M. Cobryn. Southern Illinois University Medical School at Springsfield.
A commercial product based on conventional liposomes has been introduced for the parenteral delivery of the anti-fungal drug discount 25mg sumatriptan muscle relaxant trade names, amphotericin B buy 25 mg sumatriptan mastercard spasms under eye, which is poorly tolerated in conventional formulations discount 50 mg sumatriptan otc spasms in legs. Two other lipid-based formulations of amphotericin B have also recently been commercially introduced: • Abelcet consists of ribbon-like structures having a diameter in the 2–5 µm range discount sumatriptan 50 mg muscle relaxant modiek. In spite of the large differences in structural features (a further example of “liposomal” versatility) discount sumatriptan 50 mg with mastercard spasms feel like baby kicking, all formulations have been shown to greatly reduce the toxicity of amphotericin B, allowing higher doses to be given and thereby improving clinical efficacy. DaunoXome liposomes are also long circulating liposomes, in this case encapsulating the cytostatic daunorubicin. Although a non-stealth system, long circulation times are attained by using a particularly rigid bilayer composition, in combination with a relatively small liposome size. The encapsulation of these anthracycline cytostatics in liposomes effects a modified biodistribution of the drug; the drug is distributed away from the heart, where it can exert considerable toxic effects, and is preferentially taken up by solid tumor tissue. The primary focus of their use has been in the targeted delivery of anticancer agents. The stability of these micelles depends on the nature of the hydrophilic and hydrophobic effects. Micellar systems based on amphipathic block-copolymers have gained most attention as intravenously administered drug carrier systems over the years. These block-copolymers form micelles in aqueous solution with spherical core/shell structures and diameters around 20–40 nm (Figure 5. The hydrophobic core of these micelles can be loaded with a hydrophobic drug such as doxorubicin. After intravenous administration the micelles tend to accumulate at tumor sites and release the entrapped drug there. Polymeric micelles loaded with doxorubicin have shown strongly increased antitumor activity in animal models. Work in progress to optimize the performance of polymeric micelles includes varying the copolymer characteristics, drug pay load, covalent binding strategies and using other types of drugs. Drug loading efficiency varies widely between different drugs, monomers and reaction conditions. Poor drug loading is therefore generally achieved for alkaline drugs because the polymerization reaction takes place under acidic conditions. Poly(butyl cyanoacrylate) nanoparticles are degraded fairly rapidly (1 day), whereas poly(hexyl cyanoacrylate) nanoparticles take a number of days to degrade. Poly(alkyl cyanoacrylate) nanoparticles accumulate in the liver (60–90% of the injected dose) and the spleen upon iv injection, with the macrophages in the liver being their major target. Nanoparticles loaded with doxorubicin have shown a markedly enhanced therapeutic index in a number of animal tumor models. Release of drug from the Kupffer cells upon breakdown of the nanoparticles in the lysosomal system (see Figure 5. Another application where these nanoparticles have been shown to have large therapeutic promise is the killing of pathogens that are specifically located in the Kupffer cells in the liver. The lipid core material consists of cholesterol and other lipids (cholesterol esters, triacylglycerols and phospholipids) which are transported in plasma and other body fluids in the form of lipoproteins. These endogenous lipid carriers have been studied for the site-specific delivery of lipophilic drugs. This system is being investigated for the targeting of hydrophobic antiviral prodrugs to parenchymal liver cells in viral hepatitis. This can be chemically cross-linked by the addition of a cross-linking agent such as glutaraldehyde or butadione, or thermally cross-linked by applying heat. The size of the particles is based on the droplet size of the initial emulsion, and can range from 15 nm–150 µm.
In pedi- atric patients discount sumatriptan 50 mg free shipping spasms muscle twitching, it is used primarily for treatment of hypertensive emergencies and after cardiovascular surgery (especially with cardiopulmonary bypass) to improve coronary blood flow and myocardial perfusion cheap sumatriptan 25mg visa infantile spasms 2 year old. Nitroglycerin seems to dilate veins more than arteries cheap sumatriptan 50 mg otc spasms near elbow, although the coronary arteries respond well purchase 25 mg sumatriptan mastercard muscle relaxant generic, resulting in improved myocardial oxygen delivery purchase sumatriptan 25mg visa infantile spasms 6 months old. Systemic venous dilation results in lower atrial filling pressures (preload) and ventricular end diastolic pressures; this effect reduces myocardial oxygen demand. Systemic arterial dilation also reduces myocardial oxygen demand by reducing afterload. Usual maximum dose is 5µg/kg/min, but doses to 20µg/kg/ min have been described Adults: Oral: 2. Can be used before activities that cause angina Ointment: 1 inch to 2 inches every 8 hours Patch: initial, 0. To minimize tolerance, a daily drug-free interval of 10 to 12h/day is recommended, along with the lowest effective dose possible. Tolerance may also be reversed with the administration of N-acetylcysteine Pharmacokinetics (Table 4-2) Distribution: volume of distribution in adults, 3 L/kg Half-life: 1 to 4 minutes Protein binding: 60% Metabolism: extensive first-pass; metabolized by red blood cells, blood vessel walls, and the liver Clearance: approximately 1 L/kg/min Elimination: inactive metabolites are excreted in the urine Table 4-2. Pharmacodynamics of various forms of nitroglycerin Dosage Form Onset (min) Duration I. Contraindications Hypersensitivity to nitroglycerin and organic nitrates (rare) or any component (adhesive in transdermal patches included); glaucoma; severe anemia; increased intracranial pressure; concurrent use of sildenafil; the I. Adverse Effects Cardiovascular: hypotension, reflex tachycardia, pallor, flushing, and cardiovascular collapse; acute cessation of therapy may cause severe hypotension, bradycardia, and acute coronary insufficiency Central nervous system: headache (most commonly reported side effect), dizziness, restlessness Gastrointestinal: nausea, vomiting Endocrine/metabolic: one I. Drug-Drug Interactions Nitroglycerin may antagonize the anticoagulant effect of heparin; thus, when nitroglycerin is discontinued, a reduction in heparin dose may be required. Alcohol and drugs that lower blood pressure, such as β-blockers and calcium channel blockers, may potentiate nitroglycerin’s hypotensive effect. Concomitant use of sildenafil may cause severe hypotension from excessive vasodilation. Multiple additional forms of nitroglycerin exist for oral (tablet, capsule, and aerosol) and topical (ointment and transdermal patch) administration (see, for example, Lexi-Comp’s Pediatric Dosage Handbook, 13th Edition, 20063 for additional details on these multiple formulations). Tolerance to Organic Nitrates: Mechanisms, Clinical Relevance, and Strategies for Prevention. Nitroprusside seems to cause more systemic arterial (at the arteriolar level) dilation than systemic venous dilation. Dosing Neonates (premature and full term) and infants: insufficient data on dosing exist for neonates and infants. In clinical practice, dosing guidelines developed for children are typically followed for infants 4. The dose is titrated to achieve the desired reduction in blood pressure by increasing in increments of 1µg/kg/min every 20 to 60 minutes. The dose is titrated to achieve the desired effect or until headache or nausea appear by increasing in increments of 0. Usual dose is 3µg/kg/min; maximum dose, 10µg/kg/min Pharmacokinetics Onset of action: less than 2 minutes (hypotensive effect) Half-life: parent drug, less than 10 minutes; thiocyanate, 2. Monitor closely for signs of cyanide and thiocyanate oxicity (see Poisoning Information), including acid-base status, blood cyanide level (especially patients with hepatic dysfunction), and blood thiocyanate level. Adverse Effects Cardiovascular: excessive hypotensive response, palpitations, reflex tachycardia, substernal chest pain Respiratory: tachypnea or respiratory distress (from metabolic acidosis caused by cyanide toxicity), hypoxemia Central nervous system: disorientation, restlessness, headache, psychosis, elevated intracranial pressure Gastrointestinal: nausea, vomiting 106 S. Neuromuscular and skeletal: weakness, muscle spasm Endocrine/metabolic: thyroid suppression Hematological: thiocyanate toxicity Other: diaphoresis, tinnitus Precautions Because both the liver and kidney contribute to removal of nitroprusside’s breakdown products, use with caution in patients with either hepatic or renal dysfunction.
T cell independent anti- donovani amastigotes: antibody facilitation of alternate comple- gens order sumatriptan 50 mg amex muscle relaxant amazon. Leishmaniases of the New World: current receptor is required to sustain infection in murine cutaneous concepts and implications for future research buy sumatriptan 25mg with amex muscle relaxant bodybuilding. Biochem Biophys Res Commun 2000; role of the Leishmania major ribosomal protein S3a homologue 273:793–8 buy 25mg sumatriptan with visa muscle relaxant in pediatrics. Interaction of Leishmania gp63 with cellular receptors for fibro- Nature 1997; 388:900–3 cheap 25mg sumatriptan fast delivery muscle relaxant in pregnancy. Cloning and characterization of two mouse genes mechanism of parasite control and evasion buy 25 mg sumatriptan with mastercard muscle relaxant 800 mg. Cytotoxicity of human serum for Leishmania Biochem Biophys Res Commun 1999; 260:273–9. In vitro growth of Leishmania amazonensis promastigotes resistant to pentamidine is dependent on interactions among strains. Apoptosis in a unicellular eukaryote (Trypanosoma cruzi): implications for the evolutionary origin and role of programmed cell death in the control of cell proliferation, differentiation and survival. Leishmania mexicana cysteine proteinase-deficient mutants have attenuated virulence for mice and potentiate a Th1 response. Localized mucosal leishmaniasis due to Leishmania (Leishmania) infantum: clinical and microbiologic findings in 31 patients. Canine leishmaniasis: clinical, parasitological and entomological follow-up after chemotherapy. The biogenesis and properties of the parasitophorous vacuoles that harbour Leishmania in murine macrophages. Mitochondrial release of apoptosis-inducing factor occurs downstream of cytochrome c release in response to several proapoptotic stimuli. Studies on control of visceral leishmaniasis: impact of dog control on canine and human visceral leishmaniasis in Jacobina, Bahia, Brazil. Latex agglutination test for the detection of urinary antigens in visceral leishmaniasis. Trypanothione as a target in the design of antitrypanosomal and antileishmanial agents. Treatment of visceral leishmaniasis with pentavalent antimony and interferon gamma. Natural killer cell behavior in lymph nodes revealed by static and real-time imaging. Axenic cultivation and partial characterization of Leishmania braziliensis amastigote-like stages. Inhibition of histone deacetylase 6 acetylates and disrupts the chaperone function of heat shock protein 90: a novel basis for antileukemia activity of histone deacetylase inhibitors. Mannose-coated liposomal hamycin in the treatment of experimental leishmaniasis in hamsters. Drug delivery system: targeting of pentamidines to specific sites using sugar grafted liposomes. Leishmaniasis in Bahia, Brazil: evidence that Leishmania amazonensis produces a wide spectrum of clinical disease. Resistance to pentamidine in Leishmania mexicana involves exclusion of the drug from the mitochondrion. Molecular and cellular effects of hexadecylphosphocholine (Miltefosine) in human myeloid leukaemic cell lines. Development of a natural model of cutaneous leishmaniasis: powerful effects of vector saliva and saliva preexposure on the long-term outcome of Leishmania major infection in the mouse ear dermis. The interaction of Alba, a conserved archaeal chromatin protein, with Sir2 and its regulation by acetylation.
No increase in the incidence of benign or malignant tumours was observed (Tucker et al cheap 50mg sumatriptan with mastercard spasms meaning in english. This series of events occurs readily in herpesvirus-infected tissues but poorly in normal tissues buy 25mg sumatriptan with amex spasms hiccups, since the initial phosphorylation is accomplished mainly by a herpesvirus-specific deoxynucleoside (thymidine) kinase (Elion order 25 mg sumatriptan mastercard muscle relaxant cz 10, 1983; Laskin order sumatriptan 25mg without prescription spasms right side abdomen, 1984; King order sumatriptan 25mg on line muscle relaxant pictures, 1988). The aci- clovir triphosphate is formed readily and is more persistent than the parent compound, remaining for several hours in cultured cells. When taken orally, the drug is poorly absorbed from the gastrointestinal tract, with a reported bioavailability of 15–30%, owing to its limited solubility in an aqueous environment; therefore, intravenous dosing is considered more effective (O’Brien & Campoli-Richards, 1989). The drug is widely distributed throughout the body and has been found in plasma, kidney, lung, liver, heart, vagina, brain, cerebrospinal fluid, aqueous humor, saliva and skin (Laskin, 1983; de Miranda & Blum, 1983; Rogers & Fowle, 1983; Brigden & Whiteman, 1985; O’Brien & Campoli-Richards, 1989; Vergin et al. After oral doses of 200 mg taken four to five times daily or 400 mg taken two to three times daily, the peak plasma concentration is about 2 μmol/L (0. After oral administration, the amount of aciclovir in the kidney and lung was actually higher than that in plasma, while the concentration in cerebrospinal fluid was half of that in plasma (Blum et al. After topical administration, the epidermal concentration of aciclovir was enhanced 48-fold over that observed after oral dosing, but the delivery of the drug to viruses replicating in the basal epidermis was considerably less efficient (Parry et al. The pharmacokinetics of intravenously administered aciclovir has been described best by a two-compartment open model (Laskin, 1983; Rogers & Fowle, 1983; O’Brien & Campoli-Richards, 1989). The binding of aciclovir to plasma protein has been reported to be 9–33%; the peak concentrations in plasma are typically achieved within 1. After intravenous dosing with aciclovir, 45–75% of the drug is excreted in the urine as unchanged compound, but after oral dosing this percentage is reduced to 14–22%, with a large fraction appearing in the faeces (Laskin, 1983; de Miranda & Blum, 1983; Vergin et al. Two minor urinary metabolites, 9-carboxymethoxy- methylguanine and 8-hydroxy-9-(2-hydroxyethyl)guanine, have been reported to constitute 8–14% and about 0. Active renal clearance occurs by glomerular filtration and renal tubular secretion, with a half-time of 2–3 h (Laskin, 1983; O’Brien & Campoli-Richards, 1989) and a clearance rate of 3. In patients with renal impairment, the mean elimi- nation half-time can be extended to 20 h, and the total body clearance rate can be decreased 10-fold; it is therefore necessary to reduce the dose accordingly (de Miranda & Blum, 1983; Rogers & Fowle, 1983; Brigden & Whiteman, 1985; O’Brien & Campoli-Richards, 1989). Transplacental pharmacokinetics A 39-year-old pregnant woman, presumed to be at 30 weeks of gestation, was treated with aciclovir (350 mg, or 15 mg/kg bw) intravenously every 8 h throughout the remainder of gestation. Beginning at week 38 of gestation and continuing until delivery, seven women were treated orally with 200 mg aciclovir every 8 h and eight with 400 mg aciclovir every 8 h. The drug appears to be taken up efficiently by many tissues, including the brain and skin (de Miranda et al. Like humans, dogs, rats and rhesus monkeys show a biphasic decline in the plasma concentration of aciclovir, indicating a two-compartment open model, with a half-time of 1–3 h (de Miranda et al. Gastrointestinal absorption was poor in the 8-week-old rats, with a bioavailability of 7. Absorption of aciclovir in the gastrointestinal tracts of the young rats was shown to occur by an efficient passive diffusion process, which apparently becomes inefficient at the time of weaning (Fujioka et al. Beagle dogs given 20 mg/kg bw aciclovir had a mean peak plasma concentration of 42 μmol/L (10 mg/L) by 1. The body clearance was similar to the glomerular filtration rate, indicating the absence of active tubular secretion (de Miranda et al. Skin absorption occurred by a first-order process which resulted in excretion of about 0. When aciclovir is given orally, the doses are typically low and serious adverse events are extremely rare (Goldberg et al. Oral dosing is less frequently neurotoxic but was reported to induce acute disorientation in four patients, three of whom had renal insufficiency (MacDiarmaid-Gordon et al. Renal dysfunction is not an absolute requirement for aciclovir-induced neurotoxicity; but, apart from age and neurotoxic medications (Rashiq et al.
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