Angie Rantell BSC HONS RN

• Senior Urogynaecology Nurse Specialist, King? College
• Hospital, London

The clinician is looking for areas of pain/discomfort antiviral zanamivir buy acivir pills 200 mg mastercard, for unexpected masses hiv infection symptoms pictures discount 200mg acivir pills otc, and for the possibility of urinary retention antiviral breastfeeding cheap acivir pills generic. The absence or presence of tenderness should antiviral research impact factor 2015 discount acivir pills 200 mg with visa, however antiviral soap buy acivir pills 200 mg with visa, not be allowed to play a pivotal role in the diagnostic procedure hiv infection throat acivir pills 200 mg overnight delivery. Expressed prostatic secretions are considered positive if there is a 10- fold increase in uropathogen count. The 4-glass or 2-glass tests and the ejaculate test can be used to distinguish between the inflammatory and non inflammatory forms (Weidner and 160 Ahmed S. However, in routine practice, obtaining cultures from expressed prostatic fluid is rare, although this may be indicated in research situations, one limitation being the difficulty of obtaining a sample (Pvone, 2007). Inflammatory cells are predominantly mononuclear, sparse, and widely distributed in a diffuse stromal pattern (16% of patients) (True et al, 1999). Other diagnostic approaches: As today the diagnosis is essentially based on subjective parameters, having excluded other causes of symptoms, the development of objective means of diagnosis is desirable. One recent example of the way forward is the recording of intraprostatic pressures. The recording of intraprostatic pressure is an invasive procedure that requires special equipment, which is an obvious but surmountable disadvantage. The use of this method may be helpful but requires further validation, explanation of the causative mechanisms (what is an elevated intraprostatic pressure actually mirroring It entails 6 domains: Urinary, Psychosocial, Organ-specific, Infection, Neurological/ systemic, Tenderness (of pelvic floor skeletal muscles). It was proposed that patients be classified in to one or more of these phenotypic domains as a way to characterize them and direct specific therapy (Nickel and Shoskes, 2010). A wide variety of pharmacologic and non-pharmacologic therapies have been studied in clinical trials, but most have shown limited curative efficacy in symptom alleviation (Strauss and Dimitrakov, 2010). This plenty of published clinical trials does not reflect only efforts to solve this prevalent enigmatic disease but it reflects that the etiology and pathophysiology is still not understood. In culture-negative patients, these benefits could result from the anti-inflammatory properties of antibiotics, the elimination of non culturable microorganisms, or the placebo effect (Nickel, 2007). Antibiotics have also been combined with treatment for prostatic stones to treat nanobacteria, and resulted in clinically significant improvement in symptoms in a pilot study (Shoskes et al, 2005). However, there is a common belief if the symptoms do not improve within two weeks, antibiotic therapy should not be continued. Further review of the patients enrolled in those studies would show that they were very chronic (many years of symptoms or since diagnosis), had many other treatments including previous antibiotic therapy in most, and had seen numerous physicians for their condition (Nickel and Shoskes, 2010). Alpha-blockers have traditionally been postulated to inhibit overactivation of bladder neck smooth muscle and thus increase urine flow, and more recently have been implicated in blocking proliferation and inducing prostatic apoptosis (Yun and Doux, 2006; Anglin et al, 2002). Overall, alpha blockers have been shown to give amelioration but their effect is rather mediocre and what can be obtained is at best some symptom relief but no cure (Hedelin and Fall, 2008). However, with the higher dose of the cyclooxygenase-2 inhibitor, significantly more patients responded to 6 weeks of therapy compared with placebo indicating that there was a clinical benefit in at least some of the patients (Zeng et al, 2004). El Hefnawy Pentosan polysulfate is a semi-synthetic mucopolysaccharide that may also have some anti-inflammatory properties. Standard dose therapy is 100 mg by mouth three times a day, and the dose of pentosanpolysulfate appears less important than an adequate duration of therapy, which should be at least 6 months (Nickel et al, 2005 b). Pregabalin and gabapentin have relatively favorable adverse effect profiles considering they are centrally acting drugs. Several other centrally acting drugs have also been used include, Tricyclic antidepressant Amitriptyline, opoids and and menantin with suggested potential for each of them to have a therapeutic role Amitriptyline is tricyclic antidepressant is thought to block pain by inhibiting the central neuronal reuptake of norepinephrine and serotonin, potentiating the inhibitory effect of these substances on the central pain processing receptor (Godfrey, 1996). Opoids There are several reasons for avoiding the use of opioids in patients with chronic non-cancer pain. The long-term use of opioids is associated with androgen deficiency and sexual dysfunction and the even more unfavourable phenomenon of upregulation of pain sensitivity. The overall result is that the patient may experience some pain relief but still experiences no change, or even deterioration, in their quality of life (Hedelin and Fall, 2008; Strauss and Dimitracov, 2010). Herbal therapies: It is interesting to note that several clinical trials evaluating untraditional therapies, such as phytotherapies (herbal-based compounds), did show efficacy in randomized placebo controlled trials (Nickel et al, 2008). Botox: Intraprostatic injection of botulinum toxin A is currently being investigated in these patients and may offer a new therapeutic approach (Gottsch et al, 2010). Physical Therapy Prostatic massage is the oldest traditional form of therapy for prostatitis. Evidence supporting repetitive prostate massage therapy is conflicting, and a consensus panel concluded that prostatic massage could be used as an adjunct form of therapy only in selected patients. Myofascial Trigger Point Release Pelvic pain manifests as a myofascial pain syndrome, in which abnormal muscular tension could explain much of the discomfort and abnormal urinary dysfunction seen in this disorder (Hetric et al, 2003). Genitourinary disorders such as voiding dysfunction and ejaculatory pain are intimately related to the autonomic nervous system and smooth/striated muscle balance. Any number of acute and chronic stress factors working via the sympathetic end plate may be involved. All 30 patients per group completed outpatient treatments and follow-ups without any problems and without any drop-out (Zimmermann et al, 2009). Future Prespectives Central Role, Newer Markers, Genetics and Multi-Disciplinary Treatment There are many new promising areas in which future research would be probably rewarding: Recent evolving aetiological model includes a peripheral initiating event in the genetically anatomically/physiologically susceptible patient. Combining treatment trials with imaging studies, biomarker and genomic, in addition to epidemiologic and symptom-based assessments, will maximize the ability to identify disease etiology and pathogenesis, as well as achieve effective treatment. Despite large scale clinical trials and observational cohort studies have been conducted, more collaborative work that involves biopsychosocial approach is warranted. Induction of prostate apoptosis by alpha1adrenoceptor antagonists: mechanistic significance of the quinazoline component. Comparison of the Economic Impact of Chronic Prostatitis/Chronic Pelvic Pain Syndrome and Interstitial Cystitis/Painful Bladder Syndrome. Distinguishing chronic prostatitis and benign prostatic hyperplasia symptoms: Results of a national survey of physician visits. Correlation between ultrasound alterations of the preprostatic sphincter and symptoms in patients with chronic prostatitis/chronic pelvic pain syndrome. The role of the prostatic stroma in chronic prostatitis/chronic pelvic pain syndrome. Management of chronic prostatitis/chronic pelvic pain syndrome: an evidence-based approach. Classification of benign diseases associated with prostatic pain: prostatitis or prostatodynia Advances in neuropathic pain: diagnosis, mechanisms, and treatment recommendations [see comment]. The bladder cooling reflex and the use of cooling as stimulus to the lower urinary tract. A guide to the understanding and use of tricyclic antidepressants in the overall managementof fibromyalgia and other chronic pain syndromes. Prevalence of premature ejaculation in Turkish men with chronic pelvic pain syndrome. The Prevalence of Erectile Dysfunction and Its Relation to Chronic Prostatitis in Chinese Men. Hedelin H, Fall M: Controversies in chronic abacterial prostatitis/pelvic pain syndrome. Evaluation of the cytokines interleukin 8 and epithelial neutrophil activating peptide 78 as indicators of inflammation in prostatic secretions. Chronic pelvic pains represent the most prominent urogenital symptoms of ``chronic prostatitis. Chronic prostatitis/chronic pelvic pain syndrome: seminal markers of inflammation. Epidemiology of prostatitis in Finnish men: a populationbased cross-sectional study. The chronic prostatitis-chronic pelvic pain syndrome can be characterised by prostatic tissue pressure measurements. Fears, sexual disturbances and personality features in men with prostatitis: a population-based cross-sectional study in Finland. Interleukin- 10 levels in seminal plasma: implications for chronic prostatitis-chronic pelvic pain syndrome. Prostatespecific antigen test in diagnostic evaluation of chronic prostatitis/chronic pelvic pain syndrome. Phynotipic approach to the management of chronic prostatitis/chronic pelvic pain syndrome. Leukocytes and bacteria in men with chronic prostatitis/ chronic pelvic pain syndrome compared to asymptomatic controls. Randomized, double-blind, dose-ranging study of pentosan polysulfate sodium for interstitial cystitis. Levofloxacin for chronic prostatitis/chronic pelvic pain syndrome in men: a randomized placebo-controlled multicenter trial. Pentosan polysulfate sodium therapy for men with chronic pelvic pain syndrome: a multicenter, randomized, placebo controlled study. Evidence for a mechanistic association between nonbacterial prostatitis and levels of urate and creatinine in expressed prostatic secretion. Demographic and clinical characteristics of men with chronic prostatitis: the National Institutes of Health chronic prostatitis cohort study. Brain activity for spontaneous fluctuations of pain in urologic pelvic pain syndrome. Cytokine polymorphisms in men with chronic prostatitis/ chronic pelvic pain syndrome: association with diagnosis and treatment response. Clinical phenotyping in chronic prostatitis/chronic pelvic painsyndrome and interstitial cystitis: a management strategy for urologic chronic pelvic pain syndromes. Anti-nanobacterial therapy for men with chronic prostatitis/ chronic pelvic pain syndrome and prostatic stones: preliminary experience. Sexual and relationship functioning in men with chronic prostatitis/chronic pelvic pain syndrome and their partners. Chronic prostatitis/chronic pelvic pain syndrome in males may be an autoimmune disease, potentially responsive to corticosteroid therapy. Prostate histopathology and the chronic prostatitis/chronic pelvic pain syndrome: a prospective biopsy study. Men with pelvic pain: Perceived helpfulness of medical and self-management strategies. Stress is associated with subsequent pain and disability among men with nonbacterial prostatitis/pelvic pain. Polymorphisms in Toll-like receptor genes-implications for prostate cancer development. A pollen extract (Cernilton) in patients with inflammatory chronic prostatitis-chronic pelvic pain syndrome: a mutlicentre, randomised, prospective, double-blind, placebo-controlled phase 3 study. Pain sensitization in male chronic pelvic pain syndrome: why are symptoms so difficult to treat Corticoid combined with an antibiotic for chronic nonbacterial prostatitis [Chinese]. Opening the floodgates: benign prostatic hyperplasia may represent another disease in the compendium of ailments caused by the global sympathetic bias that emerges with aging. Extracorporeal shock wave therapy for the treatment of chronic pelvic pain syndrome in males: a randomised, double-blind, placebocontrolled study. In fact, pain is always subjective and its definition avoids tying pain to the stimulus [1]. The criterion of 6 months is somewhat arbitrary; the rational is that after several months of pelvic pain, the pain itself becomes an illness rather than a manifestation of some other disease [3]. In studies of clinical populations, as up to 40% of women in a large questionnaire survey reported not seeking any medical care for their pelvic pain [7]. Chronic pelvic pain is the main complaint of 10% of gynaecologic consultations [4], leading to 17% hysterectomies [11] and more than 40% of gynaecologic diagnostic laparoscopies [12]. Recent researches suggested that even if symptoms continued, many women became dissatisfied with the care they received and refrain from seeking help [13]. Patients also report lower general physical health scores than controls and they have a high incidence of comorbidity, sleep disturbance and fatigue [14]. Pelvic pain can lead to disability and suffering, possible employment loss, marital discord and medical misadventures, so it can be considered as an important issue in the healthcare of women [6, 15, 16]. Despite there are associations with specific pathological processes, conditions related to pelvic pain are often unclear. In some cases no tissue damage or any pathophysiologic causes are found [4] suggesting psychological basis of this condition [1, 16]. Potential sources of pelvic pain include the reproductive, genitourinary and gastrointestinal tracts, but it can also origin from somatic sources like bones, ligaments, muscles and fascia [1]. For example endometriosis, bowel irritable syndrome, poor posture and emotional stresses can contribute to pain in a single patient needing a multidisciplinary approach in the evaluation and treatment. It may be useful to classify etiologies of pelvic pain in to gynecological and non gynecological disorders (interstitial cystis, irritable bowel syndrome, pelvic floor tension myalgia and abdominal myofascial pain syndrome). The most common diagnoses are endometriosis, adhesions, irritable bowel syndrome and interstitial cystitis [18, 19, 20]. It can be considered the most prevalent diagnosis associated with pelvic pain symptoms [18]. Endometriosis associated pain starts as dysmenorrhea in 90-95% of women [23] frequently associated with dyspareunia in deep vaginal penetration. However there is evidence that a clinical diagnosis may be correct in up to 80% of cases and empiric treatment may be effective [24]. As a matter of fact endometriosis does not always cause pain and the severity of the disease does not usually correlate with symptoms [27, 28]. Another mechanism hypothized is the direct innervation of ectopical endometrial growths by sensory and sympathetic fibers. Mechsner et al [33] also found a correlation between nerve fiber density and severity of pelvic pain or dysmenorrhea. In particular they found a correlation between deep dyspareunia and involvement of the uterus-sacral ligaments, painful defecation with vagina lesions, gastrointestinal symptoms with bowel involvement and lower urinary tract symptoms with bladder nodules. In their study they noticed that severe dysmenorrhea is correlated with adhesions in the Douglas pouch. Even if there are many factors that influence pain experienced in women with endometriosis, new researches suggested that a major contributing factor for pain is the sensory and autonomic activity derived from nerves sprouted from nearby tissues to innervate the ectopic growths.

Diseases

• Cardiomyopathic lentiginosis
• Pseudohypoaldosteronism type 1
• Triploid Syndrome
• Frontonasal dysplasia acromelic
• Arc syndrome
• Osteopetrosis, (generic term)
• Acanthosis nigricans

Comment the diagnosis is obvious but candidate 1 has given a more complete and comprehensive answer hiv infection risk statistics discount acivir pills 200 mg free shipping. Answering this type of oral question is rather like passing your driving test hiv symptoms five months after infection order acivir pills mastercard, demonstrating to the examiner that you are looking in the mirror before you pull out hiv infection causes cheap acivir pills 200mg online. The other modes of failure are pistoning antiviral diet order acivir pills no prescription, either the stem within cement or the stem within bone hiv infection rates louisiana buy generic acivir pills 200 mg, medial stem pivot and calcar pivot hiv infection french kissing generic 200 mg acivir pills. The question is essentially about excluding infection as a cause of early loosening. Basic science oral 2 Candidate was given a worn plastic acetabular cup and asked to comment. Keep things simple, all they were looking for was comparison of the degree of migration of the femoral head in to the acetabular component on serial radiographs. The cellular response to wear highly depends on the composition, size and shape of particles. I told them it was pistoning of the prosthesis and the cement mantle affecting all seven zones. They asked me to enumerate all the Gruen zones and describe the different modes of loosening one can get. I said I would prefer a white cell scan as a bone scan itself was of doubtful value. I then mentioned that I would like to perform an aspiration of the hip to rule out infection, which the examiners were very happy with. I said I would get the old notes to find out what type of prosthesis was used and also inform the theatre staff about bone grafting and also the different types of cabling devices and osteotomy plates available in case we have to do an extended trochanteric osteotomy. Collar or collarless: May promote direct transfer of load from the implant to the medial cement mantle and/or the bone of the medial femoral neck. Longitudinal slots/grooves: improves rotational stability of the stem within the cement mantle. Decreases stress shielding, and increases the interlock between the stem and the cement. Modularity (non-modular, modular): modular heads allow for adjustment in neck lengths. Medial (head stem) offset or femoral offset: perpendicular distance between the centre of the femoral head and the long axis of the distal part of the stem. Ratio of femoral head diameter to the femoral neck diameter: if increased there is a greater primary arc of motion. Large head (32 mm) Greater stability and range of movement but increased volumetric wear Less space is left for the acetabular component, resulting in a thinner layer of polyethylene. Stems with an oval cross-section have a better fit within the medullary canal and can occupy more of the cavity, leaving less room for cement and cancellous bone. More rectangular crosssections such as the Exeter (Stryker) are limited in size by their contact against the inner cortex of the oval cross-section of the medullary canal. Changing the Exeter stem from a polished to a matt finish resulted in a much higher failure rate. Shape stem: straight (curved only in the frontal and not sagittal plane) or anatomical (designed to fit the sagittal intramedullary anatomy). Anatomically shaped components allow better centralization of the stem and a more even thickness of the cement mantle. Compared with symmetrical stems, anatomical stems generate different strains within the cement mantle because of their specific shape. They are of the composite-beam type since their shape limits the subsidence required to achieve a stable position. Cementless femoral component Initial mechanical stability is achieved in one of two ways: 1. A distal centralizer is used to facilitate subsidence of the stem to a stable position without creating excessive stresses in the distal cement mantle. In the first year of implantation, loaded-taper stems show an initial subsidence between 0. Initial migration seems to be independent of the type of cement, its viscosity and the thickness of the cement mantle. The cement mantle surrounding these stems migrates only slightly within the femur, which does not appear to compromise long-term results. Stems relying on the composite-beam principle have more initial stability (especially longitudinal) with migration between 0. Both factors are worrying since excessive and continuous migration is predictive of failure. Non-porous coated threaded cups rely on a mechanical interlock between the acetabular bone and the implant threads for both initial stability and long-term fixation. They have fallen out of favour in recent years as a number of studies have shown unacceptable high early revision rates. Hemispheric designs the majority of acetabular components are hemispherical and are available in incremental sizes. Initial fixation of the acetabular component is usually accomplished by either a press-fit technique or a line-to-line fit. The press-fit technique involves the bone prepared being sized slightly smaller in diameter than the actual component. A line-to-line fit involves preparing bone to the same size as the implant and securing with screws. This is a less popular option today as initial enthusiasm from a few years ago has died down. Basic science oral 2: Materials properties of ceramic-on-ceramic bearing surfaces Bioinert and minimal inflammatory response. Superior wear resistance provides an excellent choice for young and active patients. The 6 Vs: Very strong Very stiff Very hard Very biocompatible Very reduced volumetric wear debris (compared with other bearings) Very brittle. Flanges on the acetabular components are designed to improve pressurization of cement. Cementless design the initial stability of an implant is achieved by mechanical interlock with the host bone. This is then converted to a longterm secondary stability by the ingrowth/ongrowth of a stable biological interface. Attempts to improve bone ingrowth in to metal implants have centred on either porous coating and/or coating with hydroxyapatite. A pore size of 50 mm is accepted as the minimum for bony ingrowth with an ideal pore size of between 50 mm and 400 mm to enhance bone ingrowth. Hydroxyapatite stimulates bone growth on to a prosthesis, achieving osseointegration and facilitating a biological bone between implant and bone. This biological bone can provide mineralized continuity around the prosthesis, with a sealing effect and a reduction in large early migration. The incidence of squeaking has been reported to vary widely, from 1% to 20%, with 3% being a generally accepted figure. A definite aetiology for squeaking in ceramic-on-ceramic bearing hips remains elusive and controversial. The cause is both complicated and multifactorial, with studies reporting mixed findings with factors such as cup position, patient age, height and weight. Recent work has implicated stem alloys, stem geometries and neck geometries as causative factors. The V-40 neck and titanium-molybdenum-zirconiumiron stem are particularly prone to cause squeaking. Retrieval analysis suggests a heavy wear pattern during activities at the extremes of motion such as rising from a seated position or other high flexion activities. On these occasions, edge loading between the ceramic head and the posterior rim of the ceramic cup occurs. Chip fractures and cracks can occur at the rim of the acetabular liners, particularly when components are malpositioned. I mentioned that I would like to assess serial radiographs of the hip and would look for periprosthetic cystic or scalloped lesions with a diameter exceeding 2 mm that was not present on the immediate postoperative films as evidence of osteolysis. The radiograph showed a rounding off of a medial edge of the resected femoral neck and fretting of the anterior aspect of the neck. I mentioned checking for femoral stem migration on serial radiographs (measured as the difference between the shoulder of the implant and the greater trochanter). The effective joint space has been defined as all periprosthetic regions that are accessible to joint fluid and thus particulate debris. An inflammatory response generated by osteolysis produces an increased hydrostatic pressure that allows for dissemination of particulate debris within the effective joint space. It is important to achieve an adequate seal to prevent this path for particulate debris. This can be achieved by either a complete cement mantle or a circumferentially proximally coated cementless implant. There is recent ongoing debate concerning unexplained hip pain, early failure and formation of pseudotumours. Joint registry data have shown an unexplained high early rate of failure for all designs of hip resurfacing. In addition to concerns about early loosening and soft-tissue reaction, there are conflicting reports on the amount of bone conservation, particularly on the acetabular side. The Australian joint registry found a significant gender difference between men (0. This was attributed to postmenopausal women having a reduced bone density or the increased risk of overpenetration of cement in to osteoporotic bone. Significant risk factors for the development of pseudotumour include female sex, age <40 years, small component size malpositioning of the acetabular component and hip dysplasia. Pseudotumours present with hip pain, a palpable lump in the groin, rash, pathological fractures, dislocations and nerve (sciatic and femoral) palsy. The periarticular mass can present with compression symptoms that include neuropathy, venous compression or thrombosis or compression of other structures. Findings at surgery are of a solid mass or fluid-filled cavity with surrounding muscle, soft tissue and bone destruction. Pseudotumours are universally reported as more common in women and are interpreted as a gender-specific higher susceptibility to metal ion hypersensitivity and stronger immune responses. Risk of neoplasm At present the primary concern of long-term induction of neoplasm is unfounded. Revision owing to femoral component loosening has a worse outcome than revision for femoral neck fracture or femoral head collapse or osteonecrosis. Histological analysis of soft tissues retrieved at revision surgery or biopsy demonstrates an immunological response, which leads to periprosthetic osteolysis. Pseudotumour (massive granuloma, neocapsule tissue reaction) A pseudotumour is a granulomatous mass or a destructive cystic lesion which is neither infective nor neoplastic and can cause extensive collateral damage. Possible problems include rim impingement, edge loading, deformation of the acetabular component, poor metallurgy and manufacture, and lack of fluid film lubrication. They recommend that worsening or severe pain, rising metal ions or increasing size of cystic or solid mass are concerning and may require revision surgery. There is increasing evidence that solid masses are more concerning than cystic ones. There is also evidence that cystic masses are found adjacent to well functioning hips. Some jigs are more user-friendly than others and are designed to minimize this risk Upsizing the head when performing the initial femoral head reaming and only downsizing if there is no chance of notching Experienced surgeon past the learning curve. Accurate component placement without notching is more difficult when the femoral head size decreases. Also, following head preparation, the ratio of femoral bone to metal component decreases disproportionately with decreasing head size. Other risk factors include varus alignment of the femoral component and a thick cement mantle at the dome of the femoral head. If the revision is performed for pseudotumours then results tend to be much poorer because of the associated soft-tissue damage. Opinion varied on the number of resurfacings needed to overcome the learning curve, ranging from 20 (36% of voters) to 50 (28% of voters) and >50 (30% of voters). I would exclude referred pain from elsewhere such as the spine, sacrum or femoral hernia. If the cup is in a reasonable position albeit opened more than ideal I would leave it. The procedure preserves the femoral neck and part of the head and does not invade the femoral canal, thus preserving bone stock.

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Immunogenicity of a protein indicates that its first administration did not elicit an immune response since the protein was not recognized as an antigen hiv infection canada statistics discount 200 mg acivir pills overnight delivery. However hiv infection rates uk best order for acivir pills, repeated protein administration led to the formation of antibodies hiv infection germany buy acivir pills with amex, causing an immune reaction anti virus protection cheap acivir pills 200mg. Antigenicity hiv infection how early symptoms order acivir pills 200mg without a prescription, on the other hand oral antiviral buy acivir pills line, refers to the ability of specific sites (epitopes) on the protein to recognize antibodies in the host immune system. Thus, the first administration of an antigenic protein would lead to an immune reaction. While proteins made in a particular organism are recognized by the immune system as "self" protein and normally do not elicit an immune response, misfolded or denatured forms of "self" proteins may be immunogenic. Approaches toward humanizing antibodies or adding specific human sequences to murine antibodies to make chimeras have greatly improved their therapeutic potential by reducing or eliminating their immune response. Proteins are metabolized by peptidases, leading to rapid loss of their biological activity. Proteins often elicit an immune response following repeated use due to the development of neutralizing antibodies or hypersensitivity reactions. Thus, protein aggregation can lead to perception of foreign epitope by host cells and generation of antibodies against the injected protein. In terms of formulation requirements, the needed volume of injection is determined by the drug dose and solubility. Preparation of concentrated protein solutions can, however, lead to high viscosity-which could make deaeration upon agitation and deliverability Protein and Peptide Drug Delivery 421 through a syringe difficult. For example, requirement of patient self-administration versus administration by a nurse in a hospital setting. For example, age of the patient significantly affects what kind of delivery devices may be used. Proteins and peptides for parenteral administration are typically formulated as readyto-use aqueous solutions or as lyophilized solid mass that is reconstituted in to a protein solution by dilution with water, isotonic dextrose solution, or isotonic sodium chloride solution immediately before administration. Proteins and peptides for inhalation and nasal routes of administration are typically formulated as dry powders. Selection of an appropriate buffer type and strength is carried out to minimize specific/ general-acid/base degradation of the protein. Addition of these components to aqueous solutions of proteins leads their hydrogen bonding on the protein surface, thus stabilizing the native protein conformation. Formulation (dilution and addition of excipients) Protein and Peptide Drug Delivery 423 3. Inspection of filled vials or syringes for the presence of any particulate matter 6. Use of a delivery device for drug administration to the patient Many of these processes may affect formulation stability. In addition, leaching of metal ions from manufacturing vessels in to the protein formulation can lead to protein instability. In such cases, freeze-drying or lyophilization is often employed to minimize the kinetics of degradation processes that occur in solutions. Lyophilized products, sometimes, can also provide the flexibility of dose concentration and injection volume. However, lyophilization can sometimes increase the degradation rate of proteins due to increased concentration of reacting species. The role of residual moisture in the lyophilized formulations on proteins stability can be complex. A protein may need some minimum moisture content to shield its highly polar groups, which would otherwise be exposed leading to aggregation, which may manifest as opalescence upon reconstitution. High moisture content, on the other hand, could increase plasticity in the system leading to high reactivity, including aggregation. For example, insulin, tetanus toxoid, somatotrophin, and human albumin aggregate in the presence of moisture, which can lead to reduced activity, stability, and diffusion. It is obviously important to choose formulation components that stabilize the protein during and after lyophilization. Sugars stabilize most proteins during lyophilization by protecting against dehydration. The secondary structure of proteins refers to the conformation of the polypeptide backbone. Oxidation of methionine to methionine sulfoxide can be reversed with a suitable reducing agent. The peptide bond between aspartic acid and proline are susceptible to hydrolysis at acidic pH. High residual moisture content may induce aggregation of the lyophilized proteins. In Pharmaceutical Formulation Development of Peptides and Proteins, Frokjaer S, Hovgaard L (eds. Walsh G (2002) Proteins: Biochemistry and Biotechnology, John Wiley & Sons, New York. Traditional drugs are designed to interact with protein molecules throughout the body that support or cause diseases. Compared to conventional small molecular weight and protein drugs, nucleic acid medicines are designed to be highly potent pharmaceutical products, which can be administered to patients by conventional routes, such as direct injection, inhalation, or intravenous injection. Several different approaches are used for turning nucleic acids in to therapeutics. The promise of these nucleic acid drugs is to allow either the production of therapeutic proteins that may be difficult to administer exogenously or the inhibition of abnormal protein production. Sometime over expression of a particular protein can lead to many diseases including cancer. Antisense drugs work at the genetic level to interrupt the process by which disease-causing proteins are produced. By acting at this earlier stage in the disease-causing process to prevent the production of a disease-causing protein, antisense drugs have the potential to provide greater therapeutic benefit than traditional drugs which do not act until the disease-causing protein has already been produced. Gene therapy aims at producing therapeutic proteins, while antisense therapy aims at blocking the production of aberrant proteins. They are rapidly degraded under physiological conditions by nucleases, primarily 3-exonucleases. Triplex helix formation may then prevent the interaction of various transcription factors, or it may physically block the initiation or elongation of the transcription complex. The various purine and pyrimidine bases are linked to the backbone by methylene carbonyl bonds. In this approach, the target site is often extracellular and hence the aptamer nucleic acid does not have to cross cell membranes after parenteral administration. The promise of gene therapy is to overcome limitations associated with the administration of therapeutic proteins, including low bioavailability, inadequate pharmacokinetic profiles, and high manufacturing cost. There are two approaches currently being used for gene transfer: viral and nonviral. A part of viral genome is replaced by a therapeutic gene and thus a viral vector consists of genetic material that can be taken up by the target cells, leading to transgene expression. Viruses are naturally evolved vehicles which efficiently transfer their genes in to host cells. This ability makes them quite attractive for engineering viral vector systems for gene delivery. The advantages and disadvantages of different viral vectors are listed in Table 23. Retroviruses still remain the most commonly used vectors for clinical trials with 27% (n = 263) of the total patients enrolled by the end of 2005. Among these, melanoma represents for 39%, followed by metastatic cancers (14%) and glioblastoma (11%). Their special ability to infect and integrate in to nondividing cells has application for the construction of lentiviral vectors for gene delivery in to nondividing terminally differentiated cells such as neuronal tissue, hematopoietic cells, and myofibers. Genes introduced in to cells using adenoviral vectors are maintained in the nucleus episomally and provide transient transgene expression. Modifications in the adenoviral genome are introduced by deletion of the viral replication specific gene known as early gene1 (E1A) and creating space for gene insertion. In these first generation adenoviral-vectors, additional partial deletions of E1B and E3 genes can be made to create more space for gene expression. Two hundred and ninety-three helper cells are needed for the generation of infectious viral particles. Disadvantages include their episomal (extrachromosomal) status in the host cell that permits only transient expression of the therapeutic gene. Furthermore, expression of the E2 viral protein provokes inflammatory reactions and toxicities that limit repeated application of adenoviral vector for therapeutic benefit. It is of special interest, as it has natural tropism toward neuronal cells and this property can be exploited for gene therapies for neuronal tumors. The virus does not integrate in to the host genome, which is the cause of transient expression in infected cell population. Therapeutic gene, gene delivery system, and gene expression plasmid are the three basic components of a nonviral gene medicine. The gene delivery system distributes the plasmid to the desired target cells, after which the plasmid is internalized in to the cells. Due to its unfavorable physico-chemical properties, there is a growing need for novel delivery systems, which should be safe 436 Pharmaceutical Dosage Forms and Drug Delivery for repeated administration. The apparent potency of a plasmid is reduced by its chemical, enzymatic, and colloidal instability; sequestration by cells of the immune system; uptake and adsorption by nontarget cells and structures; access to both target tissues; and uptake and trafficking to the nucleus of the cells. Most commonly used synthetic gene carriers are cationic polymers and lipids, which condense plasmids in to small particles and protect them from degradation by nucleases. The cationic lipid and colipid are mixed together in chloroform, which is then evaporated to dryness. Water is added to the dried lipid film and the hydrated film is then either extruded or sonicated to form cationic liposomes. Biotechnology-Based Dosage Forms 437 micellar structures) and can interact with cell membranes; (ii) a linker group; and (iii) a positively charged headgroup, which interacts with plasmid, leading to its condensation. The relative proportions of each component, and the structure of the head group influence the physico-chemical properties of liposome/plasmid complexes. The resulting complexes retain their ability to interact specifically with target cell receptors, leading to receptor-mediated internalization of the complex in to the cells. These new materials will be tailored to interact more on cellular and protein levels to achieve high degrees of specificity, activity, and functionality. These polymeric materials include (i) polymers for protein and antibody conjugates, (ii) stimuli sensitive polymers, (iii) polymer/cell matrix, (iv) functional biodegradable polymers, and (v) polymeric gene carriers. Noncondensing polymers, such as polyvinyl pyrrolidone and pluronics can also be used for delivery of nucleic acids to muscles and tumors. Which allows production of therapeutic protein or inhibition of abnormal protein production D. Which allows somatic or germ-line cells to produce therapeutic/reporter proteins E. Control the intracellular production of a gene product in response to a disease B. Gene expression can be turned on or off in response to the benefits of treatment E. Healthy subjects are evaluated in phase I clinical trials of drug product development. It also monitors all human drugs and biopharmaceuticals once they are in the market, and removes products from the market that may not be manufactured properly or may cause harm to patients. Post marketing surveillance studies may also reveal additional side effects, and rare, serious and unexpected adverse effects. According to pH-partition theory, absorption of a weak electrolyte drug depends on the extent to which the drug exists in its un-ionized form at the absorption site. However, the pH-partition theory often does not hold true, 439 440 Answers to Review Questions 2. False True False True Adsorption is different from absorption, which implies penetration through organs and tissues. The degree of adsorption depends on the chemical nature of the adsorbent and the adsorbate, surface area of the adsorbent, temperature, and partial pressure of the adsorbed gas. The pH-partition theory states that drugs are absorbed from the biological membranes by passive diffusion, depending on the fraction of un-ionized form of the drug at the pH of that biological membrane. The solution pH will affect the overall partition coefficient of an ionizable substance. The conjugate acid form will predominate at a pH lower than the pKa, and the conjugate base form will be present at a pH higher than the pKa. For example, most weak acids are well absorbed from the small intestine, which is contrary to the prediction of the pH-partition hypothesis.

Stimulant (Castor). Acivir Pills.

• Dosing considerations for Castor.
• Syphilis; arthritis; skin disorders; boils; blisters; swelling (inflammation) of the middle ear; migraines; softening cysts, warts, bunions and corns; promoting the flow of breast milk; and other conditions.
• Are there any interactions with medications?
• What is Castor?
• Birth control.
• How does Castor work?
• Are there safety concerns?
• What other names is Castor known by?
• Constipation.

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