Cyclodextrin formulation of dorzolamide and its distribution in the eye after topical administration.

Due to limited aqueous solubility of dorzolamide at physiologic pH, the pH of Trusopt eye drops (cont. 2% dorzolamide) has to be kept at about 5.65, and to increase the topical bioavailability of the drug from Trusopt the contact time of the drug with the eye surface is increased by increasing the viscosity of the eye drops to 100 cps. This low pH and high viscosity can lead to local irritation. In this study, dorzolamide hydrochloride was formulated as 2% and 4% low viscosity solutions (viscosity 3 to 5 cps) containing randomly methylated beta-cyclodextrin at pH 7.45. These formulations were evaluated in rabbits. The animals were sacrificed at various time points after topical administration of the drug and the dorzolamide concentration determined in the different parts of the eye. Trusopt was used as a reference standard. The topical availability of dorzolamide from the cyclodextrin-containing eye drops appeared to be comparable to that from Trusopt and the drug reached retina and optic nerve to give measurable concentrations for at least 8 h after administration of the eye drops.     

Diacyl glyceryl ester prodrugs for slow release in the skin: synthesis and in vitro degradation and absorption studies for naproxen derivatives

Diacyl glyceryl ester derivatives of naproxen were synthesized and tested for transdermal and dermal administration. Diacyl derivatives of aliphatic acids of various chain length were compared. The pharmaceutical properties of these compounds, such as lipophilicity, hydrolysis in a buffer solution at various pH values and degradation in human serum and hairless mouse skin homogenate, were investigated. All the diacyl derivatives were relatively stable in a neutral buffer solution, but were rapidly degraded to release naproxen in human serum and hairless mouse skin homogenate. The diacyl compounds could not penetrate hairless mouse skin in vitro. However, significant absorption into the skin could be measured, and this increased with increasing lipophilicity. A more than 100-fold difference in absorption was observed. The prodrugs were slowly hydrolyzed to naproxen inside the skin. The release of naproxen to the receptor compartment of diffusion cells showed that this type of prodrug could be used for controlled drug delivery.     

Solubilization and Stabilization of a Benzylpenicillin Chemical Delivery System by 2-Hydroxypropyl-β-cyclodextrin

A dihydropyridine pyridinium salt redox carrier-based chemical delivery system for benzylpenicillin (1) was complexed with 2-hydroxypropyl--cyclodextrin (HPCD). The solubility of the lipophilic 1, which is incompatible with aqueous formulations, was dramatically increased and showed a linear dependency on the HPCD concentration. The degree of incorporation was 20 mg of 1 per g of complex. The stability study of 1 in various pH buffers indicated the base-catalyzed hydrolysis of the acyloxyalkyl linkage and the hydration of the 5,6 double bond of the dihydropyridine as the main degradation processes. The overall loss of 1, which follows first-order kinetics, was not influenced by changes in ionic strength and elimination of oxygen from the reaction medium. The HPCD complex of 1, which has a stability constant of 720–940 M ^–1, stabilized the chemical delivery system. The influence of the temperature on the stability of 1 is also discussed.     

Aqueous hydrocortisone mouthwash solution: clinical evaluation

Patients often experience difficulties in applying topical steroids in orabase to the oral mucosa, particularly when large areas need to be covered. An aqueous hydrocortisone mouthwash solution has been developed, one that was anticipated to be more acceptable to patients. The solution contains hydrocortisone (0.3% w/v) in a 4.5% (w/v) 2-hydroxypropyl-β-cyclodextrin solution. Hydroxypropylmethylcellulose (0.5% w/v) was used to increase the viscosity of the solution and to promote the hydrocortisone±cyclodextrin complex. One hundred and two patients with aphthous ulceration, lichen planus, and other mucosal conditions used the mouthwash in an open clinical efficacy study. Most patients reported some or considerable improvement following a 2-week course of treatment with the mouthwash: 26 of 33 (78.8%) patients with aphthous ulceration were `much better', as were 26 of 54 (48.1%) patients with lichen planus and 5 of 16 (31.3%) patients with other mucosal lesions. No serious side effects were reported. Aqueous mouthwash solutions offer a potential vehicle for topical steroid therapy of oral mucosal lesions.     

Cyclodextrins: structure,physicochemical properties and pharmaceutical applications

Since their discovery over 100 years ago cyclodextrins (CDs) have been the subject of numerous scientific publications. In 2016 alone CDs were the subject of over 2200 research articles published in peer-reviewed journals and mentioned in over 2300 patents and patent applications, many of which were on pharmaceutical applications. Natural CDs and their derivatives are used as enabling pharmaceutical excipients that enhance aqueous solubility of poorly soluble drugs, increase drug permeability through biological membranes and improve drug bioavailability. Unlike conventional penetration enhancers, their hydrophilic structure and high molecular weight prevents them from penetrate into lipophilic membranes leaving biological membranes intact. The natural CDs and some of their derivatives have monographs in pharmacopeias and are also commonly used as food additives and in toiletry products. CDs form inclusion complexes with lipophilic moieties of hydrophobic drugs. Furthermore, CDs are able to form non-inclusion complexes and self-assembled aggregates; small and large complex aggregates with micellar-like structures that can enhance drug solubility. Excipients commonly used in pharmaceutical formulations may have additive or inhibiting effect on the CD solubilization. Here various methods used to investigate CD aggregate formation are reviewed as well as techniques that are used to increase the solubilizing effects of CDs; methods that enhance the apparent intrinsic solubility of drugs and/or the complexation efficacy and decrease the amount of CD needed to develop CD-containing pharmaceutical formulations. It will be explained how too much or too little CD can hamper drug bioavailability, and the role of CDs in solid dosage forms and parenteral formulations, and examples given on how CDs can enhance drug delivery after ocular, nasal and pulmonary administration.     

Trifluorothymidine: potential non-invasive diagnosis of herpes simplex infection using 19F nuclear magnetic resonance in a murine hepatitis model

Trifluorothymidine (TFT) is known to be concentrated in herpes simplex virus (HSV) infected cells in vitro in the form of phosphorylated derivatives. We studied a murine hepatitis model of HSV infection to determine whether this in vitro observation would also be demonstrable in vivo. Following i.v. injection of 100 or 160 mg/kg TFT, TFT was found in significantly higher concentrations in the livers of HSV-2 infected mice than in the livers of uninfected mice, mice infected with murine hepatitis virus (MHV-A59) or mice with hepatitis from carbon tetrachloride treatment. Neither altered renal function, nor altered pharmacokinetics could account for this difference. 19F Nuclear Magnetic Resonance spectroscopy readily detected the 19F from TFT in both liver extracts and whole livers, particularly at higher tissue levels, i.e. greater than 50 micrograms/g tissue. If further studies with living animals support these preliminary observations, clinical application could be pursued.     

Acute neurosurgical management of traumatic brain injury and spinal cord injury

PURPOSE OF REVIEW: This review discusses some of the recent advances and current controversies in the acute clinical management of traumatic brain injury (TBI) and spinal cord injury (SCI). RECENT FINDINGS: Several key risk factors for adverse prognosis in TBI have been identified, including female sex. In the management of intracranial hypertension antibiotic impregnated intraventricular catheters have been found to reduce the risk for infection, and new studies have examined the roles of mannitol, hyperventilation, and hypothermia. Moderate hypothermia has also been found to improve outcome. Hyperoxia is now being explored as a treatment option for improving brain metabolism in TBI. That acute SCI continues to be a challenging diagnosis is supported by a recent study that showed that 9.1% of SCIs are missed initially. The diagnosis and management of spinal instability has been studied in different patient groups. In SCI without radiographic abnormality, the presence of normal magnetic resonance imaging findings was associated with a good prognosis. New studies in the field of early decompression and the prevention of thromboembolism in SCI have also been published. Guidelines for the management of acute SCI recommend methylprednisolone and GM-1 ganglioside only as options. SUMMARY: In neurotrauma some established treatments have been re-examined and their efficacy proven, whereas others that were once considered the standard of care in SCI, such as methylprednisolone, have been questioned. Large multicenter trials are needed to assess treatments such as early decompression in SCI and decompressive craniectomy in TBI. A truly effective neuroprotective therapy in neurotrauma remains elusive.     

Patients,diagnoses and processes in general practice in the Nordic countries. An attempt to make data from computerised medical records available for comparable statistics

Objective - To try out a collection of a standard set of data from computerised medical records. Design - Retrospective extraction of ordinary patient record information put into the computer by general practitioners. Setting - Encounters in office hours in strategically selected practices or health centres in Denmark, Finland, Iceland, Norway and Sweden. Subjects - 59 general practitioners and a total study population of 97475 persons. Main outcome measures - Proportions, crude and specific rates of encounters, diagnoses and processes. Results - In a 4-week period there was a threefold difference in the office encounter rates between the participating sites in the Nordic countries. Gender and age patterns were similar despite these differ ences. An access to several different denominators revealed diverse patterns of referring to the specialist, prescribing, ordering blood tests, X-rays and physiotherapy. Data from computerised medical records agree well with earlier studies in the Nordic countries using other methods. Conclusions - This survey demonstrates that valid and reliable data for routine statistics are available from computerised medical records in general practice. The major obstacle extracting more epidemiological data from computerised medical records is caused by information in the databases not being uniquely linked to episodes of care.     

Encapsulation of Drug Molecules into Calix[n]arene Nanobaskets. Role of Aminocalix[n]arenes in Biopharmaceutical Field

Calix[n]arenes (CAs) are supramolecular compounds able to form guest-host inclusion complexes with metal ions, small organic molecules, and small moieties of larger molecules. Although the CA literature is extensive, relatively few publications deal with water-soluble CAs, especially those containing nitrogen-based functionality. These CAs possess antibacterial and antifungal activity. Because of their molecular structure, they are surface active and also able to form water-soluble drug complexes, giving additional potential as enabling pharmaceutical excipients. This article provides an overview of the published data regarding synthesis, physicochemical properties, and pharmaceutical application of water-soluble CAs with emphasis on those that contain nitrogen-based substituents in their structure, particularly aminoCAs. In particular, it describes state-of-the-art in complexation of water-soluble CAs with pharmaceutically relevant ions and organic molecules up to amino acids, DNA, and proteins.     

Methazolamide 1% in cyclodextrin solution lowers IOP in human ocular hypertension

PURPOSE: To formulate aqueous eye drops containing methazolamide 1% in cyclodextrin solution and to evaluate their effect on intraocular pressure (IOP) in a double-blind randomized trial in humans. Methazolamide, a carbonic anhydrase inhibitor (CAI), has been used in oral doses in the treatment of glaucoma but hitherto has not been successfully formulated in eye drops. In this study the effects of methazolamide are compared with those of dorzolamide (Trusopt). METHODS: Methazolamide 1% was formulated in a 2-hydroxypropyl-beta-cyclodextrin with hydroxypropyl methylcellulose in aqueous solution. Eight persons with ocular hypertension were treated with the methazolamide-cyclodextrin eye drops and eight persons with dorzolamide (Trusopt), both groups at dosages of three times a day for 1 week. IOP was measured before treatment was begun and on days 1, 3, and 8 at 9 AM (peak) and 3 PM (trough). RESULTS: After 1 week of treatment, the peak IOP in the methazolamide group had decreased from 24.4 +/- 2.1 mm Hg (mean +/- SD) to 21.0 +/- 2.0 mm Hg, which is a 14% pressure decrease (P: = 0.006). In the dorzolamide group, the peak IOP decreased from 23.3 +/- 2.1 mm Hg to 17.2 +/- 3.1 mm Hg, which is a 26% pressure decrease (P: < 0.001). On average, the IOP declined 3.4 +/- 1.8 mm Hg after methazolamide administration and 6.1 +/- 3.6 mm Hg after dorzolamide. CONCLUSIONS: Through cyclodextrin complexation, it is possible to produce topically active methazolamide eye drops that lower IOP. This is the first double-blind clinical trial that demonstrates the efficacy of the classic CAIs in eye drop formulation.