How drug life-cycle management patent strategies may impact formulary management.

Drug manufacturers may employ various life-cycle management patent strategies, which may impact managed care decision making regarding formulary planning and management strategies when single-source, branded oral pharmaceutical products move to generic status. Passage of the Hatch-Waxman Act enabled more rapid access to generic medications through the abbreviated new drug application process. Patent expirations of small-molecule medications and approvals of generic versions have led to substantial cost savings for health plans, government programs, insurers, pharmacy benefits managers, and their customers. However, considering that the cost of developing a single medication is estimated at $2.6 billion (2013 dollars), pharmaceutical patent protection enables companies to recoup investments, creating an incentive for innovation. Under current law, patent protection holds for 20 years from time of patent filing, although much of this time is spent in product development and regulatory review, leaving an effective remaining patent life of 7 to 10 years at the time of approval. To extend the product life cycle, drug manufacturers may develop variations of originator products and file for patents on isomers, metabolites, prodrugs, new drug formulations (eg, extended-release versions), and fixed-dose combinations. These additional patents and the complexities surrounding the timing of generic availability create challenges for managed care stakeholders attempting to gauge when generics may enter the market. An understanding of pharmaceutical patents and how intellectual property protection may be extended would benefit managed care stakeholders and help inform decisions regarding benefit management.

Monitoring plasma cardiac troponin I for the detection of myocardial injury after percutaneous transluminal coronary angioplasty.

The objective of this study was to detect myocardial injury defined by an increase of plasma cardiac troponin I (cTnI) following percutaneous transluminal coronary angioplasty (PTCA) and compare plasma cTnI with the risk of cardiac complications at 30 days. Plasma cTnI, creatine kinase (CK) MB, and total CK were determined in 83 patients before (baseline) and 6, 12 and 24 h after PTCA. Thirty-eight patients underwent conventional PTCA, 39 PTCA-stent and six rotational atherectomy. Patients with acute myocardial infarction (AMI) and increased pre-procedural cTnI >0.8 microg/l were categorized into group 1 (n=23). The remaining 60 patients (pre-procedural cTnI=0.8 microg/l) were categorized as follows: group 2 (n=15) AMI; group 3 (n=20) unstable angina (UA); group 4 (n=25) coronary artery disease (CAD). Twelve hours post-procedure, all three cardiac markers were more frequently increased over baseline in group 2 patients (40-60%) compared to patients in group 3 (5-29%, P<0.03) or group 4 (0.5-5%, P<0.01). This was also true for patients undergoing PTCA-stent compared to conventional PTCA or rotational atherectomy (27-40 vs. 4-14%, P<0.02). cTnI was more sensitive (60%) to detect release of myocardial protein after PTCA compared to total CK (47%) or CKMB (43%). A moderate increase of cTnI (0.8-1.5 microg/l) in groups 2, 3 and 4 was associated with higher risk of complications 30 days post-procedure.

Higher prevalence of GPIIIa PlA2 polymorphism in siblings of patients with premature coronary heart disease.

BACKGROUND: The Pl(A2) polymorphism of GPIIIa has been associated with unstable coronary syndromes in some studies, but the association has remained debated. None of the previous studies have focused on families at high risk. Risk factors tend to cluster within kindreds with high prevalence of premature coronary heart disease (CHD). Therefore, a heightened prevalence of the Pl(A2) polymorphism among siblings of patients with CHD would support the hypothesis that Pl(A2) is linked, directly or indirectly, to CHD. OBJECTIVES: To measure the prevalence of the Pl(A2) polymorphism among siblings of patients with CHD before the age of 60 years and to seek an association between the Pl(A2) polymorphism and established atherosclerotic and thrombogenic risk factors. METHODS: From January 1994 to April 1996, we genotyped 116 asymptomatic siblings (60 Caucasians, 56 Afro-Caribbeans) of patients with CHD manifestations before the age of 60 years for the Pl(A) polymorphism (also called HPA-1). A control cohort was used for comparison, consisting of individuals that were matched for race and geographic area but were free of CHD (n = 268, 168 Caucasians and 100 Afro-Caribbeans). In addition, we have characterized the sibling cohort for other atherogenic and thrombogenic risk factors. RESULTS: The prevalence of Pl(A2)-positive individuals (Pl(A2)[+], Pl(A1/A2) heterozygotes plus Pl(A2/A2) homozygotes) in the sibling cohort was high: 41.4%. When analyzed separately, the prevalence of Pl(A2)(+) siblings was 53.3% among Caucasians and 28.6% among Afro-Caribbeans. There was no association between Pl(A2) and other established atherogenic or thrombogenic risk factors. Interestingly, the clustering of other risk factors was lesser among Pl(A2)(+) siblings than their Pl(A1) counterparts. CONCLUSIONS: This study supports the hypothesis that the prevalence of Pl(A2)(+) individuals is high in kindreds with premature CHD. Hence, like the established risk factors that tend to cluster in families with premature CHD and contribute strongly to the accelerated atherosclerotic process affecting these individuals, the Pl(A2) polymorphism of GPIIIa may represent an inherited risk that promotes the thromboembolic complications of CHD. That these asymptomatic Pl(A2)(+) siblings had overall less established risk factors than their Pl(A1) counterparts might represent an explanation for why they remained asymptomatic despite their Pl(A2) positivity.

Reversible myocardial contraction abnormalities in patients with an acute noncardiac illness.

STUDY OBJECTIVES: Reversible myocardial contraction abnormalities are usually observed in patients with acute ischemic syndromes caused by coronary artery disease. In this study, we report the occurrence of reversible anterior-apical contraction abnormalities in patients with an acute noncardiac illness. SETTING: This was a retrospective study of 22 patients with the following characteristics: (1) hospitalization for an acute noncardiac illness; (2) appearance of deep T-wave inversion in the precordial leads of the ECG; and (3) presence of an anterior wall motion abnormality on an echocardiogram. Standard clinical information was collected together with results of serial ECGs, echocardiograms, and coronary angiograms. RESULTS: The primary diagnoses for the 22 acutely ill patients included CNS injury (n=6); sepsis (n=3); acute pulmonary disease (n=3); drug overdose or metabolic abnormality (n=7); and post noncardiac surgery (n=3). An initial echocardiogram revealed an anterior apical wall motion abnormality. At follow-up, all patients had progressive improvement in anterior wall motion with return of normal wall motion in 16 patients (73%). All patients evolved deep T-wave inversion (average, 7.8 mm) and QT interval lengthening in the precordial leads. Coronary angiography revealed a significant stenosis in the likely culprit artery (left anterior descending) in only one patient. CONCLUSION: A reversible cardiac contraction abnormality of the anterior wall and apex of the left ventricle can complicate the clinical course of critically ill patients in the absence of significant coronary artery disease. This phenomenon is associated with striking T-wave inversion and QT interval lengthening. Mechanisms other than myocardial ischemia may lead to the occurrence of reversible regional myocardial contraction abnormalities.

Molecular evidence for the gnathobasic derivation of arthropod mandibles and for the appendicular origin of the labrum and other structures.

Mandibles are feeding appendages functioning as "jaws" in the arthropod groups in which they occur. Which part of this appendage is involved in food manipulation (limb tip versus limb base), has been used to suggest phylogenetic relationships among some of the major taxa of arthropods (myriapods, crustaceans, and insects). As a way to independently verify the conclusions drawn from previous morphological analyses, we have studied the expression pattern of the gene Distal-less (Dll), which specifies the distal part of appendages. Our results show, in contrast to the traditional view, that both insect and crustacean adult mandibles are gnathobasic, handling food with the basal portion of the appendage. Furthermore, as is evident by the reduction in the number of Dll-expressing cells in the later developmental stages, adult diplopod jaws are also gnathobasic. Thus, jaws of all mandibulates (myriapods, crustaceans, and insects) seem to have a similar gnathobasic structure. We have also found that Dll is expressed in the labra of all arthropod taxa examined, suggesting that this structure is of appendicular derivation. Additionally, the spinnerets and book lungs of spiders, long considered on other grounds to be modified appendages, express Dll, confirming this interpretation. This study shows that, in addition to their use in phylogenetic and population genetic studies, molecular markers can be very useful for inferring the origins of a particular morphological feature.

Painless ischemia provoked by mental stress in the coronary care unit.

A 30-year-old man suffered a cardiac arrest after setting fire to his home. Continuous ST segment electrocardiographic monitoring in the Coronary Care Unit detected painless ST segment depression during an interview with a police officer. At angiography, the patient proved to have severe three-vessel coronary artery disease. This case demonstrates the clinical value of continuous ST segment monitoring in the ICU. In addition, the case illustrates that mental stress is a potential trigger for acute myocardial ischemia in the ICU.

Risk management alert: a summary of perinatal cases.

Connecticut Medical Insurance Company (CMIC) cases related to obstetrical care and the newborn represent the single most costly exposure to the Company. CMIC undertook the review of its perinatal cases, open and closed, to identify common elements that increased the liability exposure of individual physicians as well as the overall exposure to the Company.

A devonian spinneret: early evidence of spiders and silk use.

A nearly complete spider spinneret was found in Middle Devonian rocks (about 385 to 380 million years old) near Gilboa, New York. This is the earliest evidence yet discovered for silk production from opisthosomal spigots, and therefore for spiders. Two previously known Devonian fossils described as spiders lack any apomorphies of the order Araneae and are probably not spiders. The spigots of the Devonian spinneret resemble those of members of the living suborder Mesothelae, but the number of spigots and their distribution are like those of members of the suborder Opisthothelae, infraorder Mygalomorphae. The Devonian spider belonged to a clade that may be the sister group of all other spiders, of Mesothelae, or of Opisthothelae.

Non-vagal reflex effects on medullary inspiratory neurons during inspiratory loading.

Studies were conducted to compare the first-breath responses of medullary Dorsal and Ventral Respiratory Group inspiratory (I) neurons to the mechanical loading (tracheal occlusion, TO) of inspiration in unanesthetized (decerebrate) and anesthetized (Dial) vagotomized cats, and to determine the sources of the sensory activity causing the changes in I-neuron activity. In decerebrate cats, TO resulted in a prolongation of the firing duration in 49% of the I-neurons. There was a delayed onset of firing in 7% of the I-neurons. The responses of I-neurons to TO in anesthetized cats were similar to the responses in decerebrate cats. Changes in I-neuron activity with TO were still present in cats with their cervical (C3-7) or thoracic (T1-9) dorsal roots cut, and absent when both cervical and thoracic dorsal roots were cut. The most probable sources of the cervical and thoracic afferent information altering medullary I-neuron activity during loading are the diaphragm and inspiratory intercostal muscles.

Early land animals in north america: evidence from devonian age arthropods from gilboa, new york.

A new fossil site near Gilboa, New York, is one of only three where fossils of terrestrial arthropods of Devonian age have been found. The new Gilboan fauna is younger than the other two but richer in taxa. Fragmentary remains and nearly whole specimens assigned to Eurypterida, Arachnida (Trigonotarbida, Araneae, Amblypygi, and Acari), Chilopoda [Craterostigmatomorpha(?) and Scuterigeromorpha(?)], and tentatively to Insecta (Archaeognatha) have been found. The centipedes and possible insects may represent the earliest records known for these groups.

Alkylphenols in the defensive secretion of the nearctic opilionid,Stygnomma spinifera (Arachnida: Opiliones).

The opilionid,Stygnomma spinifera, secretes from a pair of exocrine glands on the cephalothorax between the first and second pair of legs a major volatile component, 2-methyl-5-ethylphenol, and two minor components, 2,3-dimethylphenol and 2,3-dimethyl-5-ethylphenol. These alkylphenols are constituents of a defensive secretion and repel ants, a natural predator of opilionids. The probable significance of this secretion in the biology ofS. spinifera and in the defensive strategies of opilionids in general is discussed.