Ocular penetration of acyclovir and its peptide prodrugs valacyclovir and val-valacyclovir following systemic administration in rabbits: An evaluation using ocular microdialysis and LC-MS

PURPOSE: To investigate the ocular penetration of acyclovir and its prodrugs following systemic administration and to elucidate the mechanism of penetration. METHODS: Hydrophilic peptide prodrugs of acyclovir were infused intravenously in New Zealand albino rabbits over 45 min at a dose equivalent to 30 mmoles/kg acyclovir. Aqueous and vitreous humor samples were obtained utilizing ocular microdialysis and blood samples were obtained from the mid ear vein using a cannula. RESULTS: The plasma bioavailability for acyclovir, valacyclovir and val-valacyclovir were similar with area under curve values being 896.24 (+/-143.58), 776.54 (+/-197.52), 824.69 (+/-217.43) min x micromoles/L respectively. Anterior segment area under curve values were 53.70 (+/-35.58), 139.85 (+/-9.43) and 291.05 (+/-88.13) min x micromoles/L respectively while the mean residence time values were 46.47 (+/-24.94), 76.30 (+/-7.24) and 188.39 (+/-80.73) min respectively. Vitreous levels of the prodrugs were not measurable. CONCLUSIONS: The valine and valine-valine ester prodrugs of ACV penetrated the anterior segment of the eye much better than acyclovir alone, probably via a carrier mediated transport mechanism.     

The evolving therapy of rheumatic diseases,the future is now

There are two main ways in which physicians will be urged to improve the outcome for their patients suffering from rheumatic diseases in the coming era, these are, early diagnosis and timely effective therapy. Current reserch suggests that in rheumatoid arthritis joint damage occurs early, often within the first 2 years and even in the absence of associating severe symptoms, is a call for action for primary care physicians as well as rheumatologists. Similarly in SLE patients, sometimes the treatments are ineffective or too toxic with sepsis or opportunistic infections often limiting their use or resulting in the death of the patient. As primary care physicians are the clinicians most frequently visited by patients with initial symptoms of the disease, they first need to learn when to suspect it as well as its complications, and when to refer the patient appropriately. Rheumatologists need to determine when and how to prescribe the most appropriate treatment, as well as how to incorporate the new drugs which are emerging on the scene. At the same time, earlier initiation of combination therapy with the disease modifying anti-rheumatic therapy holds an area of continued exploration. This new information has modified our approach to patients' management. The age of "wait and see" is over.     

Depersonalization-derealization syndrome induced by reboxetine

A high variety of factors have been implicated in the emergence of depersonalisation and derealisation episodes, including different drugs. A case abruptly induced by two applications of reboxetine, a selective and specific norepinephrine reuptake inhibitor, is reported occurring in a 50-year-old woman treated for a major depressive episode. The episode rapidly remitted after discontinuation of reboxetine. Previous data having indicated a role of the serotonin system in the pathophysiology of the phenomenon, a noradrenaline induced serotonin liberation of Raphe neurons is suggested as possible underlying mechanism.     

The neuronal ceroid lipofuscinoses: mutations in different proteins result in similar disease

The neuronal ceroid-lipofuscinoses (NCL) are the most common group of progressive neurodegenerative diseases in children, with an incidence as high as one in 12,500 live births. The main features of this disease are failure of psychomotor development, impaired vision, seizures, and premature death. Many biochemical and physiological studies have been initiated to determine the cellular defect underlying the disease, although only a few traits have been truly associated with the disorders. One of the paradox's of the NCL-diseases is the characteristic accumulation of autofluorescent hydrophobic material in the lysosomes of neurons and other cell types. However, the accumulation of this lysosomal storage material, which no doubt contributes to the neurologic disease, does not apparently lead to disease outside the CNS, and how these cellular alterations relate to the neurodegeneration in NCLs is unknown. Mutations have been identified in six distinct genes/proteins, namely CLN1, which encodes PPT1, a protein thiolesterase; CLN2, which encodes TPP1, a serine protease; and CLN3, CLN5, CLN6, and CLN8, which encode novel transmembrane proteins. Mutation in any one of these CLN-proteins results in a distinct type of NCL-disease. However, there are many shared similarities in the pathology of these diseases. The most obvious connection between PPT1, TPP1, CLN3, CLN5, CLN6, and CLN8 is their subcellular localization. To date, three of the four proteins whose subcellular localization has been confirmed, namely PPT1, TPP1, and CLN3, reside in the lysosome. We review the function of the CLN-proteins and discuss the possibility that a disruption in a common biological process leads to an NCL-disease.     

Silicone Intubation with Trans-Sac Fixation to Prevent Tube Dislocation

PURPOSE: To report a new technique for silicone tube fixation, after successful intubation for congenital nasolacrimal duct obstruction, to minimize its lateral dislocation. METHODS: Thirty patients (40 eyes) aged 20 months to 5 years (median, 28 months) were treated using the Ritleng bicanalicular lacrimal intubation system. After drawing the silicone stent out of the nose, a piece of 7-O Prolene suture was tied securely around one of its limbs. This limb was then pulled up, pulling the tied end of the Prolene suture to the medial canthal area. The same procedure was repeated with the other limb of the stent, pulling up the other Prolene suture end. This suture end was then un-tied. After adjusting the exposed silicone loop, the free end of the Prolene suture was tied securely to the corresponding part of the silicon stent. The nasally drawn two ends of silicone tube were tied in a single square knot. After 2 to 3 months, stents were removed in the medical office for all the patients. RESULTS: This technique was used successfully for all the patients. Of the 40 tubes in this study, 39 did not displace and one tube was displaced laterally due to loosely tied Prolene suture. On follow-up, the trans-sac suture was well tolerated and no complications were noted. CONCLUSION: The trans-sac fixation suture prevents lateral displacement of square-knotted silicone tube, which still can be removed easily at the physician's office.     

Bacterial cellulose graft versus fat graft in closure of tympanic membrane perforation

Object

To compare between results of bacterial cellulose graft myringoplasty and fat graft myingoplasty in patients had mild or moderate size safe perforation.

The differences in health concerns between mothers and health care professionals in a preventive community set up

To assess the degree to which mothers, nurses and pediatricians share common concerns regarding infants' health and well-being a cross-sectional survey with stratified demographic sampling was conducted. A 12–item questionnaire pertaining to health concerns was administered to 22 mothers of infants between 1 and 18 months of age, treated at six Well Baby community clinics with 36 nurses and 25 pediatricians. Mothers and health care professionals expressed significantly different concerns. Pediatricians and nurses shared a more similar order of concerns. However, they too differed on the degree of concern related to some of the health issues, i.e. nurses perceived the issues related to feeding, behaviour, skin, sleep and daily routines as significantly more important than did pediatricians. Additional efforts should be devoted to improve and clarify communication between mothers and health care professionals.     

NAT2*5/*5 genotype (341T>C) is a potential risk factor for schistosomiasis-associated bladder cancer in Egyptians

Arylamine N-acetyl transferase (NAT2) displays extensive genetic polymorphisms that affect the rates of acetylation of drugs and genotoxic compounds such as amine carcinogens. To investigate whether the slow acetylator genotype is a risk factor for development of bladder cancer following schistosomal infection of the urinary tract, the authors determined the frequencies of 3 common polymorphisms in the NAT2 gene (341T>C, 590G>A, and 282C>T), which are associated with impaired acetylation activity, in control subjects (n=61; mean age 34.3+/-9.2 years) and in schistosomiasis-associated bladder cancer patients (n=55; 52+/-10.9 years) from the Egyptian population. Genotyping was carried out using rapid cycle PCR on the LightCycler, and subjects were assigned to a slow, intermediate, or rapid acetylator phenotype on the basis of the genotypes. The frequencies of the mutant alleles observed in the controls from the present study were similar to those reported previously for both the Egyptian population and other Arab populations. Patients showed a higher prevalence (78.2%) of slow acetylator phenotype than controls (67.2%), but this did not reach statistical significance (P=0.19). However, there were significantly more individuals who were carriers of 2 mutant 341T>C alleles (NAT2*5/*5 genotype) in the patient group compared with controls (odds ratio 2.6, CI 1.02-6.67, P=0.026). The alloenzyme encoded by this allele has been shown to display a large reduction in its catalytic activity. In conclusion, these data suggest that the NAT2*5/*5 genotype is a potential risk factor for development of urinary bladder cancer in patients with prior schistosomiasis infection.     

Sobh Formula: A New Formula for Estimation of Creatinine Clearance in Healthy Subjects and Patients with Chronic Renal disease

Backgrounds: Cockcroft–Gault formula overestimates creatinine clearance (Ccr) in obese or edematous patients. This limitation urged us to develop a new formula that can overcome the limitation of Cockcroft–Gault formula. Methods: We developed a new formula suitable for rapid bedside estimation of creatinine clearance in healthy adults and elderly persons and patients with chronic renal disease considering the surface area as a reliable factor for estimation of creatinine clearance. This cross sectional study included 182 individuals (healthy persons and patients with chronic kidney disease). Ccr was estimated by different methods including 24 hours urine collection, Cockcroft–Gault equation, and our new formula, and ^99mTc-DTPA isotope clearance which was considered as a standard method for comparison between the other methods.Results: Our new formula had a statistically significant higher correlation coefficient with the standard ^99mTc-DTPA isotope clearance for all groups included in this study (r=0.97) than either Cockcroft–Gault formula (r=0.90) or 24 hours urine collection method (r=0.88). Conclusion: Our formula is a step forward for a better bedside assessment of kidney function in both healthy individuals and patients with chronic kidney disease.