Aminoglycosides and dosing frequency-related toxicity:-


Traditionally, aminoglycosides have been administered in two or three equally divided daily doses for patients with normal renal function. However, once-daily aminoglycoside dosing may be preferred in certain clinical situations.

Aminoglycosides have concentration-dependent killing; that is, increasing concentrations kill an increasing proportion of bacteria and at a more rapid rate. They also have a significant postantibiotic effect, such that the antibacterial activity persists beyond the time during which measurable drug is present. The postantibiotic effect of aminoglycosides can reach several hours. Because of these properties, a given total amount of aminoglycoside may have better efficacy when administered as a single large dose than when administered as multiple smaller doses.

Aminoglycoside toxicity is both time- and concentration-dependent. Toxicity is unlikely to occur until a certain threshold concentration is achieved, but once that concentration is achieved the time above this threshold becomes critical. This threshold is not precisely defined, but a trough concentration above 2 mcg/mL is predictive of toxicity. At clinically relevant doses, the time above this threshold will be greater with multiple smaller doses of drug than with a single large dose.

Numerous clinical studies demonstrate that a single daily dose of aminoglycoside is just as effective and no more (and often less) toxic than multiple smaller doses. Therefore, many authorities now recommend that aminoglycosides be administered as a single daily dose in many clinical situations. The efficacy of once-daily aminoglycoside dosing in combination therapy of enterococcal, streptococcal, and staphylococcal endocarditis remains to be defined, and the standard low-dose, thrice-daily administration is still recommended. The role of once-daily dosing in pregnancy and in neonates also is not well-defined.

Once-daily dosing has potential practical advantages. For example, determination of serum concentrations is probably unnecessary unless aminoglycoside is given for more than 3 days. A drug administered once a day rather than three times a day saves time. And once-a-day dosing lends itself to outpatient therapy.

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INSUIN-LIKE GROWTH FACTOR AND

CARCINOGENICITY

Cancer is a leading cause of mortality in the United States. Despite much research on specific carcinogens, the cause of many cancers remains unclear. The identification of novel causative agents offers the potential for cancer prevention. Diseases such as obesity and diabetes mellitus, characterized by hyperinsulinemia, are associated with increased risk of endometrial, colorectal, and breast carcinomas. There is increasing evidence that insulin is a growth factor for tumor formation. The mechanisms underlying insulin-mediated neoplasia may include enhanced DNA synthesis with resultant tumor cell growth, inhibition of apoptosis, and altered sex hormone milieu. The reduced insulin levels seen with physical activity, weight loss, and a high fiber diet may account for decreased cancer risk. The role of newer drugs that restore sensitivity to insulin, thereby reducing hyperinsulinemia, is an exciting potential area of cancer prevention. In this review, we discuss the potential role of insulin as a tumor growth factor .

Interest in the role of the insulin-like growth factor (IGF) axis in growth control and carcinogenesis has recently been increased by the finding of elevated serum insulin-like growth factor I (IGF-I) levels in association with three of the most prevalent cancers in the United States: prostate cancer, colorectal cancer, and lung cancer. IGFs serve as endocrine, autocrine, and paracrine stimulators of mitogenesis, survival, and cellular transformation. These actions are mediated through the type 1 IGF-receptor (IGF-1R), a tyrosine kinase that resembles the insulin receptor. The availability of free IGF for interaction with the IGF-1R is modulated by the insulin-like growth factor-binding proteins (IGFBPs). IGFBPs, especially IGFBP-3, also have IGF-independent effects on cell growth. IGF-independent growth inhibition by IGFBP-3 is believed to occur through IGFBP-3-specific cell surface association proteins or receptors and involves nuclear translocation. IGFBP-3-mediated apoptosis is controlled by numerous cell cycle regulators in both normal and disease processes. IGFBP activity is also regulated by IGFBP proteases, which affect the relative affinities of IGFBPs, IGFs and IGF-1R. Perturbations in each level of the IGF axis have been implicated in cancer formation and progression in various cell types.

The incidence of colon, pancreatic, and kidney cancers, as well as aggressive prostate cancer in men, and breast and endometrial cancer in women is invariably high in Western countries. Nutritional and related factors have been typically implicated. This review presents a model integrating nutrition, insulin and IGF-1 physiology ("bioactive" IGF-1), and carcinogenesis based on the following: (1) insulin and the IGF-1 axis function in an integrated fashion to promote cell growth and survival; (2) chronic exposure to these growth properties enhances carcinogenesis; (3) factors that influence bioactive IGF-1 will affect cancer risk. The model presented here summarizes the data that chronic exposure to high levels of insulin and IGF-1 may mediate many of the risk factors for some cancers that are high in Western populations. This hypothesis may help explain some of the epidemiologic patterns observed for these cancers, both from a cross-national perspective and within populations. Of particular importance is that some of relevant factors are modifiable through nutritional and lifestyle interventions. Out of a variety of perspectives presented, nutritional manipulation through the insulin pathway may be more feasible than attempting to influence total IGF-1 concentrations, which are determined largely by growth hormone. Further study is required to test these conclusions.

Doxorubicin

Doxorubicin

Doxorubicin
Chemical data
Formula
C27H29NO11
Mol. mass
543.52 g/mol
Pharmacokinetic data
Bioavailability
5% (Oral)
Metabolism
CYP3A4
Half life
12–18.5 hours[1]
Excretion
Biliary and fecal
Therapeutic considerations
Pregnancy cat.
D(AU) D(US)
Legal status
POM(UK) ℞-only(US)
Routes
Intravenous
Doxorubicin , trade name Adriamycin; also known as hydroxydaunorubicin) is a drug used in cancer chemotherapy. It is an anthracycline antibiotic,

Mechanism of action
The exact mechanism of action of doxorubicin is complex and still somewhat unclear, though it is thought to interact with DNA by intercalation.Doxorubicin is known to interact with DNA by intercalation and inhibition of macromolecular biosynthesis. This inhibits the progression of the enzyme topoisomerase II, which unwinds DNA for transcription. Doxorubicin stabilizes the topoisomerase II complex after it has broken the DNA chain for replication, preventing the DNA double helix from being resealed and thereby stopping the process of replication.
The planar aromatic chromophore portion of the molecule intercalates between two base pairs of the DNA, while the six-membered daunosamine sugar sits in the minor groove and interacts with flanking base pairs immediately adjacent to the intercalation site, as evidenced by several crystal structures

Clinical use
Doxorubicin is commonly used to treat some leukemias, Hodgkin's lymphoma, as well as cancers of the bladder, breast, stomach, lung, ovaries, thyroid, soft tissue sarcoma, multiple myeloma, and others.Commonly used doxorubicin-containing regimens are CA (cyclophosphamide, Adriamycin), TAC (Taxotere, CA), ABVD (Adriamycin, Bleomycin, Vinblastine, Dacarbazine), BEACOPP, CHOP (Cyclophosphamide, Adriamycin, Vincristine, Prednisone) and FAC (5-Fluorouracil, Adriamycin, Cyclophosphamide). Doxil is used primarily for the treatment of ovarian cancer where the disease has progressed or recurred after platinum-based chemotherapy, or for the treatment of AIDS-related Kaposi's sarcoma

Side effects
Acute side-effects of doxorubicin can include nausea, vomiting, and heart arrhythmias. It can also cause neutropenia (a decrease in white blood cells), as well as complete alopecia (hair loss). When the cumulative dose of doxorubicin reaches 550 mg/m², the risks of developing cardiac side effects, including congestive heart failure, dilated cardiomyopathy, and death, dramatically increase. Doxorubicin cardiotoxicity is characterized by a dose-dependent decline in mitochondrial oxidative phosphorylation. Reactive oxygen species, generated by the interaction of doxorubicin with iron, can then damage the myocytes (heart cells), causing myofibrillar loss and cytoplasmic vacuolization. Additionally, some patients may develop Palmar plantar erythrodysesthesia, or, "Hand-Foot Syndrome," characterized by skin eruptions on the palms of the hand or soles of the feet, characterized by swelling, pain and erythema.
Due to these side effects and its red color, doxorubicin has earned the nickname "red devil"or "red death."
Doxorubucin can also cause reactivation of Hepatitis B

Diclofenac and asthma

Diclofenac

1.Cyclooxygenase (COX) -1 and COX-2 are expressed in airway cells, where their activities influence functions such as airway hyperreactivity. Clinical data show that mixed COX-1/COX-2 inhibitors such as aspirin, but not COX-2 selective inhibitors such as rofecoxib, induce bronchoconstriction and asthma in sensitive individuals. Here, we have used tissue from genetically modified mice lacking functional COX-1 (COX-1–/–), as well as airway tissue from "aspirin-sensitive" and control patients to address this issue. Bronchi from wild-type mice contained predominantly COX-1 immunoreactivity and contracted in vitro in response to acetylcholine and U46619. Bronchi from COX-1–/– mice were hyperresponsive to bronchoconstrictors. Inhibitors of COX (naproxen, diclofenac, or ibuprofen) increased bronchoconstriction in tissue from wild-type but not from COX-1–/– mice .

2.Aspirin and other Nonsterodial anti-inflammatory drugs such as diclofenac sodium can precipitate asthma in sensitive individuals . These attacks develop about half an hour after ingestion and are frequently accompanied by flushing and rhinorhoea . Random populations surveys have found that 4-9% of asthmatics were affected .
Cross sensitivity between aspirin and the many differently structured nonsteroidal anti-inflammatory drugs molecules argues against an allergic mechanism.

Other theory suggests that NSAID decreases PGE2 via inhibition of cyclo-oxygenase enzyme and this will create an imbalance between bronchodilator and bronchoconstictor prostanoids and leukotrines .
1.FASEB Journal.
2.Roger Walker, Clinical Pharmacy .