Collagen, a major structural component of animal tissues, is being used increasingly in various biomedical and cosmetic applications. After implantation, collagen provokes minimal host inflammatory response or tissue reaction and its initial low antigenicity is practically abolished by the host’s enzymatic digestion. A collagen-based therapeutic implantable gel technology has recently been developed, in which the drug moiety (a chemotherapeutic agent) is incorporated within the meshwork of rod-shaped collagen molecules. The collagen matrix is then converted to an injectable gel by a chemical modifier. Changes in the composition and structure of the gel can adjust its solubility, strength and resorption properties. Direct injection of the gel into solid tumors and skin lesions provides high local concentrations of a drug specifically where needed (Figure 4. The gel is injected intradermally in a fanning or tracking manner to disperse the gel formulation throughout the tumor. Drug retention at the site of implantation is further enhanced by the addition of chemical modifiers such as the vasoconstrictor, epinephrine (adrenaline). This adjunct reduces blood flow and acts as a chemical tourniquet to hold the therapeutic agent in place. The most advanced products based on the implantable gel technology include the Intradose (cisplatin/ epinephrine) injectable gel for treatment of solid tumors and the Advasite (fluorouracil/epinephrine) 96 Figure 4. This is in contrast to the polymeric controlled release systems described above, where the driving force is due to the concentration difference of the drug between the formulation and the surrounding environment. Pressure differences in an implantable pump can be created by osmotic or mechanical action, as described below. The semi- permeable membrane is such that only water molecules can move through it; the movement of solutes, including drugs, is restricted (although the extent of this restriction depends on the characteristics of the membrane, see below). NaCl) is separated from water by a semipermeable membrane, the water will flow across the semipermeable membrane, into the solution containing the osmotic agent (Figure 4. Osmosis results in an increase in pressure in the solution and the excess pressure is known as the osmotic pressure. The volume flow rate arising from the influx of water into the solution is determined by a number of factors: • The osmotic pressure: ∆π is the difference in the osmotic pressure between osmotic agent-containing, and osmotic agent-free, compartments. An ideal semipermeable membrane has the σ value of 1, which means that it allows the passage of only water molecules. In contrast, a leaky semipermeable membrane with a value approaching zero does not exhibit such selectivity and permits the transport of not only water, but also an osmotic agent. An important consideration is that because the pumping principle is based on osmosis, pumping rate is unaffected by changes in experimental conditions. Hence, in vitro drug release rate is often consistent with the in vivo release profile. The characteristics of the semipermeable membrane including permeability, pore size, and thickness are key factors determining the rate at which water molecules enter the osmotic sleeve. The water that is drawn across the semipermeable membrane causes the osmotic chamber to expand. This force compresses the flexible drug reservoir, discharging the drug solution through the flow moderator. The selection of a semipermeable membrane is equally important since its properties, including A, h and σ, affect drug permeation (see Equation 4. Also, as stated above, in vitro drug release rate from the osmotic pumps is often consistent with the in vivo release profile. These advantages mean that the miniosmotic pumps are used widely in experimental animal studies, to investigate, for example, the effects of drug administration regimen upon dose-response curve, as well as pharmacokinetic and pharmacodynamic profiles and drug toxicity. Alzet osmotic kits are also available, which allow the localized administration of drugs to the central nervous system of animals.