A Dose-Finding Study to Guide Use of Verapamil as an Adjunctive Therapy in Tuberculosis.

Induction of mycobacterial efflux pumps is a cause of Mycobacterium tuberculosis (Mtb) drug tolerance, a barrier to shortening antitubercular treatment. Verapamil inhibits Mtb efflux pumps that mediate tolerance to rifampin, a cornerstone of tuberculosis (TB) treatment. Verapamil's mycobacterial efflux pump inhibition also limits Mtb growth in macrophages in the absence of antibiotic treatment. These findings suggest that verapamil could be used as an adjunctive therapy for TB treatment shortening. However, verapamil is rapidly and substantially metabolized when co-administered with rifampin. We determined in a dose-escalation clinical trial of persons with pulmonary TB that rifampin-induced clearance of verapamil can be countered without toxicity by the administration of larger than usual doses of verapamil. An oral dosage of 360 mg sustained-release (SR) verapamil given every 12 hours concomitantly with rifampin achieved median verapamil exposures of 903.1 ng.h/mL (area under the curve (AUC)0-12 h ) in the 18 participants receiving this highest studied verapamil dose; these AUC findings are similar to those in persons receiving daily doses of 240 mg verapamil SR but not rifampin. Moreover, norverapamil:verapamil, R:S verapamil, and R:S norverapamil AUC ratios were all significantly greater than those of historical controls receiving SR verapamil in the absence of rifampin. Thus, rifampin administration favors the less-cardioactive verapamil metabolites and enantiomers that retain similar Mtb efflux inhibitory activity to verapamil, increasing overall benefit. Finally, rifampin exposures were 50% greater after verapamil administration, which may also be advantageous. Our findings suggest that a higher dosage of verapamil can be safely used as adjunctive treatment in rifampin-containing treatment regimens.

A dose-finding study to guide use of verapamil as an adjunctive therapy in tuberculosis.

Induction of mycobacterial efflux pumps is a cause of Mycobacterium tuberculosis (Mtb) drug tolerance, a barrier to shortening antitubercular treatment. Verapamil inhibits Mtb efflux pumps that mediate tolerance to rifampin, a cornerstone of tuberculosis treatment. Verapamil's mycobacterial efflux pump inhibition also limits Mtb growth in macrophages in the absence of antibiotic treatment. These findings suggest that verapamil could be used as an adjunctive therapy for TB treatment shortening. However, verapamil is rapidly and substantially metabolized when co-administered with rifampin. We determined in a dose-escalation clinical trial that rifampin-induced clearance of verapamil can be countered without toxicity by the administration of larger than usual doses of verapamil. An oral dosage of 360 mg sustained-release (SR) verapamil given every 12 hours concomitantly with rifampin achieved median verapamil exposures of 903.1 ng.h/ml (AUC 0-12h), similar to those in persons receiving daily doses of 240 mg verapamil SR but not rifampin. Norverapamil:verapamil, R:S verapamil and R:S norverapamil AUC ratios were all significantly greater than those of historical controls receiving SR verapamil in the absence of rifampin, suggesting that rifampin administration favors the less-cardioactive verapamil metabolites and enantiomers. Finally, rifampin exposures were significantly greater after verapamil administration. Our findings suggest that a higher dosage of verapamil can be safely used as adjunctive treatment in rifampin-containing treatment regimens.

Posttraumatic progressive cubitus varus deformity managed by lateral column shortening: A novel surgical technique.

The outward angulation of elbow with supinated forearm is cubitus varus deformity. This deformity is often seen as sequelae of malunited supracondylar fracture of humerus in paediatric age group of 5e8 years. The deformity is usually non-progressive, but in cases of physeal injury or congenital bony bar formation in the medial condyle of humerus, the deformity is progressive and can be grotesque in appearance. Various types of osteotomies are defined for standard non-progressive cubitus varus deformity, while multiple surgeries are required for progressive deformity until skeletal maturity. In this study we described a novel surgical approach and osteotomy of distal humerus in a 5 years old boy having grotesque progressive cubitus varus deformity, achieving good surgical outcome.

Monteggia fracture dislocation equivalents--analysis of eighteen cases treated by open reduction and internal fixation.

OBJECTIVE: Monteggia fracture dislocation equivalent, though already described by Bado, is still an unclassified entity. We aimed to retrospectively analyze 18 cases of Monteggia variants and discuss the injury mechanisms, management, and outcome along with a review of the literature. METHODS: A retrospective record of Monteggia fracture dislocation (2003-2008) was reviewed from medical record department of our institute. Classic Monteggia fracture dislocation, children below 12 years or adults over 50 years, as well as open grade II and III cases were excluded from this study. Monteggia variant inclusion criteria included fracture of the proximal ulna together with a fracture of the radial head or neck and skeletal maturity. Totally 26 patients were identified with Monteggia variants and 18 were available for follow-up, including 11 males and 7 females with the mean age of 35 years. The ulna fracture was treated by compression plating along with tension band wiring. Radial head/neck was reconstructed in 12 patients while excised in 6 patients. RESULTS: Follow-up ranged from 1-4 years, mean 2.6 years. Patients were assessed clinicoradiologically. Mayo Elbow Performance Score was employed to assess the outcomes. At final follow-up, the results were excellent in 10 patients, good in 4, fair in 2 and poor in 2. Mean range of motion of the elbow was 20 degree 116 degree, 50 degree and 55 degree for extension, flexion, pronation and supination, respectively. Two patients had complications in the form of heterotopic ossification and stiffness of the elbow. One nonunion ulna, primarily treated by tension band wiring, was managed by refixation with locking reconstruction plate and bone grafting. Bone grafting was only required in this patient for nonunion. Another patient had implants removed on his request. The results in our series closely correlated with extent of intraarticular damage, coronoid fracture and comminuted fractures. CONCLUSIONS: Monteggia fracture dislocation equivalents are rare injuries and pre-surgery recognition by radiographs and 3-D CT helps make optimal plan. The poor results usually relate to intraarticular damage, coronoid fractures and comminution of the ulna and radial head fractures.

Nonunion of coronal shear fracture of femoral condyle.

Isolated coronal fractures of femoral condyle are rare in adults and nonunion of Hoffa fracture is reported only a few times in the literature. We analyzed six cases of nonunion of Hoffa fractures over a period of three years. Three patients were treated conservatively and three patients had fixation failures. Delay of presentation was 2 months to one year. Treatment protocol consisted of open reduction, excision of pseudoarthrosis, bone grafting and internal fixation along with knee arthrolysis. Union was achieved in all patients at mean 16 weeks. The treatment of nonunion of Hoffa fractures requires careful preoperative planning and meticulous surgical technique. The literature regarding the controversies in fracture management and surgical technique are reviewed.

Neglected reverse Essex-Lopresti injury with ulnar nerve compression.

A 45 year old woman was diagnosed as having anteromedial radial head dislocation and distal radius fracture five months after her injury on right forearm. The radial head dislocation led to ulnar nerve compression. She had severe restriction of her elbow movements. She was treated with arthrolysis, decompression of the ulnar nerve and radial head resection. The reverse Essex Lopresti injury and radial head dislocation compressing the ulnar nerve has not been reported in English language literature to the best of our knowledge. A mechanism is proposed for the injury. In acute presentations, restoration of both the radioulnar joints should be done and neglected nature of such injury leads to suboptimal outcomes.

Neglected isolated fracture of the trochlea humeri.

A 15 years old girl was found to have isolated trochlea fracture 10 weeks after an injury caused by a fall on her left elbow. Movement of the elbow was severely restricted. Radiographs showed a half moon-shaped and anterosuperiorly displaced osteochondral fragment. Medial approach capsulotomy of the elbow and excision of the intraarticular adhesions were done to expose the isolated trochlea fracture. Headless screws were used for fixation, combined with bone grafting. The follow-up showed union and excellent functional recovery of the elbow. Isolated trochlea fracture in adults is rare and usually associated with capitellar fractures and/or elbow dislocations. A neglected trochlea fracture is rarely reported in the English language literature to the best of our knowledge. Recognition of isolated trochlea fracture is vital to apprehend the pathomechanics of the injury and to devise a suitable treatment approach.